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Dionne O, Abolghasemi A, Corbin F, Çaku A. Implication of the endocannabidiome and metabolic pathways in fragile X syndrome pathophysiology. Psychiatry Res 2024; 337:115962. [PMID: 38763080 DOI: 10.1016/j.psychres.2024.115962] [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: 09/22/2023] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/21/2024]
Abstract
Fragile X Syndrome (FXS) results from the silencing of the FMR1 gene and is the most prevalent inherited cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorder. It is well established that Fragile X individuals are subjected to a wide array of comorbidities, ranging from cognitive, behavioural, and medical origin. Furthermore, recent studies have also described metabolic impairments in FXS individuals. However, the molecular mechanisms linking FMRP deficiency to improper metabolism are still misunderstood. The endocannabinoidome (eCBome) is a lipid-based signalling system that regulates several functions across the body, ranging from cognition, behaviour and metabolism. Alterations in the eCBome have been described in FXS animal models and linked to neuronal hyperexcitability, a core deficit of the disease. However, the potential link between dysregulation of the eCBome and altered metabolism observed in FXS remains unexplored. As such, this review aims to overcome this issue by describing the most recent finding related to eCBome and metabolic dysfunctions in the context of FXS. A better comprehension of this association will help deepen our understanding of FXS pathophysiology and pave the way for future therapeutic interventions.
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Affiliation(s)
- Olivier Dionne
- Biochemistry and Functional Genomic Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada.
| | - Armita Abolghasemi
- Biochemistry and Functional Genomic Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada
| | - François Corbin
- Biochemistry and Functional Genomic Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada
| | - Artuela Çaku
- Biochemistry and Functional Genomic Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada
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2
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Moreira LR, Silva AC, da Costa-Oliveira CN, da Silva-Júnior CD, Oliveira KKDS, Torres DJL, Barros MD, Rabello MCDS, de Lorena VMB. Interaction between peripheral blood mononuclear cells and Trypanosoma cruzi-infected adipocytes: implications for treatment failure and induction of immunomodulatory mechanisms in adipose tissue. Front Immunol 2024; 15:1280877. [PMID: 38533504 PMCID: PMC10963431 DOI: 10.3389/fimmu.2024.1280877] [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: 08/21/2023] [Accepted: 02/27/2024] [Indexed: 03/28/2024] Open
Abstract
Background/Introduction Adipose tissue (AT) has been highlighted as a promising reservoir of infection for viruses, bacteria and parasites. Among them is Trypanosoma cruzi, which causes Chagas disease. The recommended treatment for the disease in Brazil is Benznidazole (BZ). However, its efficacy may vary according to the stage of the disease, geographical origin, age, immune background of the host and sensitivity of the strains to the drug. In this context, AT may act as an ally for the parasite survival and persistence in the host and a barrier for BZ action. Therefore, we investigated the immunomodulation of T. cruzi-infected human AT in the presence of peripheral blood mononuclear cells (PBMC) where BZ treatment was added. Methods We performed indirect cultivation between T. cruzi-infected adipocytes, PBMC and the addition of BZ. After 72h of treatment, the supernatant was collected for cytokine, chemokine and adipokine assay. Infected adipocytes were removed to quantify T. cruzi DNA, and PBMC were removed for immunophenotyping. Results Our findings showed elevated secretion of interleukin (IL)-6, IL-2 and monocyte chemoattractant protein-1 (MCP-1/CCL2) in the AT+PBMC condition compared to the other controls. In contrast, there was a decrease in tumor necrosis factor (TNF) and IL-8/CXCL-8 in the groups with AT. We also found high adipsin secretion in PBMC+AT+T compared to the treated condition (PBMC+AT+T+BZ). Likewise, the expression of CD80+ and HLA-DR+ in CD14+ cells decreased in the presence of T. cruzi. Discussion Thus, our findings indicate that AT promotes up-regulation of inflammatory products such as IL-6, IL-2, and MCP-1/CCL2. However, adipogenic inducers may have triggered the downregulation of TNF and IL-8/CXCL8 through the peroxisome proliferator agonist gamma (PPAR-g) or receptor expression. On the other hand, the administration of BZ only managed to reduce inflammation in the microenvironment by decreasing adipsin in the infected culture conditions. Therefore, given the findings, we can see that AT is an ally of the parasite in evading the host's immune response and the pharmacological action of BZ.
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Affiliation(s)
- Leyllane Rafael Moreira
- Department of Tropical Medicine, Federal University of Pernambuco, Recife, Brazil
- Department of Immunology, Aggeu Magalhães Institute, Recife, Brazil
| | - Ana Carla Silva
- Department of Immunology, Aggeu Magalhães Institute, Recife, Brazil
| | | | - Claudeir Dias da Silva-Júnior
- Department of Tropical Medicine, Federal University of Pernambuco, Recife, Brazil
- Department of Immunology, Aggeu Magalhães Institute, Recife, Brazil
| | | | - Diego José Lira Torres
- Department of Tropical Medicine, Federal University of Pernambuco, Recife, Brazil
- Department of Immunology, Aggeu Magalhães Institute, Recife, Brazil
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Paul B, Buchholz DR. Minireview: Glucocorticoid-Leptin Crosstalk: Role of Glucocorticoid-Leptin Counterregulation in Metabolic Homeostasis and Normal Development. Integr Comp Biol 2023; 63:1127-1139. [PMID: 37708034 DOI: 10.1093/icb/icad119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 08/16/2023] [Accepted: 08/30/2023] [Indexed: 09/16/2023] Open
Abstract
Glucocorticoids and leptin are two important hormones that regulate metabolic homeostasis by controlling appetite and energy expenditure in adult mammals. Also, glucocorticoids and leptin strongly counterregulate each other, such that chronic stress-induced glucocorticoids upregulate the production of leptin and leptin suppresses glucocorticoid production directly via action on endocrine organs and indirectly via action on food intake. Altered glucocorticoid or leptin levels during development can impair organ development and increase the risk of chronic diseases in adults, but there are limited studies depicting the significance of glucocorticoid-leptin interaction during development and its impact on developmental programming. In mammals, leptin-induced suppression of glucocorticoid production is critical during development, where leptin prevents stress-induced glucocorticoid production by inducing a period of short-hyporesponsiveness when the adrenal glands fail to respond to certain mild to moderate stressors. Conversely, reduced or absent leptin signaling increases glucocorticoid levels beyond what is appropriate for normal organogenesis. The counterregulatory interactions between leptin and glucocorticoids suggest the potential significant involvement of leptin in disorders that occur from stress during development.
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Affiliation(s)
- Bidisha Paul
- Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221, USA
| | - Daniel R Buchholz
- Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221, USA
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Oruganti L, Reddy Sankaran K, Dinnupati HG, Kotakadi VS, Meriga B. Anti-adipogenic and lipid-lowering activity of piperine and epigallocatechin gallate in 3T3-L1 adipocytes. Arch Physiol Biochem 2023; 129:1152-1159. [PMID: 33836628 DOI: 10.1080/13813455.2021.1908366] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/22/2021] [Accepted: 03/19/2021] [Indexed: 12/26/2022]
Abstract
The present study was aimed to evaluate the anti-adipogenic activity of piperine (PIP) and epigallocatechin gallate (EGCG) in 3T3-L1 cells. In cytotoxicity studies, PIP and EGCG showed IC50 values of 260 and 218 µM respectively and in combination (20 µM each) did not show cytotoxicity. Treatment with PIP and EGCG (20 µM each) significantly (p<.01) inhibited cell differentiation, lipid droplets deposition and enhanced glycerol release in 3T3-L1 cells. The secreted level of leptin was decreased but adiponectin level was increased in treated 3T3-L1 cells than untreated cells. In molecular expression studies, key adipogenic genes PPAR-γ, SREBP-1c, FAS, Fab-4, C/EBP-α and HMG-CoA reductase were markedly down-regulated but UCP-1 was up-regulated intreated 3T3-L1 cells and the same trend was observed in expression levels of selected proteins. In conclusion, our results demonstrated a combination of PIP and EGCG exhibited strong anti-adipogenic and lipid lowering effect than individual treatments due to synergism.
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Affiliation(s)
- Lokanatha Oruganti
- Division of Cell Culture and Molecular Biology, Department of Biochemistry, Sri Venkateswara University, Tirupati, India
| | - Karunakaran Reddy Sankaran
- Division of Cell Culture and Molecular Biology, Department of Biochemistry, Sri Venkateswara University, Tirupati, India
| | | | | | - Balaji Meriga
- Division of Cell Culture and Molecular Biology, Department of Biochemistry, Sri Venkateswara University, Tirupati, India
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Carolina Costa Veras A, da Silva Bruzasco L, Beatriz Profiro Lopes A, da Silva Franco B, Spencer de Souza Holanda A, Maculano Esteves A, Milanski M, Souza Torsoni A, Martins Ignacio-Souza L, Alberto Torsoni M. Supplementation with CO induces lipogenesis in adipose tissue, leptin and insulin resistance in healthy Swiss mice. J Funct Foods 2023; 106:105600. [DOI: 10.1016/j.jff.2023.105600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
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Cimas FJ, De la Cruz-Morcillo MÁ, Cifuentes C, Moratalla-López N, Alonso GL, Nava E, Llorens S. Effect of Crocetin on Basal Lipolysis in 3T3-L1 Adipocytes. Antioxidants (Basel) 2023; 12:1254. [PMID: 37371984 DOI: 10.3390/antiox12061254] [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: 05/01/2023] [Revised: 06/08/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Crocetin (CCT) is a natural saffron-derived apocarotenoid that possesses healthy properties such as anti-adipogenic, anti-inflammatory, and antioxidant activities. Lipolysis is enhanced in obesity and correlates with a pro-inflammatory, pro-oxidant state. In this context, we aimed to investigate whether CCT affects lipolysis. To evaluate CCT's possible lipolytic effect, 3T3-L1 adipocytes were treated with CCT10μM at day 5 post-differentiation. Glycerol content and antioxidant activity were assessed using colorimetric assays. Gene expression was measured using qRT-PCR to evaluate the effect of CCT on key lipolytic enzymes and on nitric oxide synthase (NOS) expression. Total lipid accumulation was assessed using Oil Red O staining. CCT10μM decreased glycerol release from 3T3-L1 adipocytes and downregulated adipose tissue triglyceride lipase (ATGL) and perilipin-1, but not hormone-sensitive lipase (HSL), suggesting an anti-lipolytic effect. CCT increased catalase (CAT) and superoxide dismutase (SOD) activity, thus showing an antioxidant effect. In addition, CCT exhibited an anti-inflammatory profile, i.e., diminished inducible NOS (NOS2) and resistin expression, while enhanced the expression of adiponectin. CCT10μM also decreased intracellular fat and C/EBPα expression (a transcription factor involved in adipogenesis), thus revealing an anti-adipogenic effect. These findings point to CCT as a promising biocompound for improving lipid mobilisation in obesity.
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Affiliation(s)
- Francisco J Cimas
- Mecenazgo COVID-19, Regional Center for Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), 02008 Albacete, Spain
| | - Miguel Ángel De la Cruz-Morcillo
- Food Quality Research Group, Institute for Regional Development (IDR), Campus Universitario s/n, University of Castilla-La Mancha (UCLM), 02071 Albacete, Spain
| | - Carmen Cifuentes
- Regional Center for Biomedical Research (CRIB), Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha (UCLM), 02008 Albacete, Spain
| | - Natalia Moratalla-López
- Cátedra de Química Agrícola, Higher Technical School of Agronomic and Forestry Engineering and Biotechnology (ETSIAMB), University of Castilla-La Mancha (UCLM), Campus Universitario, 02006 Albacete, Spain
| | - Gonzalo L Alonso
- Cátedra de Química Agrícola, Higher Technical School of Agronomic and Forestry Engineering and Biotechnology (ETSIAMB), University of Castilla-La Mancha (UCLM), Campus Universitario, 02006 Albacete, Spain
| | - Eduardo Nava
- Regional Center for Biomedical Research (CRIB), Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha (UCLM), 02008 Albacete, Spain
| | - Sílvia Llorens
- Regional Center for Biomedical Research (CRIB), Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha (UCLM), 02008 Albacete, Spain
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Rakib A, Mandal M, Showkat A, Kiran S, Mazumdar S, Singla B, Bajwa A, Kumar S, Park F, Singh UP. Piceatannol induces regulatory T cells and modulates the inflammatory response and adipogenesis. Biomed Pharmacother 2023; 161:114514. [PMID: 36921534 PMCID: PMC10071559 DOI: 10.1016/j.biopha.2023.114514] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023] Open
Abstract
The beneficial effects of the polyphenolic compound piceatannol (PC) has been reported for metabolic diseases, antiproliferative, antioxidant, and anti-cancer properties. Despite its beneficial effects on inflammatory diseases, little is known about how PC regulates inflammatory responses and adipogenesis. Therefore, this study was designed to determine the effects of PC on the inflammatory response and adipogenesis. The effect of PC on splenocytes, 3T3-L1 adipocytes, and RAW264.7 macrophages was analyzed by flow cytometry, qRT-PCR, morphometry, and western blot analysis. PC induced apoptosis in activated T cells in a dose-dependent manner using stimulated splenocytes and reduced the activation of T cells, altered T cell frequency, and interestingly induced the frequency of regulatory T (Treg) cells as compared to controls. PC suppressed the expression of TNF-α, iNOS, IL-6R, and NF-κB activation in RAW264.7 macrophages after lipopolysaccharides (LPS)-induction as compared to the control. Interestingly, PC altered the cell morphology of 3T3-L1 adipocytes with a concomitant decrease in cell volume, lipid deposition, and TNF-α expression, but upregulation of leptin and IL-1β. Our findings suggested that PC induced apoptosis in activated T cells, decreased immune cell activation and inflammatory response, and hindered adipogenesis. This new set of data provides promising hope as a new therapeutic to treat both inflammatory disease and obesity.
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Affiliation(s)
- Ahmed Rakib
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Mousumi Mandal
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Anaum Showkat
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Sonia Kiran
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Soumi Mazumdar
- Department of Physiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Bhupesh Singla
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Aman Bajwa
- Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA; Department of Genetics, Genomics, and Informatics, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Santosh Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Frank Park
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Udai P Singh
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA.
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Kong Y, Liu C, Zhang X, Liu X, Li W, Li F, Wang X, Yue X. Characterization of fatty acid compositions in longissimus thoracis muscle and identification of candidate gene and SNPs related to polyunsaturated fatty acid in Hu sheep. J Anim Sci 2023; 101:skac382. [PMID: 36394948 PMCID: PMC9833039 DOI: 10.1093/jas/skac382] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022] Open
Abstract
Fatty acid (FA) composition contributes greatly to the quality and nutritional value of lamb meat. In the present study, FA was measured in longissimus thoracis (LT) muscles of 1,085 Hu sheep using gas chromatography. Comparative transcriptomic analysis was conducted in LT muscles to identify differentially expressed genes (DEGs) between six individuals with high polyunsaturated fatty acids (H-PUFA, 15.27% ± 0.42%) and six with low PUFA (L-PUFA, 5.22% ± 0.25%). Subsequently, the single nucleotide polymorphisms (SNPs) in a candidate gene PLIN2 were correlated with FA traits. The results showed a total of 29 FA compositions and 8 FA groups were identified, with the highest content of monounsaturated fatty acids (MUFA, 46.54%, mainly C18:1n9c), followed by saturated fatty acids (SFA, 44.32%, mainly C16:0), and PUFA (8.72%, mainly C18:2n6c), and significant correlations were observed among the most of FA traits. Transcriptomic analyses identified 110 upregulated and 302 downregulated DEGs between H-PUFA and L-PUFA groups. The functional enrichment analysis revealed three significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and 17 gene ontology (GO) terms, in which regulation of lipolysis in adipocytes, the AMPK signaling pathway, and the PPAR signaling pathway may play important roles in FA metabolism and biosynthesis. In addition, weighted gene co-expression network analysis (WGCNA) identified 37 module genes associated with PUFA-related traits. In general, PLIN1, LIPE, FABP4, LEP, ACACA, ADIPOQ, SCD, PCK2, FASN, PLIN2, LPL, FABP3, THRSP, and ACADVL may have a great impact on PUFA metabolism and lipid deposition. Four SNPs within PLIN2 were significantly associated with FA. Of those, SNP1 (g.287 G>A) was significantly associated with C18:1n9c and MUFA, and SNP4 (g.7807 T>C) was significantly correlated with PUFA (C18:3n3). In addition, the combined genotype of SNP1 (g.287 G>A), SNP3 (g.7664 T>C), and SNP4 (g.7807 T>C) were significantly correlated with C16:1, C17:0, C18:1C6, PUFA (C18:3n3, C22:6n3), and n-6/n-3 PUFA. These results contribute to the knowledge of the biological mechanisms and genetic markers involved in the composition of FA in Hu sheep.
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Affiliation(s)
- Yuanyuan Kong
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Engineering Research Center of Grassland Industry, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - Chongyang Liu
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Engineering Research Center of Grassland Industry, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - Xueying Zhang
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Engineering Research Center of Grassland Industry, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - Xing Liu
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Engineering Research Center of Grassland Industry, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - Wenqiao Li
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Engineering Research Center of Grassland Industry, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - Fadi Li
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Engineering Research Center of Grassland Industry, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
| | - Xinji Wang
- Extension Station of Animal Husbandry and Veterinary Medicine in Minqin, Minqin County 733300, China
| | - Xiangpeng Yue
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems; Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs; Engineering Research Center of Grassland Industry, Ministry of Education; College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, China
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Khan MM. Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia. World J Psychiatry 2022; 12:827-842. [PMID: 35978970 PMCID: PMC9258274 DOI: 10.5498/wjp.v12.i6.827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/03/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) and impaired energy expenditure (IEE) are irreparable metabolic comorbidities in schizophrenia. Although mechanism(s) underlying IR and IEE remains unclear, leptin and fatty acid signaling, which has profound influence on insulin secretion/sensitivity, glucose metabolism and energy expenditure, could be disrupted. However, no association of plasma leptin with erythrocyte membrane fatty acids, body mass index (BMI), and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis (FEP) or medicated patients with chronic schizophrenia (CSZ) is presented before. These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia. AIM To determine the association between plasma leptin, erythrocyte membrane fatty acids, particularly, saturated fatty acids (SFAs), BMI and psychotic symptoms in patients with FEP and CSZ. METHODS In this study, twenty-two drug naive patients with FEP, twenty-one CSZ patients treated with atypical antipsychotic drugs, and fourteen healthy control (CNT) subjects were analyzed. Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay. Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography. BMI was calculated by using the formula: weight (kg)/height (m2). Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale (BPRS), and positive and negative syndrome scale (PANSS). The total BPRS scores, positive and negative symptom scores (PANSS-PSS and PANSS-NSS, respectively) were recorded. Pearson correlation coefficient (r) analyses were performed to find the nature and strength of association between plasma leptin, PANSS scores, BMI and SFAs, particularly, palmitic acid (PA). RESULTS In patients with FEP, plasma leptin not BMI was significantly lower (P = 0.034), whereas, erythrocyte membrane SFAs were significantly higher (P < 0.005) compared to the CNT subjects. Further, plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA (r = -0.4972, P = 0.001), PANSS-PSS (r = -0.4034, P = 0.028), and PANSS-NSS (r = -0.3487, P = 0.048). However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS (r = 0.5844, P = 0.0034) and PANSS-NSS (r = 0.5380, P = 0.008). In CSZ patients, plasma leptin, BMI, and erythrocyte membrane SFAs, all were significantly higher (P < 0.05) compared to the CNT subjects. Plasma leptin showed positive correlation with BMI (r = 0.312, P = 0.032) but not with PANSS scores or erythrocyte membrane SFAs-PA. However, erythrocyte membrane SFAs-PA showed positive correlation with PANSS-NSS only (r = 0.4729, P = 0.031). Similar changes in the plasma leptin and erythrocyte membrane SFAs have also been reported in individuals at ultra-high risk of developing psychosis; therefore, the above findings suggest that leptin-fatty acid biosynthesis could be disrupted before the onset of psychosis in schizophrenia. CONCLUSION Disrupted leptin-fatty acid biosynthesis/signaling could be an early manifestation of metabolic comorbidities in schizophrenia. Large-scale studies are warranted to validate the above findings.
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Affiliation(s)
- Mohammad M Khan
- Laboratory of Translational Neurology and Molecular Psychiatry, Department of Biotechnology, Era's Lucknow Medical College and Hospital, and Faculty of Science, Era University, Lucknow 226003, India
- Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States
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10
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Abstract
Leptin is a hormone primarily produced by the adipose tissue in proportion to the size of fat stores, with a primary function in the control of lipid reserves. Besides adipose tissue, leptin is also produced by other tissues, such as the stomach, placenta, and mammary gland. Altogether, leptin exerts a broad spectrum of short, medium, and long-term regulatory actions at the central and peripheral levels, including metabolic programming effects that condition the proper development and function of the adipose organ, which are relevant for its main role in energy homeostasis. Comprehending how leptin regulates adipose tissue may provide important clues to understand the pathophysiology of obesity and related diseases, such as type 2 diabetes, as well as its prevention and treatment. This review focuses on the physiological and long-lasting regulatory effects of leptin on adipose tissue, the mechanisms and pathways involved, its main outcomes on whole-body physiological homeostasis, and its consequences on chronic diseases.
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Affiliation(s)
- Catalina Picó
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands. CIBER de Fisiopatología de La Obesidad Y Nutrición (CIBEROBN). Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
| | - Mariona Palou
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands. CIBER de Fisiopatología de La Obesidad Y Nutrición (CIBEROBN). Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
| | - Catalina Amadora Pomar
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands. CIBER de Fisiopatología de La Obesidad Y Nutrición (CIBEROBN). Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
| | - Ana María Rodríguez
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands. CIBER de Fisiopatología de La Obesidad Y Nutrición (CIBEROBN). Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain.
| | - Andreu Palou
- Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics, Biomarkers and Risk Evaluation), University of the Balearic Islands. CIBER de Fisiopatología de La Obesidad Y Nutrición (CIBEROBN). Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain
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Assinder SJ, Boumelhem BB. Oxytocin stimulates lipolysis, prostaglandin E 2 synthesis, and leptin secretion in 3T3-L1 adipocytes. Mol Cell Endocrinol 2021; 534:111381. [PMID: 34216640 DOI: 10.1016/j.mce.2021.111381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/01/2021] [Accepted: 06/29/2021] [Indexed: 11/26/2022]
Abstract
A model of oxytocin in the regulation of metabolic status has described one of oxytocin synthesis and release from the neurohypophysis in response to leptin, to suppress further leptin release. In addition, a lipogenic role for oxytocin has been suggested, consistent with an insulinergic action. This model, however, may be incorrect. Oxytocin reduces fat mass in the absence of either leptin or leptin receptor signalling, thereby challenging the interdependence between leptin and oxytocin. An oxytocin induced production of the anti-lipolytic prostaglandin E2 (PGE2) might account for this. Media from 3T3-L1 differentiated adipocytes treated with oxytocin (0-50 nmol.L-1) for 24 hrs were assayed for PGE2, leptin, adiponectin, and glycerol. Harvested cells were analysed for lipid droplet triglyceride and cytosolic free fatty acid (FFA) by flow cytometry, and for altered expression of lipolytic and lipogenic associated gene ontology transcripts by cDNA array. Both PGE2 and leptin secretion were significantly increased by oxytocin treatment whilst adiponectin secretion was not. A significant increase in cytosolic FFA was detected following oxytocin treatment, similar to that determined following treatment with isoproterenol (positive control). A significant increase in glycerol release to the culture media confirmed a lipolytic effect. No enrichment of lipolytic and lipogenic associated gene ontology transcripts was determined, but significant overrepresentation of chemosensory olfactory transcripts was. In conclusion, oxytocin stimulates lipolysis in 3T3-L1 adipocytes, mediated by autocrine/paracrine actions of PGE2 and leptin. To confirm that this response is mediated solely by the oxytocin receptor, further experiments would require those effects being blocked by a specific oxytocin antagonist.
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Affiliation(s)
- Stephen J Assinder
- Discipline of Physiology, School of Medical Science and Bosch Institute, Faculty of Medicine and Health, University of Sydney, Australia.
| | - Badwi B Boumelhem
- Discipline of Physiology, School of Medical Science and Bosch Institute, Faculty of Medicine and Health, University of Sydney, Australia
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12
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Mannino F, Pallio G, Bitto A, Altavilla D, Minutoli L, Squadrito V, Arcoraci V, Giorgi DA, Pirrotta I, Squadrito F, Irrera N. Targeting Adenosine Receptor by Polydeoxyribonucleotide: An Effective Therapeutic Strategy to Induce White-to-Brown Adipose Differentiation and to Curb Obesity. Pharmaceuticals (Basel) 2021; 14:ph14080728. [PMID: 34451825 PMCID: PMC8402160 DOI: 10.3390/ph14080728] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 11/16/2022] Open
Abstract
Obesity is a worldwide chronic metabolic disease characterized by an abnormal fat accumulation and represents one of the main risk factors for several diseases. White adipose tissue is the primary site for energy storage in the form of triglycerides, whereas brown adipose tissue does not store energy-providing lipids but rather dissipates it by producing heat. White-to-brown adipocyte trans-differentiation could represent a new target of anti-obesity strategies and result in fat reduction. Previous studies indicated that adenosine receptor activation induces trans-differentiation of white adipocytes to brown adipocytes. The aim of this study was to evaluate the effects of polydeoxyribonucleotide (PDRN), an A2Ar receptor agonist, in an in vitro model of browning. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes with specific culture media and then treated with PDRN (10 µg/mL), PDRN + ZM241385 (1 µM), CGS21680 (1 µM) and CGS + ZM241385 for 24 h. Cell viability was studied by MTT assay, and browning induction was evaluated by Oil Red O staining and by RT-qPCR to study gene expression of browning markers. PDRN, as well as CGS21680, reduced the accumulation of lipids, cell volume and lipid droplet size; increased the expression of UCP1, PRDM16 and DIO2, considered as browning markers; and reduced the expression of FASn and FABP4, considered as whitening markers. In addition, PDRN decreased leptin expression and enhanced adiponectin mRNA levels. All these effects were abrogated when PDRN was co-incubated with the A2Ar antagonist ZM241385. In conclusion, these results suggest that PDRN is able to induce the white-to-brown adipose differentiation through A2Ar stimulation. Since PDRN is a safe drug already available in the market for other therapeutic indications, its “anti-obesity” potential warrants investigation in a clinical scenario.
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Affiliation(s)
- Federica Mannino
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
| | - Giovanni Pallio
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
| | - Alessandra Bitto
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
| | - Domenica Altavilla
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy;
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
| | - Violetta Squadrito
- Department of Human Pathology and Evolutive Age “Gaetano Barresi”, University of Messina, Via C. Valeria, 98125 Messina, Italy;
| | - Vincenzo Arcoraci
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
| | - Domenico Antonio Giorgi
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
| | - Igor Pirrotta
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
| | - Francesco Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
- Correspondence:
| | - Natasha Irrera
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (F.M.); (G.P.); (A.B.); (L.M.); (V.A.); (D.A.G.); (I.P.); (N.I.)
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Cook K, Ali O, Akinci B, Foss de Freitas MC, Montenegro RM, Fernandes VO, Gupta D, Lou KJ, Tuttle E, Oral EA, Brown RJ. Effect of Leptin Therapy on Survival in Generalized and Partial Lipodystrophy: A Matched Cohort Analysis. J Clin Endocrinol Metab 2021; 106:e2953-e2967. [PMID: 33822100 PMCID: PMC8277211 DOI: 10.1210/clinem/dgab216] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Indexed: 12/16/2022]
Abstract
CONTEXT Data quantifying the impact of metreleptin therapy on survival in non-human immunodeficiency virus (HIV)-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) are unavailable. OBJECTIVE This study aimed to estimate the treatment effect of metreleptin on survival in patients with GL and PL. DESIGN/SETTING/PATIENTS Demographic and clinical characteristics were used to match metreleptin-treated and metreleptin-naïve patients with GL and PL. Differences in mortality risk were estimated between matched cohorts of metreleptin-treated and metreleptin-naïve patient cohorts using Cox proportional hazard models. Sensitivity analyses assessed the impact of study assumptions and the robustness of results. OUTCOME MEASURES This study assessed time-to-mortality and risk of mortality. RESULTS The analysis evaluated 103 metreleptin-naïve patients with characteristics matched to 103 metreleptin-treated patients at treatment initiation. Even after matching, some metabolic and organ abnormalities were more prevalent in the metreleptin-treated cohort due to bias toward treating more severely affected patients. A Cox proportional hazards model associated metreleptin therapy with an estimated 65% decrease in mortality risk (hazard ratio [HR] 0.348, 95% confidence interval (CI): 0.134-0.900; P = 0.029) even though the actual number of events were relatively small. Results were robust across a broad range of alternate methodological assumptions. Kaplan-Meier estimates of time-to-mortality for the metreleptin-treated and the matched metreleptin-naïve cohorts were comparable. CONCLUSIONS Metreleptin therapy was associated with a reduction in mortality risk in patients with lipodystrophy syndromes despite greater disease severity in treated patients, supporting the view that metreleptin can have a positive disease-modifying impact. Confirmatory studies in additional real-world and clinical datasets are warranted.
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Affiliation(s)
- Keziah Cook
- Analysis Group Inc., Menlo Park, CA 94025, USA
| | - Omer Ali
- Analysis Group Inc., Menlo Park, CA 94025, USA
| | | | | | | | | | | | - Kai-Jye Lou
- Analysis Group Inc., Menlo Park, CA 94025, USA
| | | | - Elif A Oral
- Metabolism, Endocrine and Diabetes Division, Brehm Center for Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rebecca J Brown
- National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD 20814, USA
- Correspondence: Rebecca J. Brown, MD, Lasker Tenure Track Investigator, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20814, USA. E-mail:
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14
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Secoisolariciresinol Diglucoside Regulates Adipose Tissue Metabolic Disorder in Obese Mice Induced by a Western Diet. J FOOD QUALITY 2021. [DOI: 10.1155/2021/5580772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Secoisolariciresinol diglucoside (SDG) is the main component of flax lignans. Current studies have reported a positive effect of SDG on obesity and metabolic diseases. SDG has strong blood fat- and blood sugar-lowering, anti-inflammatory, and antioxidant effects and prevents heart disease and other chronic diseases. In this study, we explored the effects of SDG on Western diet-induced obesity and lipid metabolic disorder. Supplementing Western diet-induced obese mice with 40 mg kg1 d1, SDG for 12 weeks significantly reduced body and tissue weights. Increased adiponectin levels and decreased serum leptin and resistin levels were observed in obese mice orally administered SDG. Proliferation of adipose tissue was observed by hematoxylin and eosin staining, and cell size was quantitatively analyzed. As a result, SDG inhibited the proliferation of adipose tissue. In addition, SDG suppressed the mRNA expression of lipid synthetic genes and upregulated the mRNA expression of lipolytic genes. Overall, these results indicate that SDG inhibits obesity induced by a Western diet and regulates adipose tissue metabolic disorder. These results provide a theoretical basis for further study on the regulation of obesity and lipid metabolic disorder caused by SDG.
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15
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Son M, Oh S, Choi J, Jang JT, Choi CH, Park KY, Son KH, Byun K. The Phlorotannin-Rich Fraction of Ecklonia cava Extract Attenuated the Expressions of the Markers Related with Inflammation and Leptin Resistance in Adipose Tissue. Int J Endocrinol 2020; 2020:9142134. [PMID: 32215011 PMCID: PMC7081028 DOI: 10.1155/2020/9142134] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 12/26/2019] [Accepted: 01/13/2020] [Indexed: 12/11/2022] Open
Abstract
Obesity is associated with systemic chronic inflammation, and it induces central leptin resistance which blocks the appetite-suppressing effect of leptin and leptin resistance in adipocytes. In the present study, we evaluated the effects of Ecklonia cava extract (ECE), which contained rich phlorotannins, on inflammation and leptin resistance in the adipose tissue of a diet-induced obese model. Effects of ECE on fat deposition, inflammation, M1/M2 macrophage, and T-cell infiltrations were investigated, and leptin resistance and SOCS3 were also measured in adipose tissue. Furthermore, ECE attenuated the expression of inflammation-related receptors such as TLR4 and RAGE and leptin resistance by reducing SOCS3 expression, increasing expression of leptin receptor in adipose tissue, and increasing lipolysis. ECE showed antiadiposity and anti-inflammatory effects, attenuated leptin resistance, and increased lipolysis in the diet-induced obese model. This study shows that ECE is a suitable dietary supplement candidate for the prevention or treatment of obesity or obesity-associated diseases, especially inflammation-related diseases.
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Affiliation(s)
- Myeongjoo Son
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Junwon Choi
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Ji Tae Jang
- Aqua Green Technology Co., Ltd., Smart Bldg., Jeju Science Park, Jeju 63309, Republic of Korea
| | - Chang Hu Choi
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kook Yang Park
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
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Frasca D, Diaz A, Romero M, Blomberg BB. Leptin induces immunosenescence in human B cells. Cell Immunol 2019; 348:103994. [PMID: 31831137 DOI: 10.1016/j.cellimm.2019.103994] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/14/2019] [Accepted: 10/15/2019] [Indexed: 11/16/2022]
Abstract
Leptin is an adipokine secreted primarily by the adipocytes. Leptin has endocrine and immune functions and increases the secretion of pro-inflammatory cytokines by immune cells. Here we show that incubation of B cells from young lean individuals with leptin increases the frequencies of pro-inflammatory B cells and induces intrinsic B cell inflammation, characterized by mRNA expression of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (IL-8), micro-RNAs (miR-155 and miR-16), TLR4 and p16, a cell cycle regulator associated with immunosenescence. We have previously shown that the expression of these pro-inflammatory markers in unstimulated B cells is negatively associated with the response of the same B cells after in vivo or in vitro stimulation. B cells from young lean individuals, after in vitro incubation with leptin, show reduced class switch and influenza vaccine-specific IgG production. Our results altogether show that leptin makes B cells from youn lean individuals similar to those from young obese and elderly lean individuals, suggesting that leptin may be a mechanisms of immunosenescence in human B cells.
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Affiliation(s)
- Daniela Frasca
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Alain Diaz
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Maria Romero
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Bonnie B Blomberg
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
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Trichur Khabeer S, Prashant A, Haravey Krishnan M. Dietary fatty acids from pomegranate seeds (Punica granatum) inhibit adipogenesis and impact the expression of the obesity-associated mRNA transcripts in human adipose-derived mesenchymal stem cells. J Food Biochem 2018; 43:e12739. [PMID: 31353555 DOI: 10.1111/jfbc.12739] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 10/10/2018] [Accepted: 11/04/2018] [Indexed: 11/30/2022]
Abstract
Obesity is a metabolic disorder that manifests into various forms. Recent studies have indicated that the pomegranate (Punica granatum) seed oil (PSO) has many biologically active components that help in controlling diet-induced obesity and insulin resistance. However, its impact on the adipogenic differentiation of human adipose-derived mesenchymal stem cells (HADMSC) remains unclear. Here we have attempted to study the anti-obesity potential of SHAMstat3pg, a fatty acid composite extracted from PSO. It is composed of three dietary fatty acids: punicic acid [(9Z,11E,13Z)-9,11,13-Octadecatrienoic acid], oleic acid [Cis-9-Octadecenoic acid], and linoleic acid [(9Z,12Z)-octadeca-9,12-dienoic acid]. In this study, we discuss the impact of the fatty acids on adipogenesis, inflammation, glucose uptake, and mitochondrial ATP production. The impact of SHAMstat3pg on the expression of various obesity-associated protein and mRNA transcripts in HADMSC was also analyzed. The results indicate that exposure to 10 µg/ml of SHAMstat3pg (24 hr) inhibited adipogenesis of HADMSC, ameliorated inflammation, attenuated ATP production, and glucose uptake. Also, the extract favorably regulated the mRNA expression of the studied obesity-associated gene transcripts. PRACTICAL APPLICATIONS: SHAMstat3pg has the potential to serve as a multi-targeted therapy for the management of obesity. This study demonstrated that the dietary fatty acids inhibited the differentiation of preadipocytes to adipocytes. SHAMstat3pg has also shown to have a favorable impact on the expression of the obesity-linked proteins and genes in HADMSC that are associated with adipogenesis, inflammation, satiety, energy intake/expenditure (central and peripheral signaling molecules). The study gives an overview of the vast number of genes impacted by the treatment with SHAMstat3pg paving the way for future studies to demonstrate the exact mode of action of how dietary fatty acids can help manage obesity, insulin resistance, and type 2 diabetes.
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Affiliation(s)
- Shamsiya Trichur Khabeer
- Department of Food Protectants & Infestation Control, Central Food Technological Research Institute (CSIR - CFTRI), Mysore, India.,Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
| | - Akila Prashant
- Centre of Excellence in Molecular Biology and Regenerative Medicine, Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Manonmani Haravey Krishnan
- Department of Food Protectants & Infestation Control, Central Food Technological Research Institute (CSIR - CFTRI), Mysore, India
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18
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Kirchberg FF, Brandt S, Moß A, Peissner W, Koenig W, Rothenbacher D, Brenner H, Koletzko B, Hellmuth C, Wabitsch M. Metabolomics reveals an entanglement of fasting leptin concentrations with fatty acid oxidation and gluconeogenesis in healthy children. PLoS One 2017; 12:e0183185. [PMID: 28817652 PMCID: PMC5560563 DOI: 10.1371/journal.pone.0183185] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 07/31/2017] [Indexed: 12/31/2022] Open
Abstract
Background Leptin and adiponectin communicate with organ systems in order to regulate energetic and metabolic homeostasis. Their different points of action have been well characterized; however, no study has investigated their interrelationship with the metabolism at the molecular level in vivo. Objective To examine the associations of leptin and adiponectin with the metabolic profile reflecting the intercellular and interorgan communication as well as activated metabolic pathways. Patients/Methods We measured plasma concentrations of leptin, adiponectin, and insulin along with concentrations of 196 metabolites in 400 healthy, fasting 8-years old German children who participated in the German Ulm Birth Cohort Study (UBCS). Using multiple linear mixed models, we evaluated the associations between hormones and metabolites. Results Leptin levels increased exponentially with increasing BMI. Leptin was furthermore strongly associated with alanine and aspartate (Bonferroni corrected P[PBF] = 5.7×10−8 and 1.7×10−6, respectively), and negatively associated to the sum of the non-esterified fatty acids (NEFA) and the sum of the long-chain acylcarnitines C12–C18 (PBF = 0.009 and 0.0001, respectively). Insulin showed a similar association pattern, although the associations were less strong than for leptin. Adiponectin was neither related to BMI nor to any metabolite. Conclusion Although children were presumably metabolically similar, we found strong associations of insulin and leptin with the metabolite profile. High alanine concentrations and the lower concentrations of NEFA in children with high fasting leptin concentrations might arise from an increased gluconeogenesis and from the disinhibiting effect of leptin on the carnitine-palmitoyltransferase-1, respectively. As insulin had the same trend towards these associations, both hormones seem to be related to processes that provide the body with energy in fasting state.
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Affiliation(s)
- Franca Fabiana Kirchberg
- Ludwig-Maximilians-Universität München, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, Munich, Germany
| | - Stephanie Brandt
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany
| | - Anja Moß
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany
| | - Wolfgang Peissner
- Ludwig-Maximilians-Universität München, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, Munich, Germany
| | - Wolfgang Koenig
- Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | | | - Hermann Brenner
- German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany
| | - Berthold Koletzko
- Ludwig-Maximilians-Universität München, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, Munich, Germany
- * E-mail:
| | - Christian Hellmuth
- Ludwig-Maximilians-Universität München, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, Munich, Germany
| | - Martin Wabitsch
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany
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19
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Liu X, Cao G, Zhou J, Yao X, Fang B. The effects of Bacillus coagulans-fermented and non-fermented Ginkgo biloba on abdominal fat deposition and meat quality of Peking duck. Poult Sci 2017; 96:2264-2273. [DOI: 10.3382/ps/pex017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 01/06/2017] [Indexed: 12/22/2022] Open
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20
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Contreras GA, Strieder-Barboza C, Raphael W. Adipose tissue lipolysis and remodeling during the transition period of dairy cows. J Anim Sci Biotechnol 2017; 8:41. [PMID: 28484594 PMCID: PMC5420123 DOI: 10.1186/s40104-017-0174-4] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 04/11/2017] [Indexed: 12/12/2022] Open
Abstract
Elevated concentrations of plasma fatty acids in transition dairy cows are significantly associated with increased disease susceptibility and poor lactation performance. The main source of plasma fatty acids throughout the transition period is lipolysis from adipose tissue depots. During this time, plasma fatty acids serve as a source of calories mitigating the negative energy balance prompted by copious milk synthesis and limited dry matter intake. Past research has demonstrated that lipolysis in the adipose organ is a complex process that includes not only the activation of lipolytic pathways in response to neural, hormonal, or paracrine stimuli, but also important changes in the structure and cellular distribution of the tissue in a process known as adipose tissue remodeling. This process involves an inflammatory response with immune cell migration, proliferation of the cellular components of the stromal vascular fraction, and changes in the extracellular matrix. This review summarizes current knowledge on lipolysis in dairy cattle, expands on the new field of adipose tissue remodeling, and discusses how these biological processes affect transition cow health and productivity.
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Affiliation(s)
- G Andres Contreras
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824 USA
| | - Clarissa Strieder-Barboza
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824 USA
| | - William Raphael
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824 USA
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21
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Stern JH, Rutkowski JM, Scherer PE. Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk. Cell Metab 2016; 23:770-84. [PMID: 27166942 PMCID: PMC4864949 DOI: 10.1016/j.cmet.2016.04.011] [Citation(s) in RCA: 729] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Metabolism research has made tremendous progress over the last several decades in establishing the adipocyte as a central rheostat in the regulation of systemic nutrient and energy homeostasis. Operating at multiple levels of control, the adipocyte communicates with organ systems to adjust gene expression, glucoregulatory hormone exocytosis, enzymatic reactions, and nutrient flux to equilibrate the metabolic demands of a positive or negative energy balance. The identification of these mechanisms has great potential to identify novel targets for the treatment of diabetes and related metabolic disorders. Herein, we review the central role of the adipocyte in the maintenance of metabolic homeostasis, highlighting three critical mediators: adiponectin, leptin, and fatty acids.
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Affiliation(s)
- Jennifer H Stern
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Joseph M Rutkowski
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Padmanabhan M, Arumugam G. Effect of Persea americana (avocado) fruit extract on the level of expression of adiponectin and PPAR-γ in rats subjected to experimental hyperlipidemia and obesity. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2015; 11:107-19. [PMID: 24770838 DOI: 10.1515/jcim-2013-0053] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 03/24/2014] [Indexed: 12/25/2022]
Abstract
BACKGROUND Persea americana, commonly known as avocado, is traditionally consumed fruit which possesses body fat lowering capacity. Adiponectin plays an important role in regulating obesity. In this study, the effect of hydro-alcoholic fruit extract of P. americana (HAEPA) on the level of blood lipids, glutathione, lipid peroxidation products, adiponectin and peroxisome proliferator activated receptor (PPAR)-γ expressions was investigated in rats fed a high-fat diet (HFD). METHODS Male Sprague Dawley rats were divided into four groups: groups 1 and 2 were fed normal rat chow (5% fat) and groups 3 and 4 were fed HFD (23% fat) for a period of 14 weeks. In addition, groups 2 and 4 rats were administered orally with 100 mg/kg body weight of HAEPA from third week. After 14 weeks, rats were sacrificed, and serum/plasma levels of total cholesterol, phospholipids, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and adiponectin were determined. The mRNA expression of adiponectin, PPAR-γ and protein expression of PPAR-γ were also evaluated. RESULTS The body mass index (BMI), total fat pad mass and adiposity index were significantly decreased in HAEPA co-administered rats than in HFD-fed rats. The levels of LDL and lipid peroxides were significantly higher in HFD group than in HFD+HAEPA group. Levels of reduced glutathione, adiponectin, mRNA expression of adiponectin, PPAR-γ and protein expression of PPAR-γ were found to be increased in HFD+HAEPA group than in HFD group. The hypolipidemic effect of HAEPA is also evidenced by the histological observations in liver, heart and adipose tissue. CONCLUSIONS The results indicate that HAEPA exhibits hypolipidemic activity probably by increasing the mRNA expression of adiponectin and PPAR-γ, which reduce the risk of hyperlipidemia and obesity.
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Harris RBS. Direct and indirect effects of leptin on adipocyte metabolism. Biochim Biophys Acta Mol Basis Dis 2013; 1842:414-23. [PMID: 23685313 DOI: 10.1016/j.bbadis.2013.05.009] [Citation(s) in RCA: 199] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 04/18/2013] [Accepted: 05/06/2013] [Indexed: 12/22/2022]
Abstract
Leptin is hypothesized to function as a negative feedback signal in the regulation of energy balance. It is produced primarily by adipose tissue and circulating concentrations correlate with the size of body fat stores. Administration of exogenous leptin to normal weight, leptin responsive animals inhibits food intake and reduces the size of body fat stores whereas mice that are deficient in either leptin or functional leptin receptors are hyperphagic and obese, consistent with a role for leptin in the control of body weight. This review discusses the effect of leptin on adipocyte metabolism. Because adipocytes express leptin receptors there is the potential for leptin to influence adipocyte metabolism directly. Adipocytes also are insulin responsive and receive sympathetic innervation, therefore leptin can also modify adipocyte metabolism indirectly. Studies published to date suggest that direct activation of adipocyte leptin receptors has little effect on cell metabolism in vivo, but that leptin modifies adipocyte sensitivity to insulin to inhibit lipid accumulation. In vivo administration of leptin leads to a suppression of lipogenesis, an increase in triglyceride hydrolysis and an increase in fatty acid and glucose oxidation. Activation of central leptin receptors also contributes to the development of a catabolic state in adipocytes, but this may vary between different fat depots. Leptin reduces the size of white fat depots by inhibiting cell proliferation both through induction of inhibitory circulating factors and by contributing to sympathetic tone which suppresses adipocyte proliferation. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.
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Affiliation(s)
- Ruth B S Harris
- Department of Physiology, Medical College of Georgia, Georgia Regents University, USA.
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Pagano C, Dorigo A, Nisoli E, Tonello C, Calcagno A, Tami V, Granzotto M, Carruba MO, Federspil G, Vettor R. Role of Insulin and Free Fatty Acids in the Regulation ofobGene Expression and Plasma Leptin in Normal Rats. ACTA ACUST UNITED AC 2012; 12:2062-9. [PMID: 15687408 DOI: 10.1038/oby.2004.257] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE It is under debate whether free fatty acids (FFAs) play an independent role in the regulation of adipose cell functions. In this study, we evaluated whether leptin secretion induced by FFA is due directly to an increased FFA availability or whether it is mediated by insulin levels. RESEARCH METHODS AND PROCEDURES To test this hypothesis, we compared the effects of six different experimental designs, with different FFA and insulin levels, on plasma leptin: euglycemic clamp, euglycemic clamp + FFA infusion, FFA infusion alone, FFA + somatostatin infusion, somatostatin infusion alone, and saline infusion. RESULTS Our results showed that euglycemic clamp, FFA infusion, or both in combination induced a similar increment of circulating leptin (3.31 +/- 0.30, 3.40 +/- 0.90, and 3.35 +/- 0.80 ng/mL, respectively). Moreover, the inhibition of FFA-induced insulin increase by means of somatostatin infusion completely abolished the rise of leptin in response to FFA (1.05 +/- 0.30 vs. 3.40 +/- 0.90 ng/mL, p < 0.001). DISCUSSION In conclusion, our data showed that the effects of high FFA levels on plasma leptin were mediated by the rise of insulin concentration. These data confirm a major role for insulin in the regulation of leptin secretion from rat adipose tissue and support the hypothesis that leptin secretion is coupled to net triglyceride synthesis in adipose tissue.
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Affiliation(s)
- Claudio Pagano
- Endocrine Metabolic Library, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy.
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Pérez-Montarelo D, Fernández A, Folch JM, Pena RN, Ovilo C, Rodríguez C, Silió L, Fernández AI. Joint effects of porcine leptin and leptin receptor polymorphisms on productivity and quality traits. Anim Genet 2012; 43:805-9. [PMID: 22497241 DOI: 10.1111/j.1365-2052.2012.02338.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/08/2011] [Indexed: 11/26/2022]
Abstract
Leptin signalling plays a fundamental role in growth, fatness and body composition. The aim of this study was to investigate the porcine LEP gene sequence in an Iberian × Landrace experimental cross to identify polymorphisms associated with productivity and quality traits. Because of the documented effects on these traits of the LEPR c.1987C>T polymorphism, the LEP and LEPR c.1987C>T polymorphisms and their interactions have been jointly investigated. The LEP gene sequencing has allowed the identification of 39 polymorphisms, eight of which are novel. Three intronic SNPs, LEP g.1382C>T, LEP g.1387C>T and LEP g.1723A>G, have been genotyped, and association analyses have been carried out. Analyses of LEP g.1387C>T, fully linked to LEP g.1382C>T, have revealed additive effects on live and carcass weights and dominant effects on several backfat thickness measurements. Novel effects of both LEP and LEPR polymorphisms on fatty acid composition in subcutaneous fat have been detected, probably mediated through the effects on fatness. The results reported here suggest that the T alleles of both LEP g.1387C>T and LEPR c.1987C>T, which are fixed in the Iberian pigs, would lead to an increase in growth, fatness and saturated fatty acid content in fat, which could be explained by an increased feed intake.
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Yan K, Deng X, Zhai X, Zhou M, Jia X, Luo L, Niu M, Zhu H, Qiang H, Zhou Y. p38 mitogen-activated protein kinase and liver X receptor-α mediate the leptin effect on sterol regulatory element binding protein-1c expression in hepatic stellate cells. Mol Med 2012; 18:10-8. [PMID: 21979752 DOI: 10.2119/molmed.2011.00243] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 09/30/2011] [Indexed: 12/26/2022] Open
Abstract
Leptin, a key hormone in regulating energy homeostasis, is mainly produced by adipocytes. Cogent evidence indicates a unique role of leptin in the promotion of liver fibrosis. Hepatic stellate cell (HSC) activation is a pivotal step in the process of liver fibrosis. Sterol regulatory element binding protein (SREBP)-1c, a critical transcription factor for lipid synthesis and adipocyte differentiation, functions as a key transcription factor in inhibition of HSC activation. SREBP-1c is highly expressed in quiescent HSCs and downregulated upon HSC activation. The aim of this study is to examine the effect of leptin on SREBP-1c gene expression in HSCs in vitro and in vivo and elucidate the underlying mechanisms. The results of the present study demonstrated that leptin strongly inhibited SREBP-1c expression in HSCs in vivo and in vitro. p38 MAPK was involved in leptin regulation of SREBP-1c expression in cultured HSCs. Leptin-induced activation of p38 MAPK led to the decreases in liver X receptor (LXR)-α protein level, activity and its binding to the SREBP-1c promoter, which caused the downregulation of SREBP-1c expression. Moreover, leptin inhibition of SREBP-1c expression via p38 MAPK increased the expression of alpha1(I) collagen in HSCs. Our results might provide new insights into the mechanisms of the unique role of leptin in the development of liver fibrosis and might have potential implications for clarifying the molecular mechanisms underlying liver fibrosis in diseases in which circulating leptin levels are elevated such as nonalcoholic steatohepatitis, type 2 diabetes mellitus and alcoholic cirrhosis.
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Affiliation(s)
- Kunfeng Yan
- Department of Biochemistry and Molecular Biology, Medical College, Nantong University, Jiangsu, China
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27
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Zajac DM, Cerasale DJ, Landman S, Guglielmo CG. Behavioral and physiological effects of photoperiod-induced migratory state and leptin on Zonotrichia albicollis: II. Effects on fatty acid metabolism. Gen Comp Endocrinol 2011; 174:269-75. [PMID: 21925178 DOI: 10.1016/j.ygcen.2011.08.024] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2010] [Revised: 08/26/2011] [Accepted: 08/30/2011] [Indexed: 10/17/2022]
Abstract
The migratory flights of birds are fuelled largely by fatty acids. Fatty acid transporters, including FAT/CD36, FABPpm and H-FABP, and enzymes involved in fatty acid oxidation (CPT, CS, HOAD) are seasonally up-regulated in flight muscle to meet the demands of this intense aerobic exercise. The mechanisms that control these biochemical changes in response to migration are mostly unknown. We studied the effects of a photoperiod-induced migratory state and a 7 day treatment with murine leptin (1 μg/g body mass, twice per day) on fatty acid metabolism in captive white-throated sparrows. Sparrows that were exposed to a long-day migratory photoperiod increased flight muscle FAT/CD36 and H-FABP mRNA by 154% and 589%, respectively, and had 32% higher H-FABP protein than birds kept on a short-day photoperiod that mimicked wintering conditions. Migrants increased activities of flight muscle CPT, CS and HOAD by 57%, 23% and 74%, respectively, and decreased LDH activity by 31%, reflecting an increase in aerobic relative to anaerobic capacity. The expression of fatty acid transporters and the activities of metabolic enzymes in cardiac muscle were unaffected by migratory state. Leptin had no effect on transport proteins or enzymes in either skeletal or cardiac muscle suggesting that other signaling pathways control fatty acid metabolism during migration. These data indicate that photoperiod alone is sufficient to prime flight muscles for migratory flights by promoting enhanced protein-mediated fatty acid transport and oxidation. However, the endocrine controls and other factors underlying these changes remain to be thoroughly investigated.
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Affiliation(s)
- Daria M Zajac
- Department of Biology, Advanced Facility for Avian Research, University of Western Ontario, London, ON, Canada N6A 5B7
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Kim KY, Kim JY, Sung YY, Jung WH, Kim HY, Park JS, Cheon HG, Rhee SD. Inhibitory effect of leptin on rosiglitazone-induced differentiation of primary adipocytes prepared from TallyHO/Jng mice. Biochem Biophys Res Commun 2011; 406:584-9. [PMID: 21352814 DOI: 10.1016/j.bbrc.2011.02.095] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Accepted: 02/19/2011] [Indexed: 11/25/2022]
Abstract
The effects of leptin on rosiglitazone-induced adipocyte differentiation were investigated in the primary adipocytes prepared from subcutaneous fat of TallyHO/Jng (TallyHO) mouse, a recently developed model animal for type 2 diabetes mellitus (T2DM). The treatment of leptin inhibited the rosiglitazone-induced adipocyte differentiation with a decreased expression of peroxisome proliferator-activated receptor γ (PPARγ) a key adipogenic transcription factor, both in mRNA and protein levels. Leptin (10 nM) was sufficient to inhibit the adipocyte differentiation, which seemed to come from increased expression of leptin receptor genes in the fat of TallyHO mice. The inhibition of adipogenesis by leptin was restored by the treatment of inhibitors for extracellular-signal-regulated kinase (ERK) (PD98059) and signal transducer and activator of transcription-1 (STAT1) (fludarabine). Furthermore, in vivo intraperitoneal administration of PD98059 and fludarabine increased the PPARγ expression in the subcutaneous fat of TallyHO mice. These data suggest that leptin could inhibit the PPARγ expression and adipocyte differentiation in its physiological concentration in TallyHO mice.
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Affiliation(s)
- Ki Young Kim
- Medicinal Science Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong, 305-600 Daejon, Republic of Korea
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Mehebik-Mojaat N, Ribière C, Niang F, Forest C, Jaubert AM. Leptin and insulin induce mutual resistance for nitric oxide synthase III activation in adipocytes. J Cell Biochem 2009; 108:982-8. [DOI: 10.1002/jcb.22331] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Huang ZH, Minshall RD, Mazzone T. Mechanism for endogenously expressed ApoE modulation of adipocyte very low density lipoprotein metabolism: role in endocytic and lipase-mediated metabolic pathways. J Biol Chem 2009; 284:31512-22. [PMID: 19767394 DOI: 10.1074/jbc.m109.004754] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Triglyceride-rich lipoproteins distribute energy in the form of fatty acids to peripheral tissues. We have previously shown that the absence of endogenous adipocyte apoE expression impairs adipocyte triglyceride acquisition from apoE-containing triglyceride-rich lipoproteins in vitro and in vivo. Studies were performed to evaluate the mechanism(s) for this impairment. We excluded a role for secreted apoE in accounting for the difference in very low density lipoprotein (VLDL)-induced adipocyte triglyceride accumulation using cross-incubation studies to show that secreted apoE did not enhance triglyceride synthesis in apoE knockout (EKO) adipocytes incubated with apoE-containing VLDL. Subsequent experiments established that both endocytic and lipase-mediated pathways for lipid acquisition from VLDL were impaired in EKO adipocytes. Binding and internalization of VLDL to EKO adipocytes were significantly lower due to decreased expression or redistribution of low density lipoprotein receptor family proteins. An important role for the VLDL receptor for contributing to differences in VLDL binding between wild-type and EKO adipocytes was identified. Lipoprotein lipase-dependent adipocyte lipogenesis was also significantly decreased in EKO adipocytes even though they secreted as much or more lipolytic activity. This decrease was related to impaired fatty acid internalization in EKO cells. Evaluation of potential mechanisms revealed reduced caveolin-1 and plasma membrane raft expression in EKO adipocytes. Increasing caveolin expression in EKO adipocytes increased fatty acid internalization. Our results establish a role for endogenous adipocyte apoE in VLDL-induced adipocyte lipogenesis by impacting both endocytic and lipoprotein lipase-mediated metabolic pathways. Reduced adipocyte apoE expression, for example that accompanying obesity, will suppress adipocyte acquisition of lipid from apoE-containing VLDL.
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Affiliation(s)
- Zhi Hua Huang
- Department of Medicine, University of Illinois, Chicago, Illinois 60612, USA
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31
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Gaidhu MP, Ceddia RB. Remodeling glucose and lipid metabolism through AMPK activation: relevance for treating obesity and Type 2 diabetes. ACTA ACUST UNITED AC 2009. [DOI: 10.2217/clp.09.30] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Yan GT, Lin J, Hao XH, Xue H, Zhang K, Wang LH. Heart-type fatty acid-binding protein is a useful marker for organ dysfunction and leptin alleviates sepsis-induced organ injuries by restraining its tissue levels. Eur J Pharmacol 2009; 616:244-50. [PMID: 19576209 DOI: 10.1016/j.ejphar.2009.06.039] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Revised: 05/18/2009] [Accepted: 06/22/2009] [Indexed: 12/16/2022]
Abstract
Heart-type fatty acid-binding protein (H-FABP) is widely distributed and has been used to diagnose certain diseases. However, its alteration during infection-evoked organ dysfunction, and the potential association between leptin and it in injury or infection has not been investigated. In the current study, serum H-FABP, leptin, C-reactive protein and interleukin-1beta in the patients with pulmonary infection-induced multiple organ dysfunction were detected. Moreover, a mouse model of sepsis was established, and serum alanine transaminase, uric acid, tissue H-FABP, myeloperoxidase, superoxide dismutase activity and histological alterations in lung and intestine were investigated. Serum H-FABP and leptin increased simultaneously and significantly in the patients, and leptin alleviated pulmonary and intestinal injuries by restraining tissue H-FABP secretions in the mouse model of sepsis. Other investigated variables showed different but independent alterations. In conclusion, H-FABP represents a useful diagnostic marker for organ dysfunction, and its association with leptin will be a novel target for emergency aid.
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Affiliation(s)
- Guang-tao Yan
- Research Laboratory of Biochemistry, Basic Medical Institute, Chinese PLA General Hospital, Beijing, PR China.
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Gaidhu MP, Fediuc S, Anthony NM, So M, Mirpourian M, Perry RLS, Ceddia RB. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL. J Lipid Res 2008; 50:704-15. [PMID: 19050316 DOI: 10.1194/jlr.m800480-jlr200] [Citation(s) in RCA: 163] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
This study was designed to investigate the effects of prolonged activation of AMP-activated protein kinase (AMPK) on lipid partitioning and the potential molecular mechanisms involved in these processes in white adipose tissue (WAT). Rat epididymal adipocytes were incubated with 5'-aminoimidasole-4-carboxamide-1-beta-d-ribofuranoside (AICAR;0.5 mM) for 15 h. Also, epididymal adipocytes were isolated 15 h after AICAR was injected (i.p. 0.7 g/kg body weight) in rats. Adipocytes were utilized for various metabolic assays and for determination of gene expression and protein content. Time-dependent in vivo plasma NEFA concentrations were determined. AICAR treatment significantly increased AMPK activation, inhibited lipogenesis, and increased FA oxidation. This was accompanied by upregulation of peroxisome proliferator-activated receptor (PPAR)alpha, PPARdelta, and PPARgamma-coactivator-1alpha (PGC-1alpha) mRNA levels. Lipolysis was first suppressed, but then increased, both in vitro and in vivo, with prolonged AICAR treatment. Exposure to AICAR increased adipose triglyceride lipase (ATGL) content and FA release, despite inhibition of basal and epinephrine-stimulated hormone-sensitive lipase (HSL) activity. Here, we provide evidence that prolonged AICAR-induced AMPK activation can remodel adipocyte metabolism by upregulating pathways that favor energy dissipation versus lipid storage in WAT. Additionally, we show novel time-dependent effects of AICAR-induced AMPK activation on lipolysis, which involves antagonistic modulation of HSL and ATGL.
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Affiliation(s)
- Mandeep P Gaidhu
- School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
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Kim WK, Lee CY, Kang MS, Kim MH, Ryu YH, Bae KH, Shin SJ, Lee SC, Ko Y. Effects of leptin on lipid metabolism and gene expression of differentiation-associated growth factors and transcription factors during differentiation and maturation of 3T3-L1 preadipocytes. Endocr J 2008; 55:827-37. [PMID: 18497448 DOI: 10.1507/endocrj.k08e-115] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The present study was designed to determine the effects of leptin on lipid metabolism and gene expression during differentiation and maturation of the 3T3-L1 murine preadipocyte. The preadipocytes were induced to differentiate in a growth medium containing 10% calf serum and a hormonal cocktail for 2 days. The cells were next allowed to maturate for 14 days in the growth medium supplemented with 10 microg/ml insulin or 500 ng/ml insulin-like growth factor (IGF)-I in the absence or presence of supplemented leptin. Leptin, at a dose of 5 to 500 ng/ml, had no effect on proliferation of undifferentiated 3T3-L1 cells. However, leptin suppressed the insulin- or IGF-I-stimulated lipid accumulation and enhanced the release of glycerol, a measure of lipolysis, in a dose-dependent manner during and after the maturation of the cell. Moreover, leptin at a dose of 50 ng/ml inhibited IGF-I gene expression during the entire differentiation and maturation and also peroxisome proliferator activated receptor (PPAR)-gamma expression during late maturation as monitored by semi-quantitative reverse transcription-polymerase chain reaction. However, leptin exerted no effect on the expression of transforming growth factor-beta, CCAT/enhancer binding protein-alpha and PPAR-delta. Taken together, results suggest the anti-lipogenic and lipolytic effects of leptin in differentiating and mature adipocytes may have been partly mediated by suppressing the expression of PPAR-gamma and IGF-I genes.
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Affiliation(s)
- Won Kon Kim
- Division of Biotechnology, College of Biosciences and Biotechnology, Korea University, Seoul
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Ribeiro SML, dos Santos ZA, da Silva RJ, Louzada E, Donato J, Tirapegui J. [Leptin: aspects on energetic balance, physical exercise and athletic amenorhea]. ACTA ACUST UNITED AC 2008; 51:11-24. [PMID: 17435851 DOI: 10.1590/s0004-27302007000100005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Accepted: 07/07/2006] [Indexed: 11/22/2022]
Abstract
The aim of this manuscript was to review the knowledge about leptin, detailing its relationship with energetic intake and physical activity. Leptin is an adipocyte hormone, recognized mainly for its putative role in control of energy expenditure, food intake, body weight and reproductive function. Leptin has still important peripheral actions, including its role on the ovarian tissue. The intracellular signaling mechanisms are recognized in hypothalamus, but in peripheral tissue are not fully understood. The exercise, when practiced by women, if not appropriately planned according to food intake, can modify the leptin release. When energy imbalances induced by exercise and/or deficient food ingestion occurs, low leptin levels are observed, leading to a reduction in GnRH (gonadotropin-release hormone), in LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in pituitary, and consequently a minor release of ovarian estrogens. This process is named hypothalamic amenorrhea, and has repercussions in the woman's health. In this perspective, it is important to emphasize the need to evaluate the energy expenditure from exercise and to formulate adequate alimentary plans to these individuals.
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Affiliation(s)
- Sandra Maria Lima Ribeiro
- Grupo de Estudos em Nutrição e Atividade Física, Programa de Pós Graduação Stricto Sensu em Educação Física da Universidade São Judas Tadeu, São Paulo.
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Yu IC, Lin HY, Liu NC, Wang RS, Sparks JD, Yeh S, Chang C. Hyperleptinemia without obesity in male mice lacking androgen receptor in adipose tissue. Endocrinology 2008; 149:2361-8. [PMID: 18276764 PMCID: PMC2329275 DOI: 10.1210/en.2007-0516] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Insulin resistance occurs through an inadequate response to insulin by insulin target organs such as liver, muscle, and adipose tissue with consequent insufficient glucose uptake. In previous studies we demonstrated that whole body androgen receptor (AR) knockout (AR(-/y)) mice develop obesity and exhibit insulin and leptin resistance at advanced age. By examining adipose tissue-specific AR knockout (A-AR(-/y)) mice, we found A-AR(-/y) mice were hyperleptinemic but showed no leptin resistance, although body weight and adiposity index of A-AR(-/y) mice were identical with those of male wild-type control mice. Hypotriglyceridemia and hypocholesterolemia found in nonobese A-AR(-/y) mice suggested a beneficial effect of high leptin levels independent of fat deposition. Further examination showed that androgen-AR signaling in adipose tissue plays a direct regulatory role in leptin expression via enhanced estrogen receptor transactivation activity due to elevated intraadipose estrogens. The present study in A-AR(-/y) mice suggests a differential tissue-specific role of AR in energy balance control in males.
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Affiliation(s)
- I-Chen Yu
- Department of Pathology, George Whipple Laboratory for Cancer Research, and the Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA
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Gallardo N, Bonzón-Kulichenko E, Fernández-Agulló T, Moltó E, Gómez-Alonso S, Blanco P, Carrascosa JM, Ros M, Andrés A. Tissue-specific effects of central leptin on the expression of genes involved in lipid metabolism in liver and white adipose tissue. Endocrinology 2007; 148:5604-10. [PMID: 17823267 DOI: 10.1210/en.2007-0933] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Leptin reduces adiposity and exerts antisteatotic effects on nonadipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue. Intracerebroventricular leptin infusion for 7 d did not change leptin plasma levels but decreased triacylglyceride content in liver, epididymal adipose tissue, and plasma. In both tissues this treatment markedly decreased the expression of key enzymes of the de novo fatty acid (FA) synthesis such as acetyl-coenzyme A-carboxylase, FA synthase, and stearoyl-coenzyme A desaturase-1, in parallel with a reduction in mRNA expression of sterol regulatory element binding protein-1c in liver and carbohydrate regulatory element binding protein in adipose tissue. In addition, leptin also decreased phosphoenol-pyruvate carboxykinase-C expression in adipose tissue, an enzyme involved in glyceroneogenesis in this tissue. Central leptin administration down-regulates delta-6-desaturase expression in liver and adipose tissue, in parallel with the decrease of the expression of sterol regulatory element binding protein-1c in liver and peroxisome proliferator activated receptor alpha in adipose tissue. Finally, leptin treatment, by regulating adipose triglyceride lipase/hormone sensitive lipase/diacylglycerol transferase 1 expression, also established a new partitioning in the FA-triacylglyceride cycling in adipose tissue, increasing lipolysis and probably the FA efflux from this tissue, and favoring in parallel the FA uptake and oxidation in the liver. These results suggest that leptin, acting at central level, exerts tissue-specific effects in limiting fat tissue mass and lipid accumulation in nonadipose tissues, preventing the development of obesity and type 2 diabetes.
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Affiliation(s)
- Nilda Gallardo
- Area de Bioquímica, Facultad de Químicas, Regional Centre for Biomedical Research, Avenida Camilo José Cela 10, Universidad de Castilla-La Mancha, Ciudad Real, Spain
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Ockenga J, Tietge UJF, Böker KHW, Manns MP, Brabant G, Bahr MJ. Distinct roles of free leptin, bound leptin and soluble leptin receptor during the metabolic-inflammatory response in patients with liver cirrhosis. Aliment Pharmacol Ther 2007; 25:1301-9. [PMID: 17509098 DOI: 10.1111/j.1365-2036.2007.03327.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Alteration of the leptin system appears to play a role in the inflammatory-metabolic response in catabolic diseases such as chronic liver diseases. AIM To investigate the association between leptin components, inflammatory markers and hepatic energy and substrate metabolism. METHODS We investigated in vivo hepatic substrate and leptin metabolism in 40 patients employing a combination of arterial and hepatic vein catheterization techniques and hepatic blood flow measurements. In addition to metabolic, inflammatory and neuroendocrine parameters, circulating levels of free leptin, bound leptin and soluble leptin receptor were determined. RESULTS Compared with controls, bound leptin and soluble leptin receptor levels were significantly elevated in cirrhosis, while free leptin did not increase. In cirrhosis bound leptin was correlated with soluble leptin receptor (r = 0.70, P < 0.001). Free leptin was positively correlated with metabolic parameters such as energy storage (body fat mass; r = 0.36, P < 0.05), insulin and insulin resistance (r = 0.48; r = 0.46, P < 0.01) as well as with hepatic glucose and energy release (r = 0.35 and r = 0.40, P < 0.05). In contrast, bound leptin and soluble leptin receptor were linked to proinflammatory cytokines and sympathetic activity (r = 0.61 and r = 0.56, P < 0.01). CONCLUSION The components of the leptin system (free leptin, bound leptin and soluble leptin receptor) have distinct roles in metabolic and inflammatory processes in patients with liver cirrhosis. The better understanding of this metabolic and inflammatory tissue-repair response may lead to innovative new therapeutic strategies in liver disease as well as in various other catabolic diseases.
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Affiliation(s)
- J Ockenga
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
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Shen J, Tanida M, Niijima A, Nagai K. In vivo effects of leptin on autonomic nerve activity and lipolysis in rats. Neurosci Lett 2007; 416:193-7. [PMID: 17306457 DOI: 10.1016/j.neulet.2007.02.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2006] [Revised: 01/31/2007] [Accepted: 02/02/2007] [Indexed: 11/28/2022]
Abstract
Leptin, a 16-kDa protein, is produced by white adipose tissue (WAT), and is thought to serve as a feedback signal indicating the size of fat stores. Considerable amount of data have shown that leptin can mediate lipid metabolism. However, its possible direct effects on the metabolism of lipids in vivo and the mechanisms involved have not been fully characterized. In this study, we investigated the in vivo effects of leptin on the autonomic nerve activity and lipolysis. We found that intravenous administration of leptin (10 microg/rat) excited the sympathetic nerves innervating WAT, and this effect was abolished by the pretreatment with diphenhydramine, a histamine H(1) receptor antagonist. Moreover, intraperitoneal administration of leptin (130 microg/kg) elevated the levels of plasma glycerol and free fatty acid (FFA). The effect of leptin on plasma FFA was eliminated by pretreatment with diphenhydramine and propranolol, a beta-adrenergic receptor blocker, and disappeared in suprachiasmatic nucleus (SCN)-lesioned rats. Our results suggest that leptin might regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nerves, driven by histamine neurons through the H(1) receptor, and a beta-adrenergic receptor, probably the beta(3)-receptor, is involved in the lipolytic response to leptin. The actions of leptin in this study are supposed to be controlled by the SCN.
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Affiliation(s)
- Jiao Shen
- Institute for Protein Research, Osaka University, 3-2 Yamada-Oka, Suita, Osaka 565-0871, Japan.
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Gaidhu MP, Fediuc S, Ceddia RB. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside-induced AMP-activated protein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes. J Biol Chem 2006; 281:25956-64. [PMID: 16816404 DOI: 10.1074/jbc.m602992200] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The objective of this study was to investigate the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR)-induced AMP-activated protein kinase (AMPK) activation on basal and insulin-stimulated glucose and fatty acid metabolism in isolated rat adipocytes. AICAR-induced AMPK activation profoundly inhibited basal and insulin-stimulated glucose uptake, lipogenesis, glucose oxidation, and lactate production in fat cells. We also describe the novel findings that AICAR-induced AMPK phosphorylation significantly reduced palmitate (32%) and oleate uptake (41%), which was followed by a 50% reduction in palmitate oxidation despite a marked increase in AMPK and acetyl-CoA carboxylase phosphorylation. Compound C, a selective inhibitor of AMPK, not only completely prevented the inhibitory effect of AICAR on palmitate oxidation but actually caused a 2.2-fold increase in this variable. Compound C also significantly increased palmitate oxidation in the presence of inhibitory concentrations of malonyl-CoA and etomoxir indicating an increase in CPT1 activity. In contrast to skeletal muscle in which AMPK stimulates fatty acid oxidation to provide ATP as a fuel, we propose that AMPK activation inhibits lipogenesis and fatty acid oxidation in adipocytes. Inhibition of lipogenesis would conserve ATP under conditions of cellular stress, although suppression of intra-adipocyte oxidation would spare fatty acids for exportation to other tissues where their utilization is crucial for energy production. Additionally, the stimulatory effect of compound C on long chain fatty acid oxidation provides a novel pharmacological approach to promote energy dissipation in adipocytes, which may be of therapeutic importance for obesity and type II diabetes.
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Affiliation(s)
- Mandeep Pinky Gaidhu
- School of Kinesiology and Health Science, York University, Toronto, Ontario M3J 1P3, Canada
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Wagoner B, Hausman DB, Harris RBS. Direct and indirect effects of leptin on preadipocyte proliferation and differentiation. Am J Physiol Regul Integr Comp Physiol 2006; 290:R1557-64. [PMID: 16424081 DOI: 10.1152/ajpregu.00860.2005] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Leptin has been shown to reduce body fat in vivo. Adipocytes express the leptin receptor; therefore, it is realistic to expect a direct effect of leptin on adipocyte growth and metabolism. In vitro studies examining the effect of leptin on adipocyte metabolism require supraphysiological doses of the protein to see a decrease in lipogenesis or stimulation of lipolysis, implying an indirect action of leptin. It also is possible that leptin reduces adipose mass by inhibiting preadipocyte proliferation (increase in cell number) and/or differentiation (lipid filling). Thus we determined direct and indirect effects of leptin on preadipocyte proliferation and differentiation in vitro. We tested the effect of leptin (0-500 ng/ml), serum from leptin-infused rats (0.25% by volume), and adipose tissue-conditioned medium from leptin-infused rats (0-30% by volume) on preadipocyte proliferation and differentiation in a primary culture of cells from male Sprague-Dawley rat adipose tissue. Leptin (50 ng/ml) stimulated proliferation of preadipocytes (P<0.05), but 250 and 500 ng leptin/ml inhibited proliferation of both preadipocyte and stromal vascular cell fractions (P<0.01), as measured by [3H]thymidine incorporation. Serum from leptin-infused rats inhibited proliferation of the adipose and stromal vascular fractions (P=0.01), but adipose tissue-conditioned medium had no effect on proliferation of either cell fraction. None of the treatments changed preadipocyte differentiation as measured by sn-glycerophosphate dehydrogenase activity. These results suggest that leptin could inhibit preadipocyte proliferation by modifying release of a factor from tissue other than adipose tissue.
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Affiliation(s)
- Blair Wagoner
- Department of Foods and Nutrition, Dawson Hall, University of Georgia, Athens, GA 30602, USA
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Ceddia RB. Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis. Int J Obes (Lond) 2005; 29:1175-83. [PMID: 16030519 DOI: 10.1038/sj.ijo.0803025] [Citation(s) in RCA: 115] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines, leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue, two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation and prevents fatty acid accumulation and 'lipotoxicity' in these tissues. On the other hand, under conditions of peripheral leptin resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is also discussed.
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Affiliation(s)
- R B Ceddia
- Department of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
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Oh W, Abu-Elheiga L, Kordari P, Gu Z, Shaikenov T, Chirala SS, Wakil SJ. Glucose and fat metabolism in adipose tissue of acetyl-CoA carboxylase 2 knockout mice. Proc Natl Acad Sci U S A 2005; 102:1384-9. [PMID: 15677334 PMCID: PMC547858 DOI: 10.1073/pnas.0409451102] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Acc2-/- mutant mice, when fed a high-fat/high-carbohydrate (HF/HC) diet, were protected against diet-induced obesity and diabetes. To investigate the role of acetyl-CoA carboxylase 2 (ACC2) in the regulation of energy metabolism in adipose tissues, we studied fatty acid and glucose oxidation in primary cultures of adipocytes isolated from wild-type and Acc2-/- mutant mice fed either normal chow or a HF/HC diet. When fed normal chow, oxidation of [14C]palmitate in adipocytes of Acc2-/- mutant mice was approximately 80% higher than in adipocytes of WT mice, and it remained significantly higher in the presence of insulin. Interestingly, in addition to increased fatty acid oxidation, we also observed increased glucose oxidation in adipocytes of Acc2-/- mutant mice compared with that of WT mice. When fed a HF/HC diet for 4-5 months, adipocytes of Acc2-/- mutant mice maintained a 25% higher palmitate oxidation and a 2-fold higher glucose oxidation than WT mice. The mRNA level of glucose transporter 4 (GLUT4) decreased several fold in the adipose tissue of WT mice fed a HF/HC diet; however, in the adipose tissue of Acc2-/- mutant mice, it was 7-fold higher. Moreover, lipolysis activity was higher in adipocytes of Acc2-/- mutant mice compared with that in WT mice. These findings suggest that continuous fatty acid oxidation in the adipocytes of Acc2-/- mutant mice, combined with a higher level of glucose oxidation and a higher rate of lipolysis, are major factors leading to efficient maintenance of insulin sensitivity and leaner Acc2-/- mutant mice.
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Affiliation(s)
- Wonkeun Oh
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
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Faulconnier Y, Arnal MA, Patureau Mirand P, Chardigny JM, Chilliard Y. Isomers of conjugated linoleic acid decrease plasma lipids and stimulate adipose tissue lipogenesis without changing adipose weight in post-prandial adult sedentary or trained Wistar rat. J Nutr Biochem 2004; 15:741-8. [PMID: 15607647 DOI: 10.1016/j.jnutbio.2004.07.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2003] [Revised: 07/09/2004] [Accepted: 07/12/2004] [Indexed: 12/01/2022]
Abstract
The respective effects and interactions of supplementation with two conjugated linoleic acid (CLA) isomers and exercise on plasma metabolic profile, activity of lipogenic enzymes and cellularity in two adipose tissue sites, those of the liver and heart, were examined in adult Wistar rats. Rats that were either sedentary or exercise-trained by treadmill running were fed one of four diets: a diet without CLA; a diet with either 1% cis 9, trans 11 CLA or 1% trans 10, cis 12 CLA; or a mixture of both isomers (1% of each) for 6 weeks. We observed that the exercise decreased lipogenic enzyme activities in epididymal and perirenal adipose tissue. Plasma cholesterol, insulin, and leptin concentrations were lower in exercise-trained rats than in sedentary rats. The ingestion of either CLA mixture or the trans 10, cis 12 CLA increased lipogenic enzyme activities in epididymal tissue and more markedly in perirenal adipose tissue, especially in sedentary rats, and without affecting adipose tissue weight or cellularity. A similar effect of trans 10, cis 12 CLA was observed in regard to malic enzyme activity in the liver. In addition, this isomer decreased plasma lipid and urea concentrations and increased plasma 3-hydroxybutyrate levels. The ingestion of cis 9, trans 11 CLA increased fatty acid synthase activity in perirenal adipose tissue in sedentary rats and decreased plasma cholesterol and leptin concentrations. These results show that isomers of CLA decrease plasma lipids and stimulate adipose tissue lipogenesis without changing adipose weight in adult sedentary or exercise-trained rat, thus suggesting a stimulation of adipose tissue turnover.
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Affiliation(s)
- Yannick Faulconnier
- Herbivore Research Unit, Adipose Tissue and Milk Lipids Group, National Institute for Agricultural Research-Theix, 63122 Saint-Genès Champanelle, France
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Abstract
That obesity is associated with insulin resistance and type II diabetes mellitus is well accepted. Overloading of white adipose tissue beyond its storage capacity leads to lipid disorders in non-adipose tissues, namely skeletal and cardiac muscles, pancreas, and liver, effects that are often mediated through increased non-esterified fatty acid fluxes. This in turn leads to a tissue-specific disordered insulin response and increased lipid deposition and lipotoxicity, coupled to abnormal plasma metabolic and (or) lipoprotein profiles. Thus, the importance of functional adipocytes is crucial, as highlighted by the disorders seen in both "too much" (obesity) and "too little" (lipodystrophy) white adipose tissue. However, beyond its capacity for fat storage, white adipose tissue is now well recognised as an endocrine tissue producing multiple hormones whose plasma levels are altered in obese, insulin-resistant, and diabetic subjects. The consequence of these hormonal alterations with respect to both glucose and lipid metabolism in insulin target tissues is just beginning to be understood. The present review will focus on a number of these hormones: acylation-stimulating protein, leptin, adiponectin, tumour necrosis factor alpha, interleukin-6, and resistin, defining their changes induced in obesity and diabetes mellitus and highlighting their functional properties that may protect or worsen lipid metabolism.
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Affiliation(s)
- May Faraj
- Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada
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Abstract
The physiological mechanisms that control energy balance are reciprocally linked to those that control reproduction, and together, these mechanisms optimize reproductive success under fluctuating metabolic conditions. Thus, it is difficult to understand the physiology of energy balance without understanding its link to reproductive success. The metabolic sensory stimuli, hormonal mediators and modulators, and central neuropeptides that control reproduction also influence energy balance. In general, those that increase ingestive behavior inhibit reproductive processes, with a few exceptions. Reproductive processes, including the hypothalamic-pituitary-gonadal (HPG) system and the mechanisms that control sex behavior are most proximally sensitive to the availability of oxidizable metabolic fuels. The role of hormones, such as insulin and leptin, are not understood, but there are two possible ways they might control food intake and reproduction. They either mediate the effects of energy metabolism on reproduction or they modulate the availability of metabolic fuels in the brain or periphery. This review examines the neural pathways from fuel detectors to the central effector system emphasizing the following points: first, metabolic stimuli can directly influence the effector systems independently from the hormones that bind to these central effector systems. For example, in some cases, excess energy storage in adipose tissue causes deficits in the pool of oxidizable fuels available for the reproductive system. Thus, in such cases, reproduction is inhibited despite a high body fat content and high plasma concentrations of hormones that are thought to stimulate reproductive processes. The deficit in fuels creates a primary sensory stimulus that is inhibitory to the reproductive system, despite high concentrations of hormones, such as insulin and leptin. Second, hormones might influence the central effector systems [including gonadotropin-releasing hormone (GnRH) secretion and sex behavior] indirectly by modulating the metabolic stimulus. Third, the critical neural circuitry involves extrahypothalamic sites, such as the caudal brain stem, and projections from the brain stem to the forebrain. Catecholamines, neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) are probably involved. Fourth, the metabolic stimuli and chemical messengers affect the motivation to engage in ingestive and sex behaviors instead of, or in addition to, affecting the ability to perform these behaviors. Finally, it is important to study these metabolic events and chemical messengers in a wider variety of species under natural or seminatural circumstances.
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Affiliation(s)
- Jill E Schneider
- Department of Biological Sciences, Lehigh University, 111 Research Drive, Bethlehem, PA 18015, USA.
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Kumar S, Kishimoto H, Chua HL, Badve S, Miller KD, Bigsby RM, Nakshatri H. Interleukin-1 alpha promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2004; 163:2531-41. [PMID: 14633625 PMCID: PMC1892398 DOI: 10.1016/s0002-9440(10)63608-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Progression of breast cancer involves cross-talk between epithelial and stromal cells. This cross-talk is mediated by growth factors and cytokines secreted by both cancer and stromal cells. We previously reported expression of interleukin (IL)-1 alpha in a subset of breast cancers and demonstrated that IL-1 alpha is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1 alpha in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1 alpha (MCF-7IL-1 alpha) in nude mice. MCF-7IL-1 alpha cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1 alpha expression alone was not sufficient for metastasis in vivo although in vitro studies showed induction of several prometastatic genes and matrix metalloproteinase activity in response to cross-talk between IL-1 alpha-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1 alpha cells were cachetic, which correlated with increased leptin serum levels but not other known cachexia-inducing cytokines such as IL-6, tumor necrosis factor, or interferon gamma. Serum triglycerides, but not blood glucose were lower in animals with MCF-7IL-1 alpha cell-derived tumors compared to animals with control cell-derived tumors. Cachexia was associated with atrophy of epidermal and adnexal structures of skin; a similar phenotype is reported in triglyceride-deficient mice and in ob/ob mice injected with leptin. Mouse leptin-specific transcripts could be detected only in MCF-7IL-1 alpha cell-derived tumors, which suggests that IL-1 alpha increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1 alpha cell-derived tumors were not anorexic suggesting only peripheral action of tumor-derived leptin, which principally targets lipid metabolism. Taken together, these results suggest that cancer cell-derived cytokines, such as IL-1 alpha, induce cachexia by affecting leptin-dependent metabolic pathways.
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Affiliation(s)
- Suresh Kumar
- Departments of Surgery, Indiana University School of Medicine, Indianapolis 46202, USA
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Abstract
This study examined if leptin can acutely affect glucose or fatty acid metabolism in pig adipocytes and whether leptin's actions on lipogenesis are manifested through interaction with insulin or growth hormone. Subcutaneous adipose tissue was obtained from approximately 55 kg crossbred barrows at the USDA abattoir. Isolated adipocytes were prepared using a collagenase procedure. Experiments assessed U-14C-glucose or 1-14C-palmitate metabolism in isolated adipocytes exposed to: basal medium (control), 100 nM insulin, 100 ng/ml porcine growth hormone, 100 ng/ml recombinant porcine leptin, and combinations of these hormones. Treatments were performed in triplicate and the experiment was repeated with adipocytes isolated from five different animals. Cell aliquots (250 microl) were added to 1 ml of incubation medium, then incubated for 2h at 37 degrees C for measurement of glucose and palmitate oxidation or incorporation into lipid. Incubation of isolated adipocytes with insulin increased glucose oxidation rate by 18% (P<0.05), while neither growth hormone nor leptin affected glucose oxidation (P>0.5). Total lipid synthesis from glucose was increased by approximately 25% by 100 nM insulin or insulin+growth hormone (P<0.05). Insulin+leptin reduced the insulin response by 37% (P<0.05). The combination of all three hormones increased total lipid synthesis by 35%, relative to controls (P<0.05), a rate similar to insulin alone. Fatty acid synthesis was elevated by insulin (32%, P<0.05) or growth hormone (13%, P<0.05). Leptin had no effect on fatty acid synthesis (P>0.05). Leptin reduced the esterification rate by 10% (P<0.05). Growth hormone and insulin could overcome leptin's inhibition of palmitate esterification (P>0.05).
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Affiliation(s)
- Timothy G Ramsay
- Growth Biology Laboratory, USDA-ARS, BARC-East, Bldg. 200, Rm. 201, Beltsville, MD 20705, USA.
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