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Nguyen TK, Pham DV, Park PH. Leptin impairs the therapeutic efficacy of adipose-derived mesenchymal stem cells by inducing apoptosis through NLRP3 inflammasomes activation. Biochem Pharmacol 2025; 236:116868. [PMID: 40081766 DOI: 10.1016/j.bcp.2025.116868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 02/11/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025]
Abstract
Mesenchymal stem cells (MSC) have been widely applied for regenerative medicine and the treatment of immune-disorders due to their multilineage differentiation and potent immunomodulatory properties. The therapeutic application of MSC post transplantation are influenced by various endogenous modulators. Leptin, a hormone primarily derived from adipose tissue, exerts a variety of physiological functions, in addition to the metabolic effects. In this study, we examined the effects of leptin on the viability of adipose-derived mesenchymal stem cells (ADSC) and its underlying molecular mechanisms with a particular focus on NLRP3 inflammasomes, which serve as signaling platform of the innate immune system. Leptin significantly decreased the viability of ADSC and induced apoptosis. Mechanistically, NLRP3 inflammasomes signaling critically contributes to leptin-induced apoptosis of ADSC by upregulating p53 and Puma. In addition, NLRP3 inflammasomes activation by leptin is mediated via ER stress induction and ROS accumulation. Finally, suppression of ADSC therapeutic efficacy by leptin and the critical role of NLRP3 inflammasomes in this phenomenon were confirmed in DSS-induced colitis model. Pre-conditioning with leptin before transplantation impaired the therapeutic efficacy and immunomodulatory function of ADSC, which were restored by treatment with a pharmacological inhibitor of NLRP3 inflammasomes. Taken together, the results suggest that leptin induces apoptotic cell death in ADSC and impairs the therapeutic effectiveness of ADSC by activating NLRP3 inflammasomes.
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Affiliation(s)
- Thi-Kem Nguyen
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Duc-Vinh Pham
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea; Department of Pharmacology, Hanoi University of Pharmacy, Hanoi, Vietnam
| | - Pil-Hoon Park
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea; Research Institute of Cell Culture, Yeungnam University, South Korea.
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Sabeti Akbar-Abad M, Majidpour M, Keykha F, Maleki M, Piroozan Y, Saravani R, Zandhaghighi M, Shahriari H, Sargazi S. Preliminary insight into the potential role of Leptin Receptor Polymorphisms in Type 2 Diabetes Risk: case-control study and bioinformatics analysis. J Diabetes Metab Disord 2025; 24:113. [PMID: 40331155 PMCID: PMC12049348 DOI: 10.1007/s40200-025-01617-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Accepted: 04/06/2025] [Indexed: 05/08/2025]
Abstract
Background Type 2 diabetes mellitus (T2DM) develops primarily from obesity as leptin (LEP) functions as an essential adipokine that controls metabolic regulation, energy balance activities, and glucose maintenance. The T2DM and obesity susceptibility traits are believed to be affected by genetic variations in the leptin receptor gene (LEPR), disrupting LEP signaling mechanisms. This case-control study investigates the association of these variants with T2DM risk in a Southeastern Iranian population. Methods A case-control study was conducted involving 450 T2DM patients and 450 matched healthy controls from Zahedan. Genomic DNA for this study was isolated from peripheral blood samples, and genotyping for the specified LEPR rs1137100, rs1137101, and rs1805094 polymorphisms was conducted using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Computational analysis created a gene-gene interaction network, highlighting LEPR as a central hub gene and detailing its interactions with related genes. Results Genetic models, such as codominant heterozygous (p-value = 0.009), dominant (p-value = 0.006), recessive (p-value = 0.008), and allelic (p-value = 0.011), all showed that the rs1137100 (A/G) polymorphism lowered the risk of T2DM. Several genetic models linked polymorphisms at the rs1137101 (G/A) and rs1805094 (G/C) loci to a higher risk of T2DM: The genetic models that were looked at were polymorphism rs1137101 (G/A) in codominant Homozygous (p-value = 0.031) and recessive (p-value = 0.028), as well as polymorphism rs1805094 (G/C) in codominant heterozygous (p-value = 0.009), dominant (p-value = 0.001), excess (p-value = 0.008), and allelic (p-value = 0.001). The research demonstrated a profound linkage disequilibrium (LD) among studied variants, especially in the LEPR haplotypes and across various blocks, with differing levels of association strength. The gene-gene interaction network for the LEPR gene highlights its strong associations with several key regulatory genes: LEP, PTPN11, STAT3, POMC, JAK2, IL6, and SOCS3. Conclusion We found a significant correlation between LEPR gene polymorphisms and the risk of T2DM, highlighting the prominent role of genetic factors in developing such a metabolic disorder. By elucidating the association between LEPR variations and susceptibility to T2DM, our findings enhance the understanding of molecular mechanisms involved in endocrine dysregulation and highlight the importance of including genetic profiling in clinical practice.
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Affiliation(s)
- Mahboobeh Sabeti Akbar-Abad
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mahdi Majidpour
- Clinical Immunology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Fatemeh Keykha
- Department of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran
| | - Mohsen Maleki
- Department of Nutrition, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Yegane Piroozan
- Clinical Immunology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Ramin Saravani
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mehdi Zandhaghighi
- Department of Medical Microbiology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
- Infectious Diseases and Tropical Medicine Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hossein Shahriari
- Clinical Immunology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Saman Sargazi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
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Yang Z, Kirschke CP, Huang L. Lack of maternal exposure to somatostatin leads to diet-induced insulin and leptin resistance in mouse male offspring. J Mol Endocrinol 2025; 74:e240102. [PMID: 40066865 PMCID: PMC11964479 DOI: 10.1530/jme-24-0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 02/28/2025] [Accepted: 03/11/2025] [Indexed: 03/14/2025]
Abstract
Somatostatin (Sst) is an inhibitory regulator of many hormones. The prenatal environment impacts an offspring's risk to type 2 diabetes in adulthood. However, the effect of maternal Sst deficiency on glucose and insulin metabolism in offspring and metabolic disease risk in their adult life has been poorly understood. The study was to investigate the impact of a lack of maternal Sst exposure in mouse male and female offspring on diet-induced changes in glucose metabolism and adiposity. Sst knockout offspring, SstKO born to the Sst-heterozygous dams or SstKO-MSD born to the Sst-homozygous dams were fed either a regular diet (CD) or a high-fat diet (HFD) at 3-week-old for 15 weeks. Body weight and blood glucose levels were monitored. Glucose and insulin tolerance tests were performed. Plasma hormone levels and gene expression in the hypothalamus were investigated. The results demonstrated that only male SstKO-MSD offspring developed obesity accompanied by severe insulin and leptin resistance after HFD challenge. Insulin secretion was reduced in both basal and oral glucose-challenged conditions in the CD-fed male SstKO-MSD mice. A reduced ratio of islet area to pancreas area was noted in SstKO-MSD mice in both sexes. Plasma levels of glucagon, Glp1 and Pyy were elevated in both male and female SstKO and SstKO-MSD mice. mRNA expression of leptin receptor, FoxO1, Npy and Agrp was downregulated in male SstKO-MSD mice. These results demonstrate that a lack of fetal somatostatin exposure impairs the islet development in offspring and increases risk of obesity, insulin resistance and leptin resistance later in life.
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Affiliation(s)
- Zhongyue Yang
- Department of Nutrition, University of California at Davis, Davis, California, USA
| | | | - Liping Huang
- Department of Nutrition, University of California at Davis, Davis, California, USA
- USDA/ARS/Western Human Nutrition Research Center, Davis, California, USA
- Integrative Genetics and Genomics, University of California at Davis, Davis, California, USA
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Chen HH, Highland HM, Frankel EG, Scartozzi AC, Zhang X, Roshani R, Sharma P, Kar A, Buchanan VL, Polikowsky HG, Petty LE, Seo J, Anwar MY, Kim D, Graff M, Young KL, Zhu W, Karastergiou K, Shaw DM, Justice AE, Fernández-Rhodes L, Krishnan M, Gutierrez A, McCormick PJ, Aguilar-Salinas CA, Tusié-Luna MT, Muñoz-Hernandez LL, Herrera-Hernandez M, Lee M, Gamazon ER, Cox NJ, Pajukanta P, Fried SK, Gordon-Larsen P, Shah RV, Fisher-Hoch SP, McCormick JB, North KE, Below JE. Multiomics reveal key inflammatory drivers of severe obesity: IL4R, LILRA5, and OSM. CELL GENOMICS 2025; 5:100784. [PMID: 40043711 PMCID: PMC11960538 DOI: 10.1016/j.xgen.2025.100784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 10/08/2024] [Accepted: 02/06/2025] [Indexed: 03/15/2025]
Abstract
Polygenic severe obesity (body mass index [BMI] ≥40 kg/m2) has increased, especially in Hispanic/Latino populations, yet we know little about the underlying mechanistic pathways. We analyzed whole-blood multiomics data to identify genes differentially regulated in severe obesity in Mexican Americans from the Cameron County Hispanic Cohort. Our RNA sequencing analysis identified 124 genes significantly differentially expressed between severe obesity cases (BMI ≥40 kg/m2) and controls (BMI <25 kg/m2); 33% replicated in an independent sample from the same population. Our integrative approach identified inflammatory genes, including IL4R, ZNF438, and LILRA5. Several genes displayed transcriptomic effects on severe obesity in subcutaneous adipose tissue. We further showed that the genetic regulation of these genes is associated with several traits in a large biobank, including bone fractures, obstructive sleep apnea, and hyperaldosteronism, illuminating potential risk mechanisms. Our findings furnish a molecular architecture of the severe obesity phenotype across multiple molecular domains.
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Affiliation(s)
- Hung-Hsin Chen
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA; Academia Sinica, Institute of Biomedical Sciences, Taipei, Taiwan
| | - Heather M Highland
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Elizabeth G Frankel
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alyssa C Scartozzi
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Xinruo Zhang
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Rashedeh Roshani
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Priya Sharma
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Asha Kar
- Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA
| | - Victoria L Buchanan
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hannah G Polikowsky
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lauren E Petty
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jungkyun Seo
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of MetaBiohealth, Sungkyunkwan University, Suwon, Republic of Korea
| | - Mohammad Yaser Anwar
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Daeeun Kim
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Mariaelisa Graff
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kristin L Young
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Wanying Zhu
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kalypso Karastergiou
- Obesity Research Center, Boston University School of Medicine, Boston, MA, USA; Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Douglas M Shaw
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Anne E Justice
- Department of Population Health Services, Geisinger Health, Danville, PA, USA
| | | | - Mohanraj Krishnan
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Absalon Gutierrez
- Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, Houston, TX, USA
| | - Peter J McCormick
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Carlos A Aguilar-Salinas
- Unidad de Investigación de Enfermedades Metabólicas and Research Direction of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México; Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, México City, México
| | - Maria Teresa Tusié-Luna
- Unidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas UNAM Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Linda Liliana Muñoz-Hernandez
- Unidad de Investigación de Enfermedades Metabólicas del Instituto Nacional de Ciencias, Médicas, y Nutrición Salvador Zubirán, México City, México
| | - Miguel Herrera-Hernandez
- Surgery Direction of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - Miryoung Lee
- Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health, Brownsville Regional Campus, Brownsville, TX, USA
| | - Eric R Gamazon
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Nancy J Cox
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health at University of California, Los Angeles, Los Angeles, CA, USA
| | - Susan K Fried
- Obesity Research Center, Boston University School of Medicine, Boston, MA, USA; Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Penny Gordon-Larsen
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ravi V Shah
- Vanderbilt Translational and Clinical Research Center, Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Susan P Fisher-Hoch
- Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health, Brownsville Regional Campus, Brownsville, TX, USA
| | - Joseph B McCormick
- Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health, Brownsville Regional Campus, Brownsville, TX, USA
| | - Kari E North
- Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Jennifer E Below
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
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5
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Obaideen M, Önel T, Yıldırım E, Yaba A. The role of leptin in the male reproductive system. J Turk Ger Gynecol Assoc 2024; 25:247-258. [PMID: 39658934 PMCID: PMC11632632 DOI: 10.4274/jtgga.galenos.2024.2023-7-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 07/08/2024] [Indexed: 12/12/2024] Open
Abstract
Leptin is a hormone produced from adipose tissue, targeting the hypothalamus and regulating energy expenditure, adipose tissue mass, and reproductive function. Leptin concentration reflects body weight and the amount of energy stored, as well as the level of reproductive hormones and male fertility. In this review, the aim was to focus on leptin signaling mechanisms and the significant influence of leptin on the male reproductive system and to summarize the current knowledge of clinical and experimental studies. The PubMed database was searched for studies on leptin and the male reproductive system to summarize the mechanism of leptin in the male reproductive system. Studies have shown that obesity-related, high leptin levels or leptin resistance negatively affects male reproductive functions. Leptin directly affects the testis by binding to the hypothalamic-pituitary-gonadal axis and the receptors of testicular cells, and thus the location of leptin receptors plays a key role in the regulation of the male reproductive system with the negative feedback mechanism between adipose tissue and hypothalamus. Based on the current evidence, leptin may totally inhibit male reproduction, and investigation of this role of leptin has established a potential interaction between obesity and male infertility. The mechanism of leptin in the male reproductive system should be further investigated and possible treatments for subfertility should be evaluated, supported by better understanding of leptin and associated signaling mechanisms.
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Affiliation(s)
- Melek Obaideen
- Department of Histology and Embryology Yeditepe University Faculty of Medicine, İstanbul, Turkey
| | - Tuğçe Önel
- Department of Histology and Embryology Yeditepe University Faculty of Medicine, İstanbul, Turkey
| | - Ecem Yıldırım
- Department of Histology and Embryology Yeditepe University Faculty of Medicine, İstanbul, Turkey
| | - Aylin Yaba
- Department of Histology and Embryology Yeditepe University Faculty of Medicine, İstanbul, Turkey
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Nagai N, Shioiri T, Hatano S, Sugiura N, Watanabe H. Regulatory role of Heparan sulfate in leptin signaling. Cell Signal 2024; 124:111456. [PMID: 39384005 DOI: 10.1016/j.cellsig.2024.111456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/28/2024] [Accepted: 10/04/2024] [Indexed: 10/11/2024]
Abstract
Leptin, a hormone mainly secreted by adipocytes, has attracted significant attention since its discovery in 1994. Initially known for its role in appetite suppression and energy regulation, leptin is now recognized for its influence on various physiological processes, including immune response, bone formation, and reproduction. It exerts its effects by binding to receptors and initiating an intracellular signaling cascade. Heparan sulfate (HS) is known to regulate the intracellular signaling of various ligands. HS is present as the glycan portion of HSPGs on cell surfaces and in intercellular spaces, with diverse structures due to extensive sulfation and epimerization. Although HS chains on HSPGs are involved in many physiological processes, the detailed effects of HS chains on leptin signaling are not well understood. This study examined the role of HS chains on HSPGs in leptin signaling using Neuro2A cells expressing the full-length leptin receptor (LepR). We showed that cell surface HS was essential for efficient leptin signaling. Enzymatic degradation of HS significantly reduced leptin-induced phosphorylation of downstream molecules, such as signal transducer and activator of transcription 3 and p44/p42 Mitogen-activated protein kinase. In addition, HS regulated LepR expression and internalization, as treatment with HS-degrading enzymes decreased cell surface LepR. HS was also found to exhibit a weak interaction with LepR. Enzymatic removal of HS enhanced the interaction between LepR and low-density lipoprotein receptor-related protein 1, suggesting that HS negatively regulates this interaction. In conclusion, HS plays a significant role in modulating LepR availability on the cell surface, thereby influencing leptin signaling. These findings provide new insights into the complex regulation of leptin signaling and highlight potential therapeutic targets for metabolic disorders and obesity.
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Affiliation(s)
- Naoko Nagai
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, Japan.
| | - Tatsumasa Shioiri
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, Japan.
| | - Sonoko Hatano
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, Japan.
| | - Nobuo Sugiura
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, Japan.
| | - Hideto Watanabe
- Institute for Molecular Science of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, Japan.
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Shan-Ni L, Liang H, Yasui Y, Ninomiya K, Uehara T, Nishimura T, Kobayashi K. Leptin on the apical surface inhibits casein production and STAT5 phosphorylation in mammary epithelial cells. Exp Cell Res 2024; 443:114330. [PMID: 39536931 DOI: 10.1016/j.yexcr.2024.114330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/07/2024] [Accepted: 11/11/2024] [Indexed: 11/16/2024]
Abstract
Leptin is a peptide hormone present in both the blood and milk. A close relationship between leptin and milk production in lactating mammary glands has been previously reported. However, how leptin influences milk production in lactating mammary glands remains unclear. Also, whether leptin in milk or blood influences mammary epithelial cells (MECs) during lactation needs further investigation. This study investigated the effects of leptin on mouse MECs using a culture model in which MECs produced milk components and formed less permeable tight junctions. Our results showed that β-casein production in MEC was inhibited by leptin in a concentration-dependent manner. Leptin also inactivated the signal transducer and activator of transcription 5 (STAT5), a transcription factor that facilitates milk production in MECs. Leptin treatment induced the activation of p38 and c-Jun N-terminal kinase (JNK) in MEC before STAT5 inactivation, and anisomycin, an activator of p38 and JNK, induced the inactivation of STAT5. Furthermore, leptin exposure on the apical surface of MECs inhibited β-casein production and inactivated STAT5. However, leptin exposure on the basolateral surface hardly caused these effects. These findings suggested that milk leptin, but not plasma leptin, inhibited milk production in MECs.
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Affiliation(s)
- Lu Shan-Ni
- Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, North 9, West 9, 060-8589, Sapporo, Japan.
| | - Han Liang
- Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, North 9, West 9, 060-8589, Sapporo, Japan.
| | - Yuki Yasui
- Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, North 9, West 9, 060-8589, Sapporo, Japan.
| | - Kazuki Ninomiya
- Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, North 9, West 9, 060-8589, Sapporo, Japan.
| | - Tamaki Uehara
- Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, North 9, West 9, 060-8589, Sapporo, Japan.
| | - Takanori Nishimura
- Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, North 9, West 9, 060-8589, Sapporo, Japan.
| | - Ken Kobayashi
- Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, North 9, West 9, 060-8589, Sapporo, Japan.
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Antonioli L, Armuzzi A, Fantini MC, Fornai M. JAK inhibitors: an evidence-based choice of the most appropriate molecule. Front Pharmacol 2024; 15:1494901. [PMID: 39559737 PMCID: PMC11570808 DOI: 10.3389/fphar.2024.1494901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 10/18/2024] [Indexed: 11/20/2024] Open
Abstract
Janus kinase inhibitors (JAKis) represent a fundamental therapeutic tool for the treatment of patients with immune-mediated inflammatory diseases. Although JAKis are often considered a homogeneous class of drugs whose members are thought to be largely interchangeable, there are significant differences in their efficacy and safety profiles. This narrative review analyzes the pharmacokinetic and pharmacodynamic differences among JAKIs, highlighting their clinical relevance based on the most recent available evidence. The article aims to provide rheumatologists, gastroenterologists and dermatologists with practical guidance for choosing the most appropriate JAKi for each patient, given the lack of evidence-based recommendations on this topic, to improve clinical outcomes. Due to its preferential action on JAK1, intestinal metabolization and proven absence of impact on male fertility, filgotinib may be characterized by an improved benefit/risk ratio compared with other less selective JAKis.
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Affiliation(s)
- Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Massimo C. Fantini
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Gastroenterology Unit, Azienda Ospedaliero Universitaria di Cagliari, Cagliari, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Ali M, Gupta A, Verma RD, Akhtar S, Ghosh JK. A peptide derived from the amino terminus of leptin improves glucose metabolism and energy homeostasis in myotubes and db/db mice. J Biol Chem 2024; 300:107919. [PMID: 39490585 PMCID: PMC11625344 DOI: 10.1016/j.jbc.2024.107919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 10/10/2024] [Accepted: 10/14/2024] [Indexed: 11/05/2024] Open
Abstract
Leptin is an adipokine, which plays key roles in regulation of glucose metabolism and energy homeostasis. Therefore, identification of a short peptide from leptin which improves glucose-metabolism and energy-homeostasis could be of significant therapeutic importance. Mutational studies demonstrated that N-terminal of human leptin hormone is crucial for activation of leptin-receptor while its C-terminal seems to have lesser effects in it. Thus, for finding a metabolically active peptide and complimenting the mutational studies on leptin, we have identified a 17-mer (leptin-1) and a 16-mer (leptin-2) segment from its N-terminal and C-terminal, respectively. Consistent with the mutational studies, leptin-1 improved glucose-metabolism by increasing glucose-uptake, GLUT4 expression and its translocation to the plasma membrane in L6-myotubes, while leptin-2 was mostly inactive. Leptin-1-induced glucose-uptake is mediated through activation of AMPK, PI3K, and AKT proteins since inhibitors of these proteins inhibited the event. Leptin-1 activated leptin-receptor immediate downstream target protein, JAK2 reflecting its possible interaction with leptin-receptor while leptin-2 was less active. Furthermore, leptin-1 increased mitochondrial-biogenesis and ATP-production, and increased expression of PGC1α, NRF1, and Tfam proteins, that are important regulators of mitochondrial biogenesis. The results suggested that leptin-1 improved energy-homeostasis in L6-myotubes, whereas, leptin-2 showed much lesser effects. In diabetic, db/db mice, leptin-1 significantly decreased blood glucose level and improved glucose-tolerance. Leptin-1 also increased serum adiponectin and decreased serum TNF-α and IL-6 level signifying the improvement in insulin-sensitivity and decrease in insulin-resistance, respectively in db/db mice. Overall, the results show the identification of a short peptide from the N-terminal of human leptin hormone which significantly improves glucose-metabolism and energy-homeostasis.
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Affiliation(s)
- Mehmood Ali
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Arvind Gupta
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Rahul Dev Verma
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Sariyah Akhtar
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Jimut Kanti Ghosh
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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10
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Żelechowska P, Wiktorska M, Kozłowska E, Agier J. Adipokine receptor expression in mast cells is altered by specific ligands and proinflammatory cytokines. Immunol Cell Biol 2024; 102:817-829. [PMID: 39014534 DOI: 10.1111/imcb.12809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 03/21/2024] [Accepted: 07/01/2024] [Indexed: 07/18/2024]
Abstract
Adipokines play essential roles in regulating a range of biological processes, but growing evidence indicates that they are also fundamental in immunological mechanisms and, primarily, inflammatory responses. Adipokines mediate their actions through specific receptors. However, although adipokine receptors are widely distributed in many cell and tissue types, limited data are available on their expression in mast cells (MCs) and, consequently, adipokine's significance in the modulation of MC activity within the tissues. In this study, we demonstrate that rat peritoneal MCs constitutively express the leptin receptor (i.e. LEPR), adiponectin receptors (i.e. ADIPOR1 and ADIPOR2) and the chemerin receptor (i.e. CMKLR1). We also found that LEPR, ADIPOR1, ADIPOR2 and CMKLR1 expression in MCs changes in response to stimulation by their specific ligands and some cytokines with potent proinflammatory properties. Furthermore, the involvement of intracellular signaling molecules in leptin-, adiponectin- and chemerin-induced MC response was analyzed. Overall, our findings suggest that adipokines leptin, adiponectin and chemerin can significantly affect the activity of MCs in various processes, especially during inflammation. These observations may contribute significantly to understanding the relationship between adipokines, immune mechanisms and diseases or conditions with an inflammatory component.
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Affiliation(s)
- Paulina Żelechowska
- Department of Microbiology, Genetics, and Experimental Immunology, MOLecoLAB: Lodz Centre of Molecular Studies on Civilisation Diseases, Medical University of Lodz, Lodz, Poland
| | - Magdalena Wiktorska
- Department of Molecular Cell Mechanisms, Faculty of Health Sciences, Medical University of Lodz, Lodz, Poland
| | - Elżbieta Kozłowska
- Department of Microbiology, Genetics, and Experimental Immunology, MOLecoLAB: Lodz Centre of Molecular Studies on Civilisation Diseases, Medical University of Lodz, Lodz, Poland
| | - Justyna Agier
- Department of Microbiology, Genetics, and Experimental Immunology, MOLecoLAB: Lodz Centre of Molecular Studies on Civilisation Diseases, Medical University of Lodz, Lodz, Poland
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11
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Jiménez-Cortegana C, Gutiérrez-García C, Sánchez-Jiménez F, Vilariño-García T, Flores-Campos R, Pérez-Pérez A, Garnacho C, Sánchez-León ML, García-Domínguez DJ, Hontecillas-Prieto L, Palazón-Carrión N, De La Cruz-Merino L, Sánchez-Margalet V. Impact of obesity‑associated myeloid‑derived suppressor cells on cancer risk and progression (Review). Int J Oncol 2024; 65:79. [PMID: 38940351 PMCID: PMC11251741 DOI: 10.3892/ijo.2024.5667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 06/12/2024] [Indexed: 06/29/2024] Open
Abstract
Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low‑grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid‑derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abilities. Obesity‑associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity‑associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipocytes, plays in MDSC‑driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity‑related cancer.
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Affiliation(s)
- Carlos Jiménez-Cortegana
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Cristian Gutiérrez-García
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Flora Sánchez-Jiménez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Teresa Vilariño-García
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Rocio Flores-Campos
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Carmen Garnacho
- Department of Normal and Pathological Histology and Cytology, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Maria L. Sánchez-León
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Daniel J. García-Domínguez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Lourdes Hontecillas-Prieto
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Natalia Palazón-Carrión
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Luis De La Cruz-Merino
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
- Institute of Biomedicine of Seville, Virgen Macarena University Hospital, CSIC, University of Seville, Seville 41013, Spain
| | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Institute of Biomedicine of Seville, Virgen Macarena University Hospital, CSIC, University of Seville, Seville 41013, Spain
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12
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Mondal S, Rathor R, Singh SN, Suryakumar G. miRNA and leptin signaling in metabolic diseases and at extreme environments. Pharmacol Res Perspect 2024; 12:e1248. [PMID: 39017237 PMCID: PMC11253706 DOI: 10.1002/prp2.1248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 05/27/2024] [Accepted: 07/04/2024] [Indexed: 07/18/2024] Open
Abstract
The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa-miR-204-5p, hsa-miR-211-5p, hsa-miR-30, hsa-miR-3163, hsa-miR-33a-3p, hsa-miR-548, hsa-miR-561-3p, hsa-miR-7856-5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases.
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Affiliation(s)
- Samrita Mondal
- Defence Institute of Physiology and Allied SciencesDelhiIndia
| | - Richa Rathor
- Defence Institute of Physiology and Allied SciencesDelhiIndia
| | - Som Nath Singh
- Defence Institute of Physiology and Allied SciencesDelhiIndia
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13
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Coronell-Tovar A, Pardo JP, Rodríguez-Romero A, Sosa-Peinado A, Vásquez-Bochm L, Cano-Sánchez P, Álvarez-Añorve LI, González-Andrade M. Protein tyrosine phosphatase 1B (PTP1B) function, structure, and inhibition strategies to develop antidiabetic drugs. FEBS Lett 2024; 598:1811-1838. [PMID: 38724486 DOI: 10.1002/1873-3468.14901] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 08/13/2024]
Abstract
Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.
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Affiliation(s)
- Andrea Coronell-Tovar
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Juan P Pardo
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | | | - Alejandro Sosa-Peinado
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Luz Vásquez-Bochm
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Patricia Cano-Sánchez
- Instituto de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Laura Iliana Álvarez-Añorve
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Martin González-Andrade
- Laboratorio de Biosensores y Modelaje molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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14
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Alshammari MA, Alshehri AO, Alqahtani F, Khan MR, Bakhrebah MA, Alasmari F, Alshammari TK, Alsharari SD. Increased Permeability of the Blood-Brain Barrier in a Diabetic Mouse Model ( Leprdb/db Mice). Int J Mol Sci 2024; 25:7768. [PMID: 39063010 PMCID: PMC11276738 DOI: 10.3390/ijms25147768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 07/05/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood-brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Leprdb/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Leprdb/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Leprdb/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Leprdb/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Leprdb/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research.
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Affiliation(s)
- Musaad A. Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Abdulaziz O. Alshehri
- Department of Pharmacology and Toxicology (Graduate Student), Pharmacy College, King Saud University, Riyadh 11495, Saudi Arabia;
| | - Faleh Alqahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Mohammad R. Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Muhammed A. Bakhrebah
- Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia;
| | - Fawaz Alasmari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Tahani K. Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Shakir D. Alsharari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
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15
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Zhang X, Tian L, Majumdar A, Scheller EL. Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations. Compr Physiol 2024; 14:5521-5579. [PMID: 39109972 PMCID: PMC11725182 DOI: 10.1002/cphy.c230016] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521-5579, 2024.
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Affiliation(s)
- Xiao Zhang
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Linda Tian
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
| | - Anurag Majumdar
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Erica L. Scheller
- Division of Bone and Mineral Diseases, Department of Medicine, Washington University, St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA
- Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA
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16
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Liu W, Wang X, Yu H, Yan G, Shen S, Gao M, Zhang X. Integrated Platform for Large-Scale Quantitative Profiling of Phosphotyrosine Signaling Complexes Based on Cofractionation/Mass Spectrometry and Complex-Centric Algorithm. Anal Chem 2024; 96:9849-9858. [PMID: 38836774 DOI: 10.1021/acs.analchem.4c00285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2024]
Abstract
The scarcity and dynamic nature of phosphotyrosine (pTyr)-modified proteins pose a challenge for researching protein complexes with pTyr modification, which are assembled through multiple protein-protein interactions. We developed an integrated complex-centric platform for large-scale quantitative profiling of pTyr signaling complexes based on cofractionation/mass spectrometry (CoFrac-MS) and a complex-centric algorithm. We initially constructed a trifunctional probe based on pTyr superbinder (SH2-S) for specifically binding and isolation of intact pTyr protein complexes. Then, the CoFrac-MS strategy was employed for the identification of pTyr protein complexes by integrating ion exchange chromatography in conjunction with data independent acquisition mass spectrometry. Furthermore, we developed a novel complex-centric algorithm for quantifying protein complexes based on the protein complex elution curve. Utilizing this algorithm, we effectively quantified 216 putative protein complexes. We further screened 21 regulated pTyr protein complexes related to the epidermal growth factor signal. Our study engenders a comprehensive framework for the intricate examination of pTyr protein complexes and presents, for the foremost occasion, a quantitative landscape delineating the composition of pTyr protein complexes in HeLa cells.
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Affiliation(s)
- Wei Liu
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Xuantang Wang
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Hailong Yu
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Guoquan Yan
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
| | - Shun Shen
- Pharmacy Department, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Mingxia Gao
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
- Pharmacy Department, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Xiangmin Zhang
- Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai 200438, China
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17
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Targa G, Mottarlini F, Rizzi B, Taddini S, Parolaro S, Fumagalli F, Caffino L. Anorexia-Induced Hypoleptinemia Drives Adaptations in the JAK2/STAT3 Pathway in the Ventral and Dorsal Hippocampus of Female Rats. Nutrients 2024; 16:1171. [PMID: 38674862 PMCID: PMC11054075 DOI: 10.3390/nu16081171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/04/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Leptin is an appetite-regulating adipokine that is reduced in patients with anorexia nervosa (AN), a psychiatric disorder characterized by self-imposed starvation, and has been linked to hyperactivity, a hallmark of AN. However, it remains unknown how leptin receptor (LepR) and its JAK2-STAT3 downstream pathway in extrahypothalamic brain areas, such as the dorsal (dHip) and ventral (vHip) hippocampus, crucial for spatial memory and emotion regulation, may contribute to the maintenance of AN behaviors. Taking advantage of the activity-based anorexia (ABA) model (i.e., the combination of food restriction and physical activity), we observed reduced leptin plasma levels in adolescent female ABA rats at the acute phase of the disorder [post-natal day (PND) 42], while the levels increased over control levels following a 7-day recovery period (PND49). The analysis of the intracellular leptin pathway revealed that ABA rats showed an overall decrease of the LepR/JAK2/STAT3 signaling in dHip at both time points, while in vHip we observed a transition from hypo- (PND42) to hyperactivation (PND49) of the pathway. These changes might add knowledge on starvation-induced fluctuations in leptin levels and in hippocampal leptin signaling as initial drivers of the transition from adaptative mechanisms to starvation toward the maintenance of aberrant behaviors typical of AN patients, such as perpetuating restraint over eating.
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Affiliation(s)
- Giorgia Targa
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (G.T.); (F.M.); (B.R.); (S.T.); (S.P.); (F.F.)
| | - Francesca Mottarlini
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (G.T.); (F.M.); (B.R.); (S.T.); (S.P.); (F.F.)
| | - Beatrice Rizzi
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (G.T.); (F.M.); (B.R.); (S.T.); (S.P.); (F.F.)
- Center for Neuroscience, University of Camerino, 62032 Camerino, Italy
| | - Sofia Taddini
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (G.T.); (F.M.); (B.R.); (S.T.); (S.P.); (F.F.)
| | - Susanna Parolaro
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (G.T.); (F.M.); (B.R.); (S.T.); (S.P.); (F.F.)
| | - Fabio Fumagalli
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (G.T.); (F.M.); (B.R.); (S.T.); (S.P.); (F.F.)
| | - Lucia Caffino
- Department of Pharmacological and Biomolecular Sciences ‘Rodolfo Paoletti’, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; (G.T.); (F.M.); (B.R.); (S.T.); (S.P.); (F.F.)
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18
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Guan D, Men Y, Bartlett A, Hernández MAS, Xu J, Yi X, Li HS, Kong D, Mazitschek R, Ozcan U. Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss. Cell Metab 2024; 36:857-876.e10. [PMID: 38569472 DOI: 10.1016/j.cmet.2024.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 11/02/2023] [Accepted: 02/13/2024] [Indexed: 04/05/2024]
Abstract
Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.
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Affiliation(s)
- Dongxian Guan
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yuqin Men
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Alexander Bartlett
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Jie Xu
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xinchi Yi
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hu-Song Li
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Dong Kong
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ralph Mazitschek
- Massachusetts General Hospital, Center for Systems Biology, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Umut Ozcan
- Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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19
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Salazar J, Duran P, Garrido B, Parra H, Hernández M, Cano C, Añez R, García-Pacheco H, Cubillos G, Vasquez N, Chacin M, Bermúdez V. Weight Regain after Metabolic Surgery: Beyond the Surgical Failure. J Clin Med 2024; 13:1143. [PMID: 38398456 PMCID: PMC10888585 DOI: 10.3390/jcm13041143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/20/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Patients undergoing metabolic surgery have factors ranging from anatomo-surgical, endocrine metabolic, eating patterns and physical activity, mental health and psychological factors. Some of the latter can explain the possible pathophysiological neuroendocrine, metabolic, and adaptive mechanisms that cause the high prevalence of weight regain in postbariatric patients. Even metabolic surgery has proven to be effective in reducing excess weight in patients with obesity; some of them regain weight after this intervention. In this vein, several studies have been conducted to search factors and mechanisms involved in weight regain, to stablish strategies to manage this complication by combining metabolic surgery with either lifestyle changes, behavioral therapies, pharmacotherapy, endoscopic interventions, or finally, surgical revision. The aim of this revision is to describe certain aspects and mechanisms behind weight regain after metabolic surgery, along with preventive and therapeutic strategies for this complication.
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Affiliation(s)
- Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Pablo Duran
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Bermary Garrido
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Heliana Parra
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Marlon Hernández
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Clímaco Cano
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Roberto Añez
- Departamento de Endocrinología y Nutrición, Hospital Quirónsalud, 28009 Madrid, Spain
| | - Henry García-Pacheco
- Facultad de Medicina, Departamento de Cirugía, Universidad del Zulia, Hospital General del Sur, Dr. Pedro Iturbe, Maracaibo 4004, Venezuela
- Unidad de Cirugía para Obesidad y Metabolismo (UCOM), Maracaibo 4004, Venezuela
| | | | | | - Maricarmen Chacin
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080001, Colombia
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080001, Colombia
| | - Valmore Bermúdez
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080001, Colombia
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080001, Colombia
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20
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Boyle CA, Kola PK, Oraegbuna CS, Lei S. Leptin excites basolateral amygdala principal neurons and reduces food intake by LepRb-JAK2-PI3K-dependent depression of GIRK channels. J Cell Physiol 2024; 239:e31117. [PMID: 37683049 PMCID: PMC10920395 DOI: 10.1002/jcp.31117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/08/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023]
Abstract
Leptin is an adipocyte-derived hormone that modulates food intake, energy balance, neuroendocrine status, thermogenesis, and cognition. Whereas a high density of leptin receptors has been detected in the basolateral amygdala (BLA) neurons, the physiological functions of leptin in the BLA have not been determined yet. We found that application of leptin excited BLA principal neurons by activation of the long form leptin receptor, LepRb. The LepRb-elicited excitation of BLA neurons was mediated by depression of the G protein-activated inwardly rectifying potassium (GIRK) channels. Janus Kinase 2 (JAK2) and phosphoinositide 3-kinase (PI3K) were required for leptin-induced excitation of BLA neurons and depression of GIRK channels. Microinjection of leptin into the BLA reduced food intake via activation of LepRb, JAK2, and PI3K. Our results may provide a cellular and molecular mechanism to explain the physiological roles of leptin in vivo.
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Affiliation(s)
- Cody A. Boyle
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND58203, USA
| | - Phani K. Kola
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND58203, USA
| | - Chidiebele S. Oraegbuna
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND58203, USA
| | - Saobo Lei
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND58203, USA
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21
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Masloh S, Chevrel A, Culot M, Perrocheau A, Kalia YN, Frehel S, Gaussin R, Gosselet F, Huet S, Zeisser Labouebe M, Scapozza L. Enhancing Oral Delivery of Biologics: A Non-Competitive and Cross-Reactive Anti-Leptin Receptor Nanofitin Demonstrates a Gut-Crossing Capacity in an Ex Vivo Porcine Intestinal Model. Pharmaceutics 2024; 16:116. [PMID: 38258126 PMCID: PMC10820293 DOI: 10.3390/pharmaceutics16010116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Biotherapeutics exhibit high efficacy in targeted therapy, but their oral delivery is impeded by the harsh conditions of the gastrointestinal (GI) tract and limited intestinal absorption. This article presents a strategy to overcome the challenges of poor intestinal permeability by using a protein shuttle that specifically binds to an intestinal target, the leptin receptor (LepR), and exploiting its capacity to perform a receptor-mediated transport. Our proof-of-concept study focuses on the characterization and transport of robust affinity proteins, known as Nanofitins, across an ex vivo porcine intestinal model. We describe the potential to deliver biologically active molecules across the mucosa by fusing them with the Nanofitin 1-F08 targeting the LepR. This particular Nanofitin was selected for its absence of competition with leptin, its cross-reactivity with LepR from human, mouse, and pig hosts, and its shuttle capability associated with its ability to induce a receptor-mediated transport. This study paves the way for future in vivo demonstration of a safe and efficient oral-to-systemic delivery of targeted therapies.
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Affiliation(s)
- Solene Masloh
- Blood Brain Barrier Laboratory, Faculty of Science Jean Perrin, Artois University, UR 2465, Rue Jean Souvraz, 62300 Lens, France (M.C.); (F.G.)
- Affilogic, 24 Rue de la Rainière, 44300 Nantes, France (A.P.); (R.G.)
- School of Pharmaceutical Sciences, University of Geneva, 1 Rue Michel Servet, 1201 Geneva, Switzerland (L.S.)
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1 Rue Michel Servet, 1201 Geneva, Switzerland
| | - Anne Chevrel
- Affilogic, 24 Rue de la Rainière, 44300 Nantes, France (A.P.); (R.G.)
| | - Maxime Culot
- Blood Brain Barrier Laboratory, Faculty of Science Jean Perrin, Artois University, UR 2465, Rue Jean Souvraz, 62300 Lens, France (M.C.); (F.G.)
| | | | - Yogeshvar N. Kalia
- School of Pharmaceutical Sciences, University of Geneva, 1 Rue Michel Servet, 1201 Geneva, Switzerland (L.S.)
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1 Rue Michel Servet, 1201 Geneva, Switzerland
| | - Samuel Frehel
- Affilogic, 24 Rue de la Rainière, 44300 Nantes, France (A.P.); (R.G.)
| | - Rémi Gaussin
- Affilogic, 24 Rue de la Rainière, 44300 Nantes, France (A.P.); (R.G.)
| | - Fabien Gosselet
- Blood Brain Barrier Laboratory, Faculty of Science Jean Perrin, Artois University, UR 2465, Rue Jean Souvraz, 62300 Lens, France (M.C.); (F.G.)
| | - Simon Huet
- Affilogic, 24 Rue de la Rainière, 44300 Nantes, France (A.P.); (R.G.)
| | - Magali Zeisser Labouebe
- School of Pharmaceutical Sciences, University of Geneva, 1 Rue Michel Servet, 1201 Geneva, Switzerland (L.S.)
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1 Rue Michel Servet, 1201 Geneva, Switzerland
| | - Leonardo Scapozza
- School of Pharmaceutical Sciences, University of Geneva, 1 Rue Michel Servet, 1201 Geneva, Switzerland (L.S.)
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1 Rue Michel Servet, 1201 Geneva, Switzerland
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22
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Jo S, Alejandro EU. RISING STARS: Mechanistic insights into maternal-fetal cross talk and islet beta-cell development. J Endocrinol 2023; 259:e230069. [PMID: 37855321 PMCID: PMC10692651 DOI: 10.1530/joe-23-0069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 10/18/2023] [Indexed: 10/20/2023]
Abstract
The metabolic health trajectory of an individual is shaped as early as prepregnancy, during pregnancy, and lactation period. Both maternal nutrition and metabolic health status are critical factors in the programming of offspring toward an increased propensity to developing type 2 diabetes in adulthood. Pancreatic beta-cells, part of the endocrine islets, which are nutrient-sensitive tissues important for glucose metabolism, are primed early in life (the first 1000 days in humans) with limited plasticity later in life. This suggests the high importance of the developmental window of programming in utero and early in life. This review will focus on how changes to the maternal milieu increase offspring's susceptibility to diabetes through changes in pancreatic beta-cell mass and function and discuss potential mechanisms by which placental-driven nutrient availability, hormones, exosomes, and immune alterations that may impact beta-cell development in utero, thereby affecting susceptibility to type 2 diabetes in adulthood.
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Affiliation(s)
- Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Emilyn U Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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23
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Lim PQ, Lai YJ, Ling PY, Chen KH. Cellular and molecular overview of gestational diabetes mellitus: Is it predictable and preventable? World J Diabetes 2023; 14:1693-1709. [PMID: 38077798 PMCID: PMC10704206 DOI: 10.4239/wjd.v14.i11.1693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/18/2023] [Accepted: 10/11/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND In contrast to overt diabetes mellitus (DM), gestational DM (GDM) is defined as impaired glucose tolerance induced by pregnancy, which may arise from exaggerated physiologic changes in glucose metabolism. GDM prevalence is reported to be as high as 20% among pregnancies depending on the screening method, gestational age, and the population studied. Maternal and fetal effects of uncontrolled GDM include stillbirth, macrosomia, neonatal diabetes, birth trauma, and subsequent postpartum hemorrhage. Therefore, it is essential to find the potential target population and associated predictive and preventive measures for future intensive peripartum care. AIM To review studies that explored the cellular and molecular mechanisms of GDM as well as predictive measures and prevention strategies. METHODS The search was performed in the Medline and PubMed databases using the terms "gestational diabetes mellitus," "overt diabetes mellitus," and "insulin resistance." In the literature, only full-text articles were considered for inclusion (237 articles). Furthermore, articles published before 1997 and duplicate articles were excluded. After a final review by two experts, all studies (1997-2023) included in the review met the search terms and search strategy (identification from the database, screening of the studies, selection of potential articles, and final inclusion). RESULTS Finally, a total of 79 articles were collected for review. Reported risk factors for GDM included maternal obesity or overweight, pre-existing DM, and polycystic ovary syndrome. The pathophysiology of GDM involves genetic variants responsible for insulin secretion and glycemic control, pancreatic β cell depletion or dysfunction, aggravated insulin resistance due to failure in the plasma membrane translocation of glucose transporter 4, and the effects of chronic, low-grade inflammation. Currently, many antepartum measurements including adipokines (leptin), body mass ratio (waist circumference and waist-to-hip ratio], and biomarkers (microRNA in extracellular vesicles) have been studied and confirmed to be useful markers for predicting GDM. For preventing GDM, physical activity and dietary approaches are effective interventions to control body weight, improve glycemic control, and reduce insulin resistance. CONCLUSION This review explored the possible factors that influence GDM and the underlying molecular and cellular mechanisms of GDM and provided predictive measures and prevention strategies based on results of clinical studies.
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Affiliation(s)
- Pei-Qi Lim
- Department of Obstetrics and Gynecology, Taiwan Adventist Hospital, Taipei 105, Taiwan
| | - Yen-Ju Lai
- Department of Obstetrics and Gynecology, Taiwan Adventist Hospital, Taipei 105, Taiwan
| | - Pei-Ying Ling
- Department of Obstetrics and Gynecology, Taiwan Adventist Hospital, Taipei 105, Taiwan
- School of Medicine, George Washington University, Washington, DC 20052, United States
| | - Kuo-Hu Chen
- Department of Obstetrics and Gynecology, Taipei Tzu-Chi General Hospital, Taipei 231, Taiwan
- School of Medicine, Tzu-Chi University, Hualien 970, Taiwan
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24
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Hua KF, Li LH, Yu HC, Wong WT, Hsu HT. Leptin Induces MMP-1 Expression Through the RhoA/ERK1/2/NF-κB Axis in Human Intervertebral Disc Cartilage Endplate-Derived Stem Cells. J Inflamm Res 2023; 16:5235-5248. [PMID: 38026238 PMCID: PMC10657743 DOI: 10.2147/jir.s431026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Purpose Intervertebral disc (IVD) degeneration, associated with aging, may cause low back pain and disability, with obesity as a significant risk factor. In a prior study, we found a positive correlation between IVD degeneration and levels of matrix metalloproteinase-1 (MMP-1) and leptin. Yet, the interaction between MMP-1 and leptin in IVD degeneration is unclear. Our research seeks to explore leptin's influence on MMP-1 expression and the underlying mechanisms in human intervertebral disc cartilage endplate-derived stem cells, specifically SV40 cells. Methods The mRNA and protein expression in leptin-stimulated SV40 cells were assessed using RT-real-time PCR and Western blotting or ELISA, respectively. We examined leptin-mediated RhoA activation through a GTP-bound RhoA pull-down assay. Furthermore, the phosphorylation levels of mitogen-activated protein kinases and AKT in leptin-stimulated SV40 cells were analyzed using Western blotting. The activation of NF-κB by leptin was investigated by assessing phosphorylation of IKKα/β, IκBα, and NF-κB p65, along with the nuclear translocation of NF-κB p65. To understand the underlying mechanism behind leptin-mediated MMP-1 expression, we employed specific inhibitors. Results Leptin triggered the mRNA and protein expression of MMP-1 in SV40 cells. In-depth mechanistic investigations uncovered that leptin heightened RhoA activity, promoted ERK1/2 phosphorylation, and increased NF-κB activity. However, leptin did not induce phosphorylation of JNK1/2, p38, or AKT. When we inhibited RhoA, ERK1/2, and NF-κB, it resulted in a decrease in MMP-1 expression. Conversely, inhibition of reactive oxygen species and NADPH oxidase did not yield the same outcome. Additionally, inhibiting RhoA or ERK1/2 led to a reduction in leptin-induced NF-κB activation. Moreover, inhibiting RhoA also decreased leptin-mediated ERK1/2 phosphorylation. Conclusion These results indicated that leptin induced MMP-1 expression in SV40 cells through the RhoA/ERK1/2/NF-κB axis. This study provided the pathogenic role of leptin and suggested the potential therapeutic target for IVD degeneration.
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Affiliation(s)
- Kuo-Feng Hua
- Department of Biotechnology and Animal Science, National Ilan University, Yilan, 26047, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404333, Taiwan
| | - Lan-Hui Li
- Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, 108, Taiwan
| | - Hsin-Chiao Yu
- Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan
| | - Wei-Ting Wong
- Department of Biotechnology and Animal Science, National Ilan University, Yilan, 26047, Taiwan
| | - Hsien-Ta Hsu
- Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, 231, Taiwan
- School of Medicine, Buddhist Tzu Chi University, Hualien, 970, Taiwan
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25
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Khoramipour K, Rezaei MH, Madadizadeh E, Hosseini MS, Soltani Z, Schierbauer J, Moser O. High Intensity Interval Training can Ameliorate Hypothalamic Appetite Regulation in Male Rats with Type 2 Diabetes: The Role of Leptin. Cell Mol Neurobiol 2023; 43:4295-4307. [PMID: 37828299 PMCID: PMC11407713 DOI: 10.1007/s10571-023-01421-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 09/27/2023] [Indexed: 10/14/2023]
Abstract
Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1).
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Affiliation(s)
- Kayvan Khoramipour
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Maryam Hossein Rezaei
- Department of Exercise Physiology, Faculty of Physical Education, Shahid Bahonar University, Kerman, Iran
| | - Elham Madadizadeh
- Department of Exercise Physiology, Faculty of Physical Education, Shahid Bahonar University, Kerman, Iran
| | - Mahdieh Sadat Hosseini
- Student Research Committee, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Soltani
- Student Research Committee, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Janis Schierbauer
- Exercise Physiology and Metabolism (Sports Medicine), BaySpo-Bayreuth Centre of Sports Science, University of Bayreuth, Bayreuth, Germany
| | - Othmar Moser
- Exercise Physiology and Metabolism (Sports Medicine), BaySpo-Bayreuth Centre of Sports Science, University of Bayreuth, Bayreuth, Germany
- Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
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26
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Xu ZH, Xiong CW, Miao KS, Yu ZT, Zhang JJ, Yu CL, Huang Y, Zhou XD. Adipokines regulate mesenchymal stem cell osteogenic differentiation. World J Stem Cells 2023; 15:502-513. [PMID: 37424950 PMCID: PMC10324509 DOI: 10.4252/wjsc.v15.i6.502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/26/2023] [Accepted: 04/24/2023] [Indexed: 06/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can differentiate into various tissue cell types including bone, adipose, cartilage, and muscle. Among those, osteogenic differentiation of MSCs has been widely explored in many bone tissue engineering studies. Moreover, the conditions and methods of inducing osteogenic differentiation of MSCs are continuously advancing. Recently, with the gradual recognition of adipokines, the research on their involvement in different pathophysiological processes of the body is also deepening including lipid metabolism, inflammation, immune regulation, energy disorders, and bone homeostasis. At the same time, the role of adipokines in the osteogenic differentiation of MSCs has been gradually described more completely. Therefore, this paper reviewed the evidence of the role of adipokines in the osteogenic differentiation of MSCs, emphasizing bone formation and bone regeneration.
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Affiliation(s)
- Zhong-Hua Xu
- Department of Orthopedics, Jintan Hospital Affiliated to Jiangsu University, Changzhou 213200, Jiangsu Province, China
| | - Chen-Wei Xiong
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Kai-Song Miao
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Zhen-Tang Yu
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Jun-Jie Zhang
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Chang-Lin Yu
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Yong Huang
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
| | - Xin-Die Zhou
- Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, Jiangsu Province, China
- Department of Orthopedics, Gonghe County Hospital of Traditional Chinese Medicine, Hainan Tibetan Autonomous Prefecture 811800, Qinghai Province, China
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27
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Niwczyk O, Grymowicz M, Szczęsnowicz A, Hajbos M, Kostrzak A, Budzik M, Maciejewska-Jeske M, Bala G, Smolarczyk R, Męczekalski B. Bones and Hormones: Interaction between Hormones of the Hypothalamus, Pituitary, Adipose Tissue and Bone. Int J Mol Sci 2023; 24:ijms24076840. [PMID: 37047811 PMCID: PMC10094866 DOI: 10.3390/ijms24076840] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 03/30/2023] [Accepted: 04/01/2023] [Indexed: 04/14/2023] Open
Abstract
The bony skeleton, as a structural foundation for the human body, is essential in providing mechanical function and movement. The human skeleton is a highly specialized and dynamic organ that undergoes continuous remodeling as it adapts to the demands of its environment. Advances in research over the last decade have shone light on the various hormones that influence this process, modulating the metabolism and structural integrity of bone. More recently, novel and non-traditional functions of hypothalamic, pituitary, and adipose hormones and their effects on bone homeostasis have been proposed. This review highlights recent work on physiological bone remodeling and discusses our knowledge, as it currently stands, on the systemic interplay of factors regulating this interaction. In this review, we provide a summary of the literature on the relationship between bone physiology and hormones including kisspeptin, neuropeptide Y, follicle-stimulating hormone (FSH), prolactin (PRL), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), leptin, and adiponectin. The discovery and understanding of this new functionality unveils an entirely new layer of physiologic circuitry.
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Affiliation(s)
- Olga Niwczyk
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Monika Grymowicz
- Department of Gynecological Endocrinology, Medical University of Warsaw, 00-315 Warsaw, Poland
| | - Aleksandra Szczęsnowicz
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Marta Hajbos
- Department of Gynecological Endocrinology, Medical University of Warsaw, 00-315 Warsaw, Poland
| | - Anna Kostrzak
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Michał Budzik
- Department of Gynecological Endocrinology, Medical University of Warsaw, 00-315 Warsaw, Poland
- Department of Cancer Prevention, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Marzena Maciejewska-Jeske
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Gregory Bala
- UCD School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Roman Smolarczyk
- Department of Gynecological Endocrinology, Medical University of Warsaw, 00-315 Warsaw, Poland
| | - Błażej Męczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
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Smooth Muscle Cells from a Rat Model of Obesity and Hyperleptinemia Are Partially Resistant to Leptin-Induced Reactive Oxygen Species Generation. Antioxidants (Basel) 2023; 12:antiox12030728. [PMID: 36978976 PMCID: PMC10045401 DOI: 10.3390/antiox12030728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/05/2023] [Accepted: 03/11/2023] [Indexed: 03/18/2023] Open
Abstract
The aim of this study was to evaluate the effect of leptin on reactive oxygen species’ (ROS) generation of smooth muscle cells (SMCs) from a rat model of obesity and hyperleptinemia. Obesity and hyperleptinemia were induced in rats by a sucrose-based diet for 24 weeks. ROS generation was detected by using dichloro-dihydrofluorescein (DCF), a fluorescent ROS probe in primary SMCs culture. An increase in plasma leptin and oxidative stress markers was observed in sucrose-fed (SF) rats. At baseline SMCs from SF rats showed a more than twofold increase in fluorescence intensity (FI) compared to that obtained in control (C) cells. When the C cells were treated with 20 ng leptin, the FI increased by about 200%, whereas the leptin-induced FI in the SF cells increased only by 60%. In addition, sucrose feeding increased the levels of p22phox and gp91phox, subunits of Nox as an O2•− source in SMCs. Treatment of cells with leptin significantly increased p22phox and gp91phox levels in C cells and did not affect SF cells. Regarding STAT3 phosphorylation and the content of PTP1B and SOCS3 as protein markers of leptin resistance, they were found to be significantly increased in SF cells. These results suggest that SF aortic SMCs are partially resistant to leptin-induced ROS generation.
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Skórzyńska-Dziduszko KE, Makarewicz A, Błażewicz A. Peripubertal Alterations of Leptin Levels in Patients with Autism Spectrum Disorder and Elevated or Normal Body Weight. Int J Mol Sci 2023; 24:ijms24054878. [PMID: 36902307 PMCID: PMC10003704 DOI: 10.3390/ijms24054878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Leptin, which plays a key role in energy homeostasis, is known as a neurotrophic factor possibly linking nutrition and neurodevelopment. Available data on the association between leptin and autism spectrum disorder (ASD) are confusing. The aim of this study was to explore whether plasma levels of leptin in pre- and post-pubertal children with ASD and/or overweightness/obesity differ from those of BMI- and age-matched healthy controls. Leptin levels were determined in 287 pre-pubertal children (mean age 8.09 years), classified as follows: ASD with overweightness/obesity (ASD+/Ob+); ASD without overweightness/obesity (ASD+/Ob-); non-ASD with overweightness/obesity (ASD-/Ob+); non-ASD without overweightness/obesity (ASD-/Ob-). The assessment was repeated in 258 of the children post-pubertally (mean age 14.26 years). There were no significant differences in leptin levels either before or after puberty between ASD+/Ob+ and ASD-/Ob+ or between ASD+/Ob- and ASD-/Ob-, although there was a strong trend toward significance for higher pre-pubertal leptin levels in ASD+/Ob- than in ASD-/Ob-. Post-pubertal leptin levels were significantly lower than pre-pubertal levels in ASD+/Ob+, ASD-/Ob+, and ASD+/Ob- and higher in ASD-/Ob-. Leptin levels, elevated pre-pubertally in the children with overweightness/obesity as well as in children with ASD and normal BMI, decrease with age, in contrast to the increasing leptin levels in healthy controls.
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Affiliation(s)
| | - Agata Makarewicz
- Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, 20-439 Lublin, Poland
| | - Anna Błażewicz
- Department of Pathobiochemistry and Interdisciplinary Applications of Ion Chromatography, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland
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30
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Bhardwaj P, Iyengar NM, Zahid H, Carter KM, Byun DJ, Choi MH, Sun Q, Savenkov O, Louka C, Liu C, Piloco P, Acosta M, Bareja R, Elemento O, Foronda M, Dow LE, Oshchepkova S, Giri DD, Pollak M, Zhou XK, Hopkins BD, Laughney AM, Frey MK, Ellenson LH, Morrow M, Spector JA, Cantley LC, Brown KA. Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2. Sci Transl Med 2023; 15:eade1857. [PMID: 36812344 PMCID: PMC10557057 DOI: 10.1126/scitranslmed.ade1857] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 01/23/2023] [Indexed: 02/24/2023]
Abstract
Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.
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Affiliation(s)
- Priya Bhardwaj
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Neil M. Iyengar
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Heba Zahid
- Department of Medical Laboratory Technology, College of Applied Medical Science, Taibah University, Medina 42353, Saudi Arabia
| | | | - Dong Jun Byun
- Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Korea
| | - Man Ho Choi
- Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Korea
| | - Qi Sun
- Computational Biology Service Unit of Life Sciences Core Laboratories Center, Cornell University, Ithaca, NY 14853, USA
| | - Oleksandr Savenkov
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY 10065, USA
| | - Charalambia Louka
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Catherine Liu
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Phoebe Piloco
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Monica Acosta
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Rohan Bareja
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Miguel Foronda
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Lukas E. Dow
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Sofya Oshchepkova
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Dilip D. Giri
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michael Pollak
- Departments of Medicine and Oncology, McGill University, Montreal, Canada
| | - Xi Kathy Zhou
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY 10065, USA
| | - Benjamin D. Hopkins
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ashley M. Laughney
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Melissa K. Frey
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Lora Hedrick Ellenson
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Monica Morrow
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Jason A. Spector
- Laboratory of Bioregenerative Medicine and Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Lewis C. Cantley
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Kristy A. Brown
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
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Tawfik MK, Badran DI, Keshawy MM, Makary S, Abdo M. Alternate-day fat diet and exenatide modulate the brain leptin JAK2/STAT3/SOCS3 pathway in a fat diet-induced obesity and insulin resistance mouse model. Arch Med Sci 2023; 19:1508-1519. [PMID: 37732053 PMCID: PMC10507768 DOI: 10.5114/aoms/158534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 12/24/2022] [Indexed: 09/22/2023] Open
Abstract
Introduction Obesity is one of the most burdensome health problems and is closely linked to leptin resistance. The study examined whether an alternate-day high-fat diet (ADF) and/or GLP-1 agonist (exenatide) modulate brain leptin resistance caused by a high-fat diet (HFD). Material and methods Sixty adult male mice were divided into 6 groups: (i) normal palatable diet (NPD), (ii) exenatide control (NPD received exenatide) (iii) HFD, (iv) ADF treated, (v) exenatide treated, (vi) ADF and exenatide treated. All animal groups were fed a HFD for 8 weeks, before they received treatment (ADF and/or exenatide) for 8 additional weeks. Body weight was assessed at the start and at the end of the experiment. Lipid profile, brain leptin and its receptor expression with the leptin-sensitive pathway, JAK2/STAT3/SOCS3/PTP1B, fasting blood glucose (FBG), serum insulin, liver metabolic handling via its regulators IRS1/PI3K/GLUT4 for hyperinsulinemia/obesity-induced PDK3/NAFLD2 modification, and liver enzymes were determined at the end of the experiment. Results ADF and exenatide reduced body weight and FBG in HFD-obese mice (p < 0.05). The combined ADF and exenatide regimen enhanced the brain anorexic leptin/JAK2/STAT3 and attenuated the SOCS3/PTP1B pathway (p < 0.05). The ADF/exenatide anorexigenic brain effect also modulated liver glucose via IRS1/PI3K/GLUT4 expression (p < 0.05), attenuating NAFLD2 and PDK3 expression (p < 0.05). Liver enzymes and the histopathological profile confirmed the improvement. Conclusions In HFD caloric consumption, a combination of ADF and GLP-1 agonist enhances the brain leptin anorexigenic effect with the improvement of the metabolic sequelae of hyperinsulinemia, hyperlipidemia and liver steatosis.
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Affiliation(s)
- Mona K. Tawfik
- Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Dahlia I. Badran
- Department of Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- Department of Biochemistry, Faculty of Medicine, Badr University, Cairo, Egypt
| | - Mohammed M. Keshawy
- Department of Internal Medicine, Nephrology Division, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Samy Makary
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamed Abdo
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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Afrin S, Ramaiyer M, Begum UAM, Borahay MA. Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment. Nutrients 2023; 15:nu15030715. [PMID: 36771423 PMCID: PMC9919329 DOI: 10.3390/nu15030715] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/18/2023] [Accepted: 01/28/2023] [Indexed: 02/01/2023] Open
Abstract
Uterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin treatment on human myometrium and leiomyoma cells. We isolated primary leiomyoma and myometrium cells from hysterectomy or myomectomy patients. Protein expression levels of phosphorylated ERK1/2/total ERK1/2, phosphorylated STAT3/total STAT3, and phosphorylated AKT1/2/3/total AKT1/2/3 were quantified using immunoblotting in immortalized and primary leiomyoma and myometrial cells cocultured with human adipocytes and treated with leptin. An enzyme-linked immunosorbent assay (ELISA) was used to assess pro-inflammatory, fibrotic, and angiogenic factors in immortalized human myometrium and leiomyoma cells treated with leptin. The effects of STAT3, ERK, and AKT inhibitors were assessed in leiomyoma cell lines additionally cultured with adipocytes. Adipocyte coculture and leptin treatment increases the expression of JAK2/STAT3, MAPK/ERK, and PI3K/AKT signaling while inhibitors suppressed this effect. Leptin induces a tumor-friendly microenvironment through upregulation of pro-inflammatory (IFNγ, IL-8, IL-6, GM-CSF, MCP-1, and TNF-α), fibrotic (TGF-β1, TGF-β2, and TGF-β3), and angiogenic (VEGF-A, HGF, and Follistatin) factors in human leiomyoma cells. Furthermore, adipocyte coculture and leptin treatment increases leiomyoma cells growth through activation of MAPK/ERK, JAK2/STAT3, and PI3k/AKT signaling pathways. Finally, STAT3, ERK, and AKT inhibitor treatment suppressed PCNA, TNF-α, TGF-β3, and VEGF-A intracellular staining intensity in both adipocyte coculture and leptin treated leiomyoma cells. These findings suggest that, in obese women, adipocyte secreted hormone or adipocytes may contribute to leiomyoma development and growth by activating leptin receptor signaling pathways.
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Affiliation(s)
- Sadia Afrin
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Malini Ramaiyer
- School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Umme Aoufa Mafruha Begum
- Department of Gynecology and Obstetrics, Khulna City Medical College Hospital, 25-26, KDA Ave., Khulna 9100, Bangladesh
| | - Mostafa A. Borahay
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Correspondence: ; Tel.: +1-(410)-550-0337
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Ma S, Zhang K, Shi S, Li X, Che C, Chen P, Liu H. Low-protein diets supplemented with isoleucine alleviate lipid deposition in broilers through activating 5' adenosine monophosphate-activated protein kinase and janus kinase 2/signal transducer and activator of transcription 3 signaling pathways. Poult Sci 2022; 102:102441. [PMID: 36599221 PMCID: PMC9823210 DOI: 10.1016/j.psj.2022.102441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/04/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
This study aimed to evaluate the effect of isoleucine (Ile) on growth performance, meat quality and lipid metabolism of broilers fed a low-protein diet (LPD). The 396 one-day-old male Cobb broilers were allocated to 4 treatment groups as follows: control diet (CON), LPD, LPD + 0.13% Ile (LPD-LI) and LPD + 0.26% Ile (LPD-HI), with nine replicates of 11 broilers each for 42 d. The Ile increased average daily gain, average daily feed intake, fiber density and the mRNA level of myosin heavy chain (MyHC)-I in breast muscle, and decreased feed to gain ratio, shear force, fiber diameter and the mRNA level of MyHC-IIb in breast muscle, which were impaired by the LPD. Compared to the LPD group, broilers in LPD-LI and LPD-HI groups had lower serum lipid levels, liver fat content, abdominal adipose percentage and mRNA levels of peroxisome proliferator-activated receptor-γ, CCAAT/enhancer binding protein-α, ki-67, topoisomerase II alpha (TOP2A) and thioredoxin-dependent peroxidase 2 in abdominal adipose and liver X receptors-α, sterol regulatory element binding protein 1 (SREBP1), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in liver, and higher mRNA levels of peroxisome proliferator activated receptor-α, carnitine palmitoyl-transferase 1 (CPT-1), and acyl-CoA oxidase 1 (ACOX1) in liver, which were equal to the CON levels. A LPD supplemented with Ile decreased enzyme activities of ACC and FAS in liver and glycerol-3-phosphate dehydrogenase and TOP2A in abdominal adipose, and increased enzyme activities of CPT-1 and ACOX1 in liver. Furthermore, Ile supplementation enhanced the mRNA level of leptin receptor and protein levels of phospho-5' adenosine monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin, ribosomal protein 70 S6 kinase, janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3), and decreased the protein level of SREBP1 in the liver of broilers in LPD group. In conclusion, dietary supplementation with Ile to 0.83% could improve growth performance and meat quality and alleviate lipid deposition of broilers fed a LPD through activating AMPK and JAK2/STAT3 signaling pathways.
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Affiliation(s)
- Shengnan Ma
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Kai Zhang
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Shuyan Shi
- Qingdao Yebio Bioengineering Co., Ltd., Qingdao 266114, China
| | - Xuemin Li
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Chuanyan Che
- College of Animal Science, Anhui Science and Technology University, Fengyang 233100, China
| | - Peng Chen
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Huawei Liu
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China.
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Roczniak W, Szymlak A, Mazur B, Chobot A, Stojewska M, Oświęcimska J. Nutritional Status and Selected Adipokines in Children with Irritable Bowel Syndrome. Nutrients 2022; 14:nu14245282. [PMID: 36558441 PMCID: PMC9782519 DOI: 10.3390/nu14245282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/29/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The aim of this study was to assess the nutritional status and serum concentrations of adipokines in children with irritable bowel syndrome (IBS) and healthy controls. We also sought to evaluate their relation to metabolic parameters. METHODS We studied 33 IBS patients (11 girls, 22 boys) aged 5-17 years and 30 healthy age-matched controls (11 girls, 19 boys). The analysis included anthropometric measurements, body composition parameter measurements using bioimpedance, and biochemical tests and measurements of serum concentrations of leptin, adiponectin, chemerin, and omentin-1. RESULTS The results of the anthropometric measurements were comparable between the patients and the controls. The patients had higher triglycerides, HOMA-IRs, and chemerin concentrations than the healthy subjects. The HDL cholesterol and omentin-1 levels were lower than in the controls. Leptin and adiponectin did not differ significantly between the groups. An analysis of the receiver operator curves (ROCs) showed that serum concentrations of chemerin ≥ 232.8 ng/mL had 30% sensitivity and 87% specificity when they were used to differentiate between children with IBS and healthy subjects. In the case of serum omentin-1 concentrations ≤ 279.4 ng/mL, the sensitivity and specificity were 60% and 80%, respectively. CONCLUSIONS The nutritional status of children with IBS did not differ from that of the healthy controls. We found significant differences in serum chemerin and omentin-1 concentrations between IBS patients and healthy children. These adipokines could be used as IBS biomarkers as they demonstrate good specificity and moderate sensitivity. The serum concentrations of chemerin and omentin-1 in IBS patients were related to nutritional status and insulin resistance.
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Affiliation(s)
- Wojciech Roczniak
- Institute of Medicine, Jan Grodek State University in Sanok, ul. Mickiewicza 21, 38-500 Sanok, Poland
- Correspondence:
| | - Agnieszka Szymlak
- Department of General Paediatrics, University Hospital No 1 in Zabrze, Medical University of Silesia in Katowice, ul. 3 Maja 13-15, 41-800 Zabrze, Poland
| | - Bogdan Mazur
- Department of Microbiology and Immunology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. Jordana 19, 41-808 Zabrze, Poland
| | - Agata Chobot
- Department of Pediatrics, Institute of Medical Sciences, University of Opole, al. W.Witosa 26, 45-401 Opole, Poland
| | - Małgorzata Stojewska
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, ul. 3-Maja 13-15, 41-800 Zabrze, Poland
| | - Joanna Oświęcimska
- Institute of Medicine, Jan Grodek State University in Sanok, ul. Mickiewicza 21, 38-500 Sanok, Poland
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Jiménez-Cortegana C, Hontecillas-Prieto L, García-Domínguez DJ, Zapata F, Palazón-Carrión N, Sánchez-León ML, Tami M, Pérez-Pérez A, Sánchez-Jiménez F, Vilariño-García T, de la Cruz-Merino L, Sánchez-Margalet V. Obesity and Risk for Lymphoma: Possible Role of Leptin. Int J Mol Sci 2022; 23:15530. [PMID: 36555171 PMCID: PMC9779026 DOI: 10.3390/ijms232415530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 11/30/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022] Open
Abstract
Obesity, which is considered a pandemic due to its high prevalence, is a risk factor for many types of cancers, including lymphoma, through a variety of mechanisms by promoting an inflammatory state. Specifically, over the last few decades, obesity has been suggested not only to increase the risk of lymphoma but also to be associated with poor clinical outcomes and worse responses to different treatments for those diseases. Within the extensive range of proinflammatory mediators that adipose tissue releases, leptin has been demonstrated to be a key adipokine due to its pleotropic effects in many physiological systems and diseases. In this sense, different studies have analyzed leptin levels and leptin/leptin receptor expressions as a probable bridge between obesity and lymphomas. Since both obesity and lymphomas are prevalent pathophysiological conditions worldwide and their incidences have increased over the last few years, here we review the possible role of leptin as a promising proinflammatory mediator promoting lymphomas.
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Affiliation(s)
- Carlos Jiménez-Cortegana
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY 10065, USA
- Oncology Service, Department of Medicines, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Lourdes Hontecillas-Prieto
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Oncology Service, Department of Medicines, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Daniel J. García-Domínguez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Oncology Service, Department of Medicines, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Fernando Zapata
- Oncology Service, Department of Medicines, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Natalia Palazón-Carrión
- Oncology Service, Department of Medicines, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - María L. Sánchez-León
- Oncology Service, Department of Medicines, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Malika Tami
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Oncology Service, Department of Medicines, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Flora Sánchez-Jiménez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Teresa Vilariño-García
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Luis de la Cruz-Merino
- Oncology Service, Department of Medicines, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
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Venugopal P, George M, Kandadai SD, Balakrishnan K, Uppugunduri CRS. Prioritization of microRNA biomarkers for a prospective evaluation in a cohort of myocardial infarction patients based on their mechanistic role using public datasets. Front Cardiovasc Med 2022; 9:981335. [PMID: 36407428 PMCID: PMC9668885 DOI: 10.3389/fcvm.2022.981335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022] Open
Abstract
Background MicroRNAs (miR) have proven to be promising biomarkers for several diseases due to their diverse functions, stability and tissue/organ-specific nature. Identification of new markers with high sensitivity and specificity will help in risk reduction in acute myocardial infarction (AMI) patients with chest pain and also prevent future adverse outcomes. Hence the aim of this study was to perform a detailed in silico analysis for identifying the mechanistic role of miRs involved in the pathogenesis/prognosis of AMI for prospective evaluation in AMI patients. Methods miR profiling data was extracted from GSE148153 and GSE24591 datasets using the GEO2R gene expression omnibus repository and analyzed using limma algorithm. Differentially expressed miRs were obtained by comparing MI patients with corresponding controls after multiple testing corrections. Data mining for identifying candidate miRs from published literature was also performed. Target prediction and gene enrichment was done using standard bioinformatics tools. Disease specific analysis was performed to identify target genes specific for AMI using open targets platform. Protein-protein interaction and pathway analysis was done using STRING database and Cytoscape platform. Results and conclusion The analysis revealed significant miRs like let-7b-5p, let-7c-5p, miR-4505, and miR-342-3p in important functions/pathways including phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin, advanced glycation end products and its receptor and renin–angiotensin–aldosterone system by directly targeting angiotensin II receptor type 1, forkhead box protein O1, etc. With this approach we were able to prioritize the miR candidates for a prospective clinical association study in AMI patients of south Indian origin.
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Affiliation(s)
| | - Melvin George
- Clinical Research Department, Hindu Mission Hospital, Chennai, India
| | | | | | - Chakradhara Rao S. Uppugunduri
- CANSEARCH Research Platform in Pediatric Oncology and Hematology, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland
- *Correspondence: Chakradhara Rao S. Uppugunduri,
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Reschke L, Afrin S, El Sabah M, Charewycz N, Miyashita-Ishiwata M, Borahay MA. Leptin induces leiomyoma cell proliferation and extracellular matrix deposition via JAK2/STAT3 and MAPK/ERK pathways. F&S SCIENCE 2022; 3:383-391. [PMID: 35598777 PMCID: PMC9669119 DOI: 10.1016/j.xfss.2022.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To investigate the molecular effects of leptin on uterine leiomyoma cells. DESIGN Experimental study using in vitro culture of immortalized human leiomyoma (HuLM) cells. SETTING Academic university center. PATIENT(S) Women with uterine fibroids who underwent a hysterectomy or myomectomy. INTERVENTION(S) Administration of human recombinant leptin to the media of cultured HuLM cells separately or in combination with pharmacologic Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) inhibitors. MAIN OUTCOME MEASURE(S) We examined HuLM tissues and cells for the expression of the leptin receptor, termed OB-R. Cellular proliferation was measured at 6, 24, and 48 hours using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Protein expression levels of proliferating cell nuclear antigen, collagen 1, phosphorylated STAT3/total STAT3, and phosphorylated ERK1/2 and total ERK1/2 were quantified using immunoblotting. Pharmacologic inhibitors were employed to further assess the role of the JAK2/STAT3 and MAPK/ERK pathways in the proliferative response. RESULT(S) The presence of OB-R was confirmed in clinical leiomyoma and myometrial tissue obtained from 3 separate human subjects using immunofluorescence staining, and the expression of OB-R in HuLM cells was identified using immunoblotting. There was no significant difference in the expression of the leptin receptor in the myometrium compared with that in the leiomyoma tissue. Leptin stimulated cell proliferation and extracellular matrix (ECM) deposition at 24 hours after treatment. Pretreatment with a JAK2/STAT3 inhibitor attenuated ECM deposition, and pretreatment with a MAPK/ERK inhibitor significantly decreased leptin's stimulatory effect on cell proliferation and ECM deposition. CONCLUSION(S) Leptin induces a proliferative response and ECM deposition in HuLM cells. These findings suggest that leptin, acting through the JAK2/STAT3 and MAPK/ERK pathways, is involved in the development of uterine leiomyomas, which may partly explain their increased incidence in obese women.
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Affiliation(s)
- Lauren Reschke
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sadia Afrin
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Malak El Sabah
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Natasha Charewycz
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mariko Miyashita-Ishiwata
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mostafa A Borahay
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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de Lima RMS, Barth B, Mar Arcego D, de Mendonça Filho EJ, Patel S, Wang Z, Pokhvisneva I, Parent C, Levitan RD, Kobor MS, de Vasconcellos Bittencourt APS, Meaney MJ, Dalmaz C, Silveira PP. Leptin receptor co-expression gene network moderates the effect of early life adversity on eating behavior in children. Commun Biol 2022; 5:1092. [PMID: 36241774 PMCID: PMC9568584 DOI: 10.1038/s42003-022-03992-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 09/13/2022] [Indexed: 12/02/2022] Open
Abstract
Leptin influences eating behavior. Exposure to early adversity is associated with eating behaviour disorders and metabolic syndrome, but the role of the leptin receptor on this relationship is poorly explored. We investigated whether individual differences in brain region specific leptin receptor (LepR) gene networks could moderate the effects of early adversity on eating behavior and metabolism. We created an expression-based polygenic risk score (ePRS) reflecting variations in the function of LepR gene network in prefrontal cortex and hypothalamus to investigate the interactions between a cumulative index of postnatal adversity on eating behavior in two independent birth cohorts (MAVAN and GUSTO). To explore whether variations in the prefrontal cortex or hypothalamic genetic scores could be associated with metabolic measurements, we also assessed the relationship between LepR-ePRS and fasting blood glucose and leptin levels in a third independent cohort (ALSPAC). We identified significant interaction effects between postnatal adversity and prefrontal-based LepR-ePRS on the Child Eating Behavior Questionnaire scores. In MAVAN, we observed a significant interaction effect on food enjoyment at 48 months (β = 61.58, p = 0.015) and 72 months (β = 97.78, p = 0.001); food responsiveness at 48 months (β = 83.79, p = 0.009) satiety at 48 months (β = −43.63, p = 0.047). Similar results were observed in the GUSTO cohort, with a significant interaction effect on food enjoyment (β = 30.48, p = 0.006) food fussiness score (β = −24.07, p = 0.02) and satiety score at 60 months (β = −17.00, p = 0.037). No effects were found when focusing on the hypothalamus-based LepR-ePRS on eating behavior in MAVAN and GUSTO cohorts, and there was no effect of hypothalamus and prefrontal cortex based ePRSs on metabolic measures in ALSPAC. Our study indicated that exposure to postnatal adversity interacts with prefrontal cortex LepR-ePRS to moderate eating behavior, suggesting a neurobiological mechanism associated with the development of eating behavior problems in response to early adversity. The knowledge of these mechanisms may guide the understanding of eating patterns associated with risk for obesity in response to fluctuations in stress exposure early in life. An expression-based polygenic risk score analysis of leptin receptor (LepR) genes suggests that LepR-specific genes co-expressed in the prefrontal cortex interact with exposure to postnatal adversity, potentially modulating eating behavior in children.
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Affiliation(s)
- Randriely Merscher Sobreira de Lima
- Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada.,Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Barbara Barth
- Integrated Program in Neuroscience (IPN), McGill University, Montreal, QC, Canada
| | - Danusa Mar Arcego
- Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - Euclides José de Mendonça Filho
- Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada.,Programa de Pós-Graduação em Psicologia, Instituto de Psicologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Sachin Patel
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Research Centre, McGill University, Montreal, QC, Canada
| | - Zihan Wang
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Research Centre, McGill University, Montreal, QC, Canada
| | - Irina Pokhvisneva
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Research Centre, McGill University, Montreal, QC, Canada
| | - Carine Parent
- Ludmer Centre for Neuroinformatics and Mental Health, Douglas Research Centre, McGill University, Montreal, QC, Canada
| | - Robert D Levitan
- Department of Psychiatry, University of Toronto and Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, Canada
| | - Michael S Kobor
- Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, The University of British Columbia, 938 West 28th Avenue, Vancouver, BC, Canada
| | | | - Michael J Meaney
- Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada.,Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Carla Dalmaz
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Programa de Pós-graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Patrícia Pelufo Silveira
- Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada. .,Ludmer Centre for Neuroinformatics and Mental Health, Douglas Research Centre, McGill University, Montreal, QC, Canada.
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Chen J, Xu X, Dalhaimer P, Zhao L. Tetra-Primer Amplification-Refractory Mutation System (ARMS)-PCR for Genotyping Mouse Leptin Gene Mutation. Animals (Basel) 2022; 12:ani12192680. [PMID: 36230421 PMCID: PMC9558987 DOI: 10.3390/ani12192680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 09/24/2022] [Indexed: 11/05/2022] Open
Abstract
Due to spontaneous deficiency in leptin, ob/ob mice are one of the most commonly used experimental animal models in diabetes research. In this study, we reported a quick and easy-to-conduct genotyping method using tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) to differentiate mice with a mutated allele from the wild-type genotype. The amplicon patterns of different genotypes are clearly visible and distinguishable on 1.5% agarose gel. This method can serve as a valuable tool to differentiate genotypes for breeding purposes, to maintain animal colonies, control the available space in the animal facility, and identify appropriate individuals for animal experiments.
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Affiliation(s)
- Jiangang Chen
- Department of Public Health, The University of Tennessee, Knoxville, TN 37996, USA
- Correspondence: (J.C.); (L.Z.)
| | - Xinyun Xu
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, USA
| | - Paul Dalhaimer
- Department of Chemical and Biomolecular Engineering, The University of Tennessee, Knoxville, TN 37996, USA
| | - Ling Zhao
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, USA
- Correspondence: (J.C.); (L.Z.)
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40
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Hales C, Burnet L, Coombs M, Collins AM, Ferreira DM. Obesity, leptin and host defence of Streptococcus pneumoniae: the case for more human research. Eur Respir Rev 2022; 31:31/165/220055. [PMID: 36002169 DOI: 10.1183/16000617.0055-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/05/2022] [Indexed: 11/05/2022] Open
Abstract
Pneumococcal pneumonia is the leading cause of community-acquired pneumonia. Obesity is a risk factor for pneumonia. Host factors play a critical role in susceptibility to pulmonary pathogens and outcome from pulmonary infections. Obesity impairs innate and adaptive immune responses, important in the host defence against pneumococcal disease. One area of emerging interest in understanding the complex relationship between obesity and pulmonary infections is the role of the hormone leptin. There is a substantive evidence base supporting the associations between obesity, leptin, pulmonary infections and host defence mechanisms. Despite this, there is a paucity of research that specifically focuses on Streptococcus pneumoniae (pneumococcal) infections, which are the leading cause of community-acquired pneumonia hospitalisations and mortality worldwide. Much of the evidence examining the role of leptin in relation to S. pneumoniae infections has used genetically mutated mice. The purpose of this mini review is to explore the role leptin plays in the host defence of S. pneumoniae in subjects with obesity and posit an argument for the need for more human research.
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Affiliation(s)
- Caz Hales
- School of Nursing Midwifery and Health Practice, Faculty of Health, Victoria University of Wellington, Wellington, New Zealand .,Dept of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
| | - Laura Burnet
- School of Nursing Midwifery and Health Practice, Faculty of Health, Victoria University of Wellington, Wellington, New Zealand
| | - Maureen Coombs
- School of Nursing Midwifery and Health Practice, Faculty of Health, Victoria University of Wellington, Wellington, New Zealand
| | - Andrea M Collins
- Dept of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.,Liverpool University Foundation Hospital Trusts, Liverpool, UK
| | - Daniela M Ferreira
- Dept of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.,Oxford Vaccine Group, Dept of Paediatrics, University of Oxford, Oxford, UK
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41
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Bagheri S, Zolghadri S, Stanek A. Beneficial Effects of Anti-Inflammatory Diet in Modulating Gut Microbiota and Controlling Obesity. Nutrients 2022; 14:3985. [PMID: 36235638 PMCID: PMC9572805 DOI: 10.3390/nu14193985] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022] Open
Abstract
Obesity has consistently been associated with an increased risk of metabolic abnormalities such as diabetes, hyperlipidemia, and cardiovascular diseases, as well as the development of several types of cancer. In recent decades, unfortunately, the rate of overweight/obesity has increased significantly among adults and children. A growing body of evidence shows that there is a relationship between metabolic disorders such as obesity and the composition of the gut microbiota. Additionally, inflammation is considered to be a driving force in the obesity-gut microbiota connection. Therefore, it seems that anti-inflammatory nutrients, foods, and/or diets can play an essential role in the management of obesity by affecting the intestinal flora and controlling inflammatory responses. In this review, we describe the links between the gut microbiota, obesity, and inflammation, and summarize the benefits of anti-inflammatory diets in preventing obesity.
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Affiliation(s)
- Soghra Bagheri
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran
| | - Samaneh Zolghadri
- Department of Biology, Jahrom Branch, Islamic Azad University, Jahrom 7414785318, Iran
| | - Agata Stanek
- Department of Internal Medicine, Angiology and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Batorego 15 St, 41-902 Bytom, Poland
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42
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da Silva RKB, de Vasconcelos DAA, da Silva AVE, da Silva RPB, de Oliveira Neto OB, Galindo LCM. Effects of maternal high-fat diet on the hypothalamic components related to food intake and energy expenditure in mice offspring. Life Sci 2022; 307:120880. [PMID: 35963301 DOI: 10.1016/j.lfs.2022.120880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 11/25/2022]
Abstract
Maternal exposure to a high-fat diet (HFD) during pregnancy and lactation has been related to changes in the hypothalamic circuits involved in the regulation of food intake. Furthermore, maternal HFD during the critical period of development can alter the offspring's metabolic programming with long-term repercussions. This study systematically reviewed the effects of HFD consumption during pre-pregnancy, pregnancy and/or lactation. The main outcomes evaluated were food intake; body weight; cellular or molecular aspects of peptides and hypothalamic receptors involved in the regulation of energy balance in mice. Two independent authors performed a search in the electronic databases Medline/PubMed, LILACS, Web of Science, EMBASE, SCOPUS and Sigle via Open Gray. Included were experimental studies of mice exposed to HFD during pregnancy and/or lactation that evaluated body composition, food intake, energy expenditure and hypothalamic components related to energy balance. Internal validity was assessed using the SYRCLE risk of bias. The Kappa index was measured to analyze the agreement between reviewers. The PRISMA statement was used to report this systematic review. Most studies demonstrated that there was a higher body weight, body fat deposits and food intake, as well as alterations in the expression of hypothalamic neuropeptides in offspring that consumed HFD. Therefore, the maternal diet can affect the phenotype and metabolism of the offspring, in addition to harming the hypothalamic circuits and favoring the orexigenic pathways.
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Affiliation(s)
- Regina Katiuska Bezerra da Silva
- Post-Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil
| | - Diogo Antonio Alves de Vasconcelos
- Post-Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil; Department of Nutrition, Federal University of Pernambuco, 50670-901 Recife, PE, Brazil; Nutrition and Phenotypic Plasticity Study Unit, Department of Nutrition, Federal University of Pernambuco, 50670-901 Recife, PE, Brazil
| | | | - Roxana Patrícia Bezerra da Silva
- Post-Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil
| | | | - Lígia Cristina Monteiro Galindo
- Post-Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, 55608-680 Vitória de Santo Antão, PE, Brazil; Department of Anatomy, Federal University of Pernambuco, 50670-901 Recife, PE, Brazil; Nutrition and Phenotypic Plasticity Study Unit, Department of Nutrition, Federal University of Pernambuco, 50670-901 Recife, PE, Brazil.
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43
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Liu J, Lai F, Hou Y, Zheng R. Leptin signaling and leptin resistance. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:363-384. [PMID: 37724323 PMCID: PMC10388810 DOI: 10.1515/mr-2022-0017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/12/2022] [Indexed: 09/20/2023]
Abstract
With the prevalence of obesity and associated comorbidities, studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest. In 1994, the cloning of leptin was a milestone in metabolic research. As an adipocytokine, leptin governs food intake and energy homeostasis through leptin receptors (LepR) in the brain. The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance, which encompasses complex pathophysiological processes. Within the brain, LepR-expressing neurons are distributed in hypothalamus and other brain areas, and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects. In LepR-expressing neurons, the binding of leptin to LepR initiates multiple signaling cascades including janus kinase (JAK)-signal transducers and activators of transcription (STAT) phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), extracellular regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, etc., mediating leptin actions. These findings place leptin at the intersection of metabolic and neuroendocrine regulations, and render leptin a key target for treating obesity and associated comorbidities. This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis, and guides the development of safe and effective interventions to treat obesity and associated diseases.
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Affiliation(s)
- Jiarui Liu
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Futing Lai
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Yujia Hou
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Ruimao Zheng
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
- Neuroscience Research Institute, Peking University, Beijing, China
- Key Laboratory for Neuroscience of Ministry of Education, Peking University, Beijing, China
- Key Laboratory for Neuroscience of National Health Commission, Peking University, Beijing 100191, China
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44
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Simcox J, Lamming DW. The central moTOR of metabolism. Dev Cell 2022; 57:691-706. [PMID: 35316619 PMCID: PMC9004513 DOI: 10.1016/j.devcel.2022.02.024] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/20/2022] [Accepted: 02/24/2022] [Indexed: 12/21/2022]
Abstract
The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.
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Affiliation(s)
- Judith Simcox
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
| | - Dudley W Lamming
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
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45
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The ontogenies of endometrial and myometrial leptin and adiponectin receptors in pregnant rats: Their putative impact on uterine contractility. Life Sci 2022; 297:120465. [PMID: 35271883 DOI: 10.1016/j.lfs.2022.120465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/02/2022] [Accepted: 03/04/2022] [Indexed: 11/23/2022]
Abstract
AIMS Limited data are available about the functions and expressions of leptin and adiponectin receptors (LEPR, AdipoRs) in the uterus. Our aim was to investigate the effects of leptin and adiponectin on the contractions of intact and denuded nonpregnant and pregnant uteri, as well as the changes in mRNA and protein expressions of LEPR and AdipoRs during the gestational period. MAIN METHODS Contractions of nonpregnant and 5-, 15-, 18-, 20- or 22-day pregnant uterine rings were measured in an isolated organ bath system. The tissue contractions were stimulated with KCl and modified by cumulative concentrations of leptin or adiponectin. The mRNAs, protein expressions and localizations of LEPR and AdipoRs were determined by RT-PCR, Western blot and immunohistochemistry, respectively. KEY FINDINGS Both adipokines relaxed the nonpregnant intact uterus more effectively than the denuded myometrium. Leptin inhibited the contractions of endometrium-denuded uteri throughout pregnancy, while its action was weakened on intact uteri towards term. The changes in LEPR receptor densities were independent of the relaxing effect. Adiponectin inhibited contractions, but this effect ceased on pregnancy day 22, while a gradual decrease was detected towards term on denuded myometria. These modifications were in harmony with changes in the expressions of AdipoRs. SIGNIFICANCE Both leptin and adiponectin play a role in the relaxation of the pregnant uterus, but their efficacy significantly decreases towards the end of gestation. Their endometrial receptors may have a fine-tuning role in uterine contractions, predicting the importance of these adipokines in uterine contractions under altered adipokine level conditions.
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Matsumoto H, Kimura S, Nagai Y, Fukuda Y, Miyazaki K, Imai S, Inenaga T, Kashimura A. Leptin gene contributes to beef marbling standard, meat brightness, meat firmness, and beef fat standard of the Kumamoto sub-breed of Japanese Brown cattle. Anim Sci J 2022; 93:e13698. [PMID: 35247014 DOI: 10.1111/asj.13698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/14/2022] [Accepted: 02/09/2022] [Indexed: 11/29/2022]
Abstract
The Kumamoto sub-breed of Japanese Brown cattle has unique characteristics, such as great growth rate, and their contribution as future breeding materials is expected. To develop a DNA marker for their breeding, we investigated the effects of Leptin gene, controlling energy homeostasis, on carcass traits of the Kumamoto sub-breed. Sequence comparison identified five single nucleotide polymorphisms (SNPs): four linked synonymous mutations and one nonsynonymous mutation. Statistical analysis revealed that c.239C > T (p.A80V) had significant effects on the traits related with quality grade: beef marbling standard (p = 0.0132), meat brightness (p = 0.0383), and meat firmness (p = 0.0115). The C allele showed favorable effects; these scores of the C/C cattle were significantly higher than those of the C/T cattle. On the other hand, the effect of c.399T > C was observed on meat firmness (p = 0.0172) and beef fat standards (BFS) (p = 0.0129). The C/C cattle showed higher values of these traits than the T/T cattle. Our data suggested that these SNPs in Leptin gene could be used as a DNA marker for breeding of the Kumamoto sub-breed.
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Affiliation(s)
- Hirokazu Matsumoto
- Department of Animal Science, School of Agriculture, Tokai University, Kumamoto, Japan
| | - Satoshi Kimura
- Course of Agricultural Sciences, Graduate School of Agriculture, Tokai University, Kumamoto, Japan
| | - Yohsuke Nagai
- Department of Animal Science, School of Agriculture, Tokai University, Kumamoto, Japan
| | - Yuta Fukuda
- Department of Animal Science, School of Agriculture, Tokai University, Kumamoto, Japan
| | - Kunio Miyazaki
- Department of Animal Science, School of Agriculture, Tokai University, Kumamoto, Japan
| | - Saki Imai
- Department of Animal Science, School of Agriculture, Tokai University, Kumamoto, Japan
| | - Toshiaki Inenaga
- Department of Animal Science, School of Agriculture, Tokai University, Kumamoto, Japan
| | - Atsushi Kashimura
- Department of Animal Science, School of Agriculture, Tokai University, Kumamoto, Japan
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Ait Eldjoudi D, Cordero Barreal A, Gonzalez-Rodríguez M, Ruiz-Fernández C, Farrag Y, Farrag M, Lago F, Capuozzo M, Gonzalez-Gay MA, Mera Varela A, Pino J, Gualillo O. Leptin in Osteoarthritis and Rheumatoid Arthritis: Player or Bystander? Int J Mol Sci 2022; 23:ijms23052859. [PMID: 35270000 PMCID: PMC8911522 DOI: 10.3390/ijms23052859] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/10/2022] Open
Abstract
White adipose tissue (WAT) is a specialized tissue whose main function is lipid synthesis and triglyceride storage. It is now considered as an active organ secreting a plethora of hormones and cytokines namely adipokines. Discovered in 1994, leptin has emerged as a key molecule with pleiotropic functions. It is primarily recognized for its role in regulating energy homeostasis and food intake. Currently, further evidence suggests its potent role in reproduction, glucose metabolism, hematopoiesis, and interaction with the immune system. It is implicated in both innate and adaptive immunity, and it is reported to contribute, with other adipokines, in the cross-talking networks involved in the pathogenesis of chronic inflammation and immune-related diseases of the musculo-skeletal system such as osteoarthritis (OA) and rheumatoid arthritis (RA). In this review, we summarize the most recent findings concerning the involvement of leptin in immunity and inflammatory responses in OA and RA.
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Affiliation(s)
- Djedjiga Ait Eldjoudi
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; (D.A.E.); (A.C.B.); (M.G.-R.); (C.R.-F.); (Y.F.); (M.F.); (J.P.)
| | - Alfonso Cordero Barreal
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; (D.A.E.); (A.C.B.); (M.G.-R.); (C.R.-F.); (Y.F.); (M.F.); (J.P.)
- International PhD School, University of Santiago de Compostela (EDIUS), 15706 Santiago de Compostela, Spain
| | - María Gonzalez-Rodríguez
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; (D.A.E.); (A.C.B.); (M.G.-R.); (C.R.-F.); (Y.F.); (M.F.); (J.P.)
- International PhD School, University of Santiago de Compostela (EDIUS), 15706 Santiago de Compostela, Spain
| | - Clara Ruiz-Fernández
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; (D.A.E.); (A.C.B.); (M.G.-R.); (C.R.-F.); (Y.F.); (M.F.); (J.P.)
- International PhD School, University of Santiago de Compostela (EDIUS), 15706 Santiago de Compostela, Spain
| | - Yousof Farrag
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; (D.A.E.); (A.C.B.); (M.G.-R.); (C.R.-F.); (Y.F.); (M.F.); (J.P.)
| | - Mariam Farrag
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; (D.A.E.); (A.C.B.); (M.G.-R.); (C.R.-F.); (Y.F.); (M.F.); (J.P.)
| | - Francisca Lago
- Molecular and Cellular Cardiology Group, SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), Research Laboratory 7, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain;
| | - Maurizio Capuozzo
- National Health Service, Local Health Authority ASL 3 Napoli Sud, Department of Pharmacy, Ercolano, 80056 Naples, Italy;
| | - Miguel Angel Gonzalez-Gay
- Hospital Universitario Marqués de Valdecilla, Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, IDIVAL, University of Cantabria, Avenida de Valdecilla s/n, 39011 Santander, Spain;
| | - Antonio Mera Varela
- SERGAS, Servizo Galego de Saude, Santiago University Clinical Hospital, Division of Rheumatology, 15706 Santiago de Compostela, Spain;
| | - Jesús Pino
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; (D.A.E.); (A.C.B.); (M.G.-R.); (C.R.-F.); (Y.F.); (M.F.); (J.P.)
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain; (D.A.E.); (A.C.B.); (M.G.-R.); (C.R.-F.); (Y.F.); (M.F.); (J.P.)
- Correspondence:
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48
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Huo DL, Bao MH, Cao J, Zhao ZJ. The nonshivering thermogenesis of brown adipose tissue and fat mobilization of striped hamsters exposed to cycles of cold and warm temperatures. THE EUROPEAN ZOOLOGICAL JOURNAL 2022. [DOI: 10.1080/24750263.2022.2025931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Affiliation(s)
- D.-L. Huo
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - M.-H. Bao
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - J. Cao
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Z.-J. Zhao
- College of Life and Environmental Science, Wenzhou University, Wenzhou, China
- State Key Laboratory of Integrated Management for Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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49
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Kang N, Oh S, Kim SY, Ahn H, Son M, Heo SJ, Byun K, Jeon YJ. Anti-obesity effects of Ishophloroglucin A from the brown seaweed Ishige okamurae (Yendo) via regulation of leptin signal in ob/ob mice. ALGAL RES 2022. [DOI: 10.1016/j.algal.2021.102533] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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50
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Barrios V, Campillo-Calatayud A, Guerra-Cantera S, Canelles S, Martín-Rivada Á, Frago LM, Chowen JA, Argente J. Opposite Effects of Chronic Central Leptin Infusion on Activation of Insulin Signaling Pathways in Adipose Tissue and Liver Are Related to Changes in the Inflammatory Environment. Biomolecules 2021; 11:1734. [PMID: 34827732 PMCID: PMC8615824 DOI: 10.3390/biom11111734] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 12/13/2022] Open
Abstract
Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling.
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Affiliation(s)
- Vicente Barrios
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain; (A.C.-C.); (S.G.-C.); (S.C.); (Á.M.-R.); (L.M.F.); (J.A.C.)
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28009 Madrid, Spain
| | - Ana Campillo-Calatayud
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain; (A.C.-C.); (S.G.-C.); (S.C.); (Á.M.-R.); (L.M.F.); (J.A.C.)
| | - Santiago Guerra-Cantera
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain; (A.C.-C.); (S.G.-C.); (S.C.); (Á.M.-R.); (L.M.F.); (J.A.C.)
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28009 Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, E-28029 Madrid, Spain
| | - Sandra Canelles
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain; (A.C.-C.); (S.G.-C.); (S.C.); (Á.M.-R.); (L.M.F.); (J.A.C.)
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28009 Madrid, Spain
| | - Álvaro Martín-Rivada
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain; (A.C.-C.); (S.G.-C.); (S.C.); (Á.M.-R.); (L.M.F.); (J.A.C.)
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, E-28029 Madrid, Spain
| | - Laura M. Frago
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain; (A.C.-C.); (S.G.-C.); (S.C.); (Á.M.-R.); (L.M.F.); (J.A.C.)
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28009 Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, E-28029 Madrid, Spain
| | - Julie A. Chowen
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain; (A.C.-C.); (S.G.-C.); (S.C.); (Á.M.-R.); (L.M.F.); (J.A.C.)
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28009 Madrid, Spain
- IMDEA Food Institute, CEI UAM + CSIC, E-28049 Madrid, Spain
| | - Jesús Argente
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain; (A.C.-C.); (S.G.-C.); (S.C.); (Á.M.-R.); (L.M.F.); (J.A.C.)
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28009 Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, E-28029 Madrid, Spain
- IMDEA Food Institute, CEI UAM + CSIC, E-28049 Madrid, Spain
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