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Miro C, Cicatiello AG, Nappi A, Sagliocchi S, Acampora L, Restolfer F, Cuomo O, de Alteris G, Pugliese G, Torabinejad S, Maritato R, Murolo M, Di Cicco E, Velotti N, Capuano M, La Civita E, Terracciano D, Ciampaglia R, Stornaiuolo M, Musella M, Aprea G, Pignataro G, Savastano S, Dentice M. Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance. Cell Metab 2025; 37:936-953.e7. [PMID: 39986272 DOI: 10.1016/j.cmet.2025.01.025] [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: 03/29/2024] [Revised: 10/15/2024] [Accepted: 01/27/2025] [Indexed: 02/24/2025]
Abstract
Thyroid hormones (THs) are key modulators of energy metabolism and cross-talk with other endocrine and metabolic factors. Notably, leptin can increase hypothalamic control of TH synthesis as an adaptive metabolic response regulating body weight. In this study, we found that the TH signal is heightened in overweight humans and is lost with obesity. In mice, systemic and intracerebroventricular leptin injection induces the expression of type 2 deiodinase (D2), the TH-activating enzyme, in skeletal muscle. Mechanistically, leptin enhances the transcription of D2 by a STAT3- and α-melanocyte-stimulating hormone (α-MSH)/cyclic AMP (cAMP)-dependent regulation. Notably, mice lacking D2 or with a mutation in the TH receptor do not exhibit the metabolic effects of leptin, such as increased insulin sensitivity and oxygen consumption, indicating that leptin's peripheral metabolic effects in skeletal muscle are mediated by TH. These findings underscore the critical role of leptin in integrating the TH-induced metabolic activation, while also contributing to appetite suppression in response to perceived fat stores.
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Affiliation(s)
- Caterina Miro
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | | | - Annarita Nappi
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Serena Sagliocchi
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Lucia Acampora
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Federica Restolfer
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Ornella Cuomo
- Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples "Federico II," 80131 Naples, Italy
| | - Giulia de Alteris
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Gabriella Pugliese
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Sepehr Torabinejad
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Rosa Maritato
- Department of Translational Medical Sciences, University of Naples "Federico II," 80131 Naples, Italy
| | - Melania Murolo
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Emery Di Cicco
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Nunzio Velotti
- Department of Advanced Biomedical Sciences, University of Naples "Federico II," 80131 Naples, Italy
| | - Marianna Capuano
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Evelina La Civita
- Department of Translational Medical Sciences, University of Naples "Federico II," 80131 Naples, Italy
| | - Daniela Terracciano
- Department of Translational Medical Sciences, University of Naples "Federico II," 80131 Naples, Italy
| | - Roberto Ciampaglia
- Department of Pharmacy, University of Naples "Federico II," 80149 Naples, Italy
| | - Mariano Stornaiuolo
- Department of Pharmacy, University of Naples "Federico II," 80149 Naples, Italy
| | - Mario Musella
- Department of Advanced Biomedical Sciences, University of Naples "Federico II," 80131 Naples, Italy
| | - Giovanni Aprea
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Giuseppe Pignataro
- Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples "Federico II," 80131 Naples, Italy
| | - Silvia Savastano
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy
| | - Monica Dentice
- Department of Clinical Medicine and Surgery, University of Naples "Federico II," 80131 Naples, Italy; CEINGE - Biotecnologie Avanzate S.c.a.r.l., 80131 Naples, Italy.
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Nath D, Barbhuiya PA, Sen S, Pathak MP. A Review on In-vivo and In-vitro Models of Obesity and Obesity-Associated Co-Morbidities. Endocr Metab Immune Disord Drug Targets 2025; 25:458-478. [PMID: 39136512 DOI: 10.2174/0118715303312932240801073903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/20/2024] [Accepted: 06/26/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Obesity is becoming a global pandemic with pandemic proportions. According to the WHO estimates, there were over 1.9 billion overweight individuals and over 650 million obese adults in the globe in 2016. In recent years, scientists have encountered difficulties in choosing acceptable animal models, leading to a multitude of contradicting aspects and incorrect outcomes. This review comprehensively evaluates different screening models of obesity and obesity-associated comorbidities to reveal the advantages and disadvantages/limitations of each model while also mentioning the time duration each model requires to induce obesity. METHODS For this review, the authors have gone through a vast number of article sources from different scientific databases, such as Google Scholar, Web of Science, Medline, and PubMed. RESULTS In-vivo models used to represent a variety of obesity-inducing processes, such as diet-induced, drug-induced, surgical, chemical, stress-induced, and genetic models, are discussed. Animal cell models are examined with an emphasis on their use in understanding the molecular causes of obesity, for which we discussed in depth the important cell lines, including 3T3-L1, OP9, 3T3-F442A, and C3H10T1/2. Screening models of obesity-associated co-morbidities like diabetes, asthma, cardiovascular disorders, cancer, and polycystic ovarian syndrome (PCOS) were discussed, which provided light on the complex interactions between obesity and numerous health problems. CONCLUSION Mimicking obesity in an animal model reflects multifactorial aspects is a matter of challenge. Future studies could address the ethical issues surrounding the use of animals in obesity research as well as investigate newly developed models, such as non-mammalian models. In conclusion, improving our knowledge and management of obesity and related health problems will require ongoing assessment and improvement of study models.
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Affiliation(s)
- Digbijoy Nath
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Pervej Alom Barbhuiya
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Saikat Sen
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Manash Pratim Pathak
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
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Zuccaro MV, LeDuc CA, Thaker VV. Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity. Curr Obes Rep 2024; 13:626-641. [PMID: 38822963 PMCID: PMC11694263 DOI: 10.1007/s13679-024-00567-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/10/2024] [Indexed: 06/03/2024]
Abstract
PURPOSE OF REVIEW The goal of this paper is to aggregate information on monogenic contributions to obesity in the past five years and to provide guidance for genetic testing in clinical care. RECENT FINDINGS Advances in sequencing technologies, increasing awareness, access to testing, and new treatments have increased the utilization of genetics in clinical care. There is increasing recognition of the prevalence of rare genetic obesity from variants with mean allele frequency < 5% -new variants in known genes as well as identification of novel genes- causing monogenic obesity. While most of these genes are in the leptin melanocortin pathway, those in adipocytes may also contribute. Common variants may contribute either to higher lifetime tendency for weight gain or provide protection from monogenic obesity. While specific genetic mutations are rare, these segregate in individuals with early-onset severe obesity; thus, collectively genetic etiologies are not as rare. Some genetic conditions are amenable to targeted treatment. Research into the discovery of novel genetic causes as well as targeted treatment is growing over time. The utility of therapeutic strategies based on the genetic risk of obesity is an advancing frontier.
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Affiliation(s)
- Michael V Zuccaro
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, United States
| | - Charles A LeDuc
- Division of Molecular Genetics, Department of Pediatrics, Columbia University Irving Medical Center, 1150, St. Nicholas Avenue, NY 10032, United States
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, United States
| | - Vidhu V Thaker
- Division of Molecular Genetics, Department of Pediatrics, Columbia University Irving Medical Center, 1150, St. Nicholas Avenue, NY 10032, United States.
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, United States.
- Division of Pediatric Endocrinology, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, 10032, United States.
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Alshammari MA, Alshehri AO, Alqahtani F, Khan MR, Bakhrebah MA, Alasmari F, Alshammari TK, Alsharari SD. Increased Permeability of the Blood-Brain Barrier in a Diabetic Mouse Model ( Leprdb/db Mice). Int J Mol Sci 2024; 25:7768. [PMID: 39063010 PMCID: PMC11276738 DOI: 10.3390/ijms25147768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 07/05/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood-brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Leprdb/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Leprdb/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Leprdb/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Leprdb/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Leprdb/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research.
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Affiliation(s)
- Musaad A. Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Abdulaziz O. Alshehri
- Department of Pharmacology and Toxicology (Graduate Student), Pharmacy College, King Saud University, Riyadh 11495, Saudi Arabia;
| | - Faleh Alqahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Mohammad R. Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Muhammed A. Bakhrebah
- Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia;
| | - Fawaz Alasmari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Tahani K. Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
| | - Shakir D. Alsharari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia; (F.A.); (M.R.K.); (F.A.); (T.K.A.); (S.D.A.)
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Vijayashankar U, Ramashetty R, Rajeshekara M, Vishwanath N, Yadav AK, Prashant A, Lokeshwaraiah R. Leptin and ghrelin dynamics: unraveling their influence on food intake, energy balance, and the pathophysiology of type 2 diabetes mellitus. J Diabetes Metab Disord 2024; 23:427-440. [PMID: 38932792 PMCID: PMC11196531 DOI: 10.1007/s40200-024-01418-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/12/2024] [Indexed: 06/28/2024]
Abstract
Purpose Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. In recent years, there has been growing interest in the role of hunger and satiety hormones such as ghrelin and leptin in the development and progression of T2DM. In this context, the present literature review aims to provide a comprehensive overview of the current understanding of how ghrelin and leptin influences food intake and maintain energy balance and its implications in the pathophysiology of T2DM. Methods A thorough literature search was performed using PubMed and Google Scholar to choose the studies that associated leptin and ghrelin with T2DM. Original articles and reviews were included, letters to editors and case reports were excluded. Results This narrative review article provides a comprehensive summary on mechanism of action of leptin and ghrelin, its association with obesity and T2DM, how they regulate energy and glucose homeostasis and potential therapeutic implications of leptin and ghrelin in managing T2DM. Conclusion Ghrelin, known for its appetite-stimulating effects, and leptin, a hormone involved in the regulation of energy balance, have been implicated in insulin resistance and glucose metabolism. Understanding the complexities of ghrelin and leptin interactions in the context of T2DM may offer insights into novel therapeutic strategies for this prevalent metabolic disorder. Further research is warranted to elucidate the molecular mechanisms underlying these hormone actions and to explore their clinical implications for T2DM prevention and management.
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Affiliation(s)
- Uma Vijayashankar
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015 India
| | - Rajalakshmi Ramashetty
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015 India
| | - Mahesh Rajeshekara
- Department of Surgical Gastroenterology, Bangalore Medical College and Research Institute, Bangalore, 560002 India
| | - Nagashree Vishwanath
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015 India
| | - Anshu Kumar Yadav
- Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru-15, Mysuru, 570015 India
| | - Akila Prashant
- Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru-15, Mysuru, 570015 India
| | - Rajeshwari Lokeshwaraiah
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015 India
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Pena-Leon V, Perez-Lois R, Villalon M, Prida E, Muñoz-Moreno D, Fernø J, Quiñones M, Al-Massadi O, Seoane LM. Novel mechanisms involved in leptin sensitization in obesity. Biochem Pharmacol 2024; 223:116129. [PMID: 38490517 DOI: 10.1016/j.bcp.2024.116129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/21/2024] [Accepted: 03/12/2024] [Indexed: 03/17/2024]
Abstract
Leptin is a hormone that is secreted by adipocytes in proportion to adipose tissue size, and that informs the brain about the energy status of the body. Leptin acts through its receptor LepRb, expressed mainly in the hypothalamus, and induces a negative energy balance by potent inhibition of feeding and activation of energy expenditure. These actions have led to huge expectations for the development of therapeutic targets for metabolic complications based on leptin-derived compounds. However, the majority of patients with obesity presents elevated leptin production, suggesting that in this setting leptin is ineffective in the regulation of energy balance. This resistance to the action of leptin in obesity has led to the development of "leptin sensitizers," which have been tested in preclinical studies. Much research has focused on generating combined treatments that act on multiple levels of the gastrointestinal-brain axis. The gastrointestinal-brain axis secretes a variety of different anorexigenic signals, such as uroguanylin, glucagon-like peptide-1, amylin, or cholecystokinin, which can alleviate the resistance to leptin action. Moreover, alternative mechanism such as pharmacokinetics, proteostasis, the role of specific kinases, chaperones, ER stress and neonatal feeding modifications are also implicated in leptin resistance. This review will cover the current knowledge regarding the interaction of leptin with different endocrine factors from the gastrointestinal-brain axis and other novel mechanisms that improve leptin sensitivity in obesity.
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Affiliation(s)
- Veronica Pena-Leon
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Raquel Perez-Lois
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Maria Villalon
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Eva Prida
- Translational Endocrinology group, Endocrinology Section, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (IDIS/CHUS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Diego Muñoz-Moreno
- Translational Endocrinology group, Endocrinology Section, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (IDIS/CHUS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Johan Fernø
- Hormone Laboratory, Department of Biochemistry and Pharmacology, Haukeland University Hospital, 5201 Bergen, Norway
| | - Mar Quiñones
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; CIBER de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Omar Al-Massadi
- Translational Endocrinology group, Endocrinology Section, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (IDIS/CHUS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; CIBER de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
| | - Luisa M Seoane
- Grupo Fisiopatología Endocrina, Departamento de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; CIBER de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
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Manglani K, Anika NN, Patel D, Jhaveri S, Avanthika C, Sudan S, Alimohamed Z, Tiwari K. Correlation of Leptin in Patients With Type 2 Diabetes Mellitus. Cureus 2024; 16:e57667. [PMID: 38707092 PMCID: PMC11070180 DOI: 10.7759/cureus.57667] [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] [Accepted: 04/05/2024] [Indexed: 05/07/2024] Open
Abstract
The exponential increase in diabetes mellitus (DM) poses serious public health concerns. In this review, we focus on the role of leptin in type 2 DM. The peripheral actions of leptin consist of upregulating proinflammatory cytokines which play an important role in the pathogenesis of type 2 DM and insulin resistance. Moreover, leptin is known to inhibit insulin secretion and plays a significant role in insulin resistance in obesity and type 2 DM. A literature search was conducted on Medline, Cochrane, Embase, and Google Scholar for relevant articles published until December 2023. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "Leptin," "NPY," and "Biomarker." This article aims to discuss the physiology of leptin in type 2 DM, its glucoregulatory actions, its relationship with appetite, the impact that various lifestyle modifications can have on leptin levels, and, finally, explore leptin as a potential target for various treatment strategies.
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Affiliation(s)
- Kajol Manglani
- Internal Medicine, MedStar Washington Hospital Center, Washington, USA
| | | | - Dhriti Patel
- Medicine and Surgery, B.J. Medical College and Civil Hospital, Ahmedabad, IND
| | - Sharan Jhaveri
- Medicine and Surgery, Smt. Nathiba Hargovandas Lakhmichand Municipal Medical College, Gujarat University, Ahmedabad, IND
| | - Chaithanya Avanthika
- Pediatrics, Icahn School of Medicine at Mount Sinai, Elmhurst Hospital Center, New York, USA
- Medicine and Surgery, Karnataka Institute of Medical Sciences, Hubballi, IND
| | - Sourav Sudan
- Internal Medicine, Government Medical College, Rajouri, Rajouri, IND
| | - Zainab Alimohamed
- Division of Research & Academic Affairs, Larkin Health System, South Miami, USA
| | - Kripa Tiwari
- Internal Medicine, Maimonides Medical Center, New York, USA
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Melnyk S, Hakkak R. Effect of Metformin Treatment on Serum Metabolic Profile Changes in Lean and Obese Zucker Rat Model for Fatty Liver Disease. Biomolecules 2023; 13:1234. [PMID: 37627299 PMCID: PMC10452862 DOI: 10.3390/biom13081234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/28/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Excessive weight and obesity are the leading risk factors for the development of chronic diseases, including diabetes. Metformin is capable of significantly improving coexisting complications of diabetes. We used a metabolomics approach to examine the effects of metformin administration on lean and obese (fa/fa) Zucker rats. After 1 week of acclimation, twenty-eight 5-week-old female lean and obese rats were randomly assigned to and maintained in the following four groups (seven rats/group) for 10 weeks: (1) lean control (LC); (2) obese control (OC); (3) lean metformin (LM); and (4) obese metformin (OM). At the end of 10 weeks, serum was collected and analyzed using HPLC with electrochemical detection, HPLC with UV detection, and liquid chromatography mass spectrometry. We selected 50 metabolites' peaks that were shared by all four groups of rats. Peak heights, as a defining factor, generally decreased in metformin-treated lean rats vs. untreated lean controls (3 LM:16 LC). Peak heights generally increased in metformin-treated obese rats vs. untreated obese controls (14 OM:5 OC). Overall, individual peaks were distributed as 11 that represented only lean rats, 11 that represented only obese rats, and 8 that were common among both lean and obese rats. In future studies, we will use a targeted metabolomics approach to identify those metabolites, map them to biochemical pathways and create a list of biomarkers. In summary, the current study contributed to a better understanding of the basic metabolic changes of lean and obese rats and demonstrated that both obesity and metformin make a significant impact on the metabolome of Zucker rats.
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Affiliation(s)
- Stepan Melnyk
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
| | - Reza Hakkak
- Arkansas Children’s Research Institute, Little Rock, AR 72202, USA
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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Becetti I, Bwenyi EL, de Araujo IE, Ard J, Cryan JF, Farooqi IS, Ferrario CR, Gluck ME, Holsen LM, Kenny PJ, Lawson EA, Lowell BB, Schur EA, Stanley TL, Tavakkoli A, Grinspoon SK, Singhal V. The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets: A Report from the 23rd Annual Harvard Nutrition Obesity Symposium. Am J Clin Nutr 2023; 118:314-328. [PMID: 37149092 PMCID: PMC10375463 DOI: 10.1016/j.ajcnut.2023.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 04/03/2023] [Accepted: 05/01/2023] [Indexed: 05/08/2023] Open
Abstract
Obesity is increasing at an alarming rate. The effectiveness of currently available strategies for the treatment of obesity (including pharmacologic, surgical, and behavioral interventions) is limited. Understanding the neurobiology of appetite and the important drivers of energy intake (EI) can lead to the development of more effective strategies for the prevention and treatment of obesity. Appetite regulation is complex and is influenced by genetic, social, and environmental factors. It is intricately regulated by a complex interplay of endocrine, gastrointestinal, and neural systems. Hormonal and neural signals generated in response to the energy state of the organism and the quality of food eaten are communicated by paracrine, endocrine, and gastrointestinal signals to the nervous system. The central nervous system integrates homeostatic and hedonic signals to regulate appetite. Although there has been an enormous amount of research over many decades regarding the regulation of EI and body weight, research is only now yielding potentially effective treatment strategies for obesity. The purpose of this article is to summarize the key findings presented in June 2022 at the 23rd annual Harvard Nutrition Obesity Symposium entitled "The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets." Findings presented at the symposium, sponsored by NIH P30 Nutrition Obesity Research Center at Harvard, enhance our current understanding of appetite biology, including innovative techniques used to assess and systematically manipulate critical hedonic processes, which will shape future research and the development of therapeutics for obesity prevention and treatment.
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Affiliation(s)
- Imen Becetti
- Division of Pediatric Endocrinology, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA, United States.
| | - Esther L Bwenyi
- Metabolism Unit, Massachusetts General Hospital, Boston, MA, United States; Nutrition Obesity Research Center at Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
| | - Ivan E de Araujo
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York City, NY, United States; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Jamy Ard
- Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, United States; Bariatric and Weight Management Center, Wake Forest Baptist Health, Winston-Salem, NC, United States; Center on Diabetes, Obesity, and Metabolism, Wake Forest University School of Medicine, Winston-Salem, NC, United States; Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, United States; Hypertension and Vascular Research Center, Cardiovascular Sciences Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States; Maya Angelou Center for Healthy Equity, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Ismaa Sadaf Farooqi
- University of Cambridge Metabolic Research Laboratories and National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom; Wellcome-Medical Research Council (MRC) Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom
| | - Carrie R Ferrario
- Department of Pharmacology, Psychology Department (Biopsychology Area), University of Michigan, Ann Arbor, MI, United States
| | - Marci E Gluck
- National Institutes of Health, Phoenix, AZ, United States; National Institute of Diabetes and Digestive and Kidney Disease, Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ, United States
| | - Laura M Holsen
- Harvard Medical School, Boston, MA, United States; Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States; Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, United States
| | - Paul J Kenny
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York City, NY, United States; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Elizabeth A Lawson
- Nutrition Obesity Research Center at Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States; Department of Medicine, Harvard Medical School, Boston, MA, United States; Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, United States
| | - Bradford B Lowell
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Ellen A Schur
- Division of General Internal Medicine, University of Washington, Seattle, WA, United States; Univeristy of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, United States; Univeristy of Washington Nutrition and Obesity Research Center, University of Washington, Seattle, WA, United States; Clinical and Translational Research Services Core, University of Washington, Seattle, WA, United States
| | - Takara L Stanley
- Division of Pediatric Endocrinology, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA, United States; Metabolism Unit, Massachusetts General Hospital, Boston, MA, United States; Nutrition Obesity Research Center at Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States
| | - Ali Tavakkoli
- Division of General and Gastrointestinal (GI) Surgery, Center for Weight Management and Wellness, Advanced Minimally Invasive Fellowship, Harvard Medical School, Boston, MA, United States
| | - Steven K Grinspoon
- Metabolism Unit, Massachusetts General Hospital, Boston, MA, United States; Nutrition Obesity Research Center at Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Vibha Singhal
- Division of Pediatric Endocrinology, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Pediatric Endocrinology and Obesity Medicine, Massachusetts General Hospital, Boston, MA, United States; Pediatric Program MGH Weight Center, Massachusetts General Hospital, Boston, MA, United States
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10
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Davis X, Williamson L, Stuck J, Howell K, Lahni P, Piraino G, Wolfe V, Mukherjee R, Sanchez-Gurmaches J, Zingarelli B, Kaplan J. SEX-DEPENDENT EFFECTS OF ADIPOCYTE STAT3 INHIBITION ON THE INFLAMMATORY RESPONSE DURING SEVERE SEPSIS. Shock 2023; 59:779-790. [PMID: 36840516 PMCID: PMC10149172 DOI: 10.1097/shk.0000000000002105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2023]
Abstract
ABSTRACT Introduction: Sepsis is a dysregulated host response to infection that can lead to life-threatening organ dysfunction. Clinical and animal studies consistently demonstrate that female subjects are less susceptible to the adverse effects of sepsis, demonstrating the importance of understanding how sex influences sepsis outcomes. The signal transducer and activator of transcription 3 (STAT3) pathway are a major signaling pathway that facilitates inflammation during sepsis. STAT3 is abundantly expressed in white adipose tissue; however, little is known about the contribution of white adipose tissue STAT3 activation during sepsis. We hypothesize that adipocyte STAT3 inhibition during severe sepsis will exaggerate the inflammatory response and impact organ injury, in a sex-dependent manner. Methods: We generated STAT3 flox/flox (wild-type [WT]) and adipocyte STAT3 knock out (A-STAT3 KO) mice using Cre-lox technology. Studies were done in 12- to 16-week-old male and female mice. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Control nonseptic mice did not undergo CLP (0 h CLP). Tissues were harvested 18 h after CLP. Body composition was determined by echo magnetic resonance imaging. Energy metabolism was determined by indirect calorimetry. White adipose tissue morphology was determined by hematoxylin and eosin staining, while STAT3 activation in the white adipose tissue was determined by western blot analysis and immunohistochemistry staining of STAT3 activation/phosphorylation at tyrosine 705. Plasma cytokines (TNF-α, IL-6, and leptin) were determined by luminex assay. Neutrophil infiltration of the lung and liver was assessed by myeloperoxidase activity assay. Histological signs of organ injury on lung and liver tissue were assessed by hematoxylin and eosin staining. Liver injury was further assessed by measuring plasma alanine and aspartate aminotransferase. In a separate cohort of mice, sepsis was induced by CLP and mice were monitored every 6-12 h over a 7-day period to assess survival rate. Results: We demonstrate that neither body composition nor energy metabolism is altered with adipocyte STAT3 inhibition in male or female mice, under nonseptic conditions. Sepsis was associated with reduced adipocyte size in female WT and A-STAT3 KO mice, suggesting that this event is STAT3 independent. Sepsis did not alter adipocyte size in male WT and A-STAT3 KO mice, suggesting that this event is also sex dependent. Although STAT3 phosphorylation at tyrosine 705 expression is negligible in male and female A-STAT3 KO mice, septic female WT and A-STAT3 KO mice have higher white adipose tissue STAT3 activation than male WT and A-STAT3 KO mice. Adipocyte STAT3 inhibition did not alter the proinflammatory cytokine response during sepsis in male or female mice, as measured by plasma TNF-α, IL-6, and leptin levels. Adipocyte STAT3 inhibition reduced lung neutrophil infiltration and histological signs of lung injury during sepsis in male mice. On the contrary, adipocyte STAT3 inhibition had no effect on lung neutrophil infiltration or lung injury in female mice. We further demonstrate that neither liver neutrophil infiltration nor histological signs of liver injury are altered by adipocyte STAT3 inhibition during sepsis, in male or female mice. Lastly, adipocyte STAT3 inhibition did not affect survival rate of male or female mice during sepsis. Conclusions: Our study demonstrates that sex influences white adipose tissue STAT3 activation and morphology during sepsis, which is not dependent on the presence of functional STAT3 in mature adipocytes. Furthermore, genetic inhibition of adipocyte STAT3 activation in male, but not female mice, results in reduced lung neutrophil infiltration and lung injury during sepsis. The results from our study demonstrate the importance of considering biological sex and the white adipose tissue as potential sources and targets of inflammation during sepsis.
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Affiliation(s)
- Xenia Davis
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
- Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, Ohio
| | - Lauren Williamson
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
| | - Joanna Stuck
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
| | - Kendra Howell
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
| | - Patrick Lahni
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
| | - Giovanna Piraino
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
| | - Vivian Wolfe
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
| | - Rajib Mukherjee
- Cincinnati Children’s Hospital Medical Center, Division of Endocrinology, Cincinnati, Ohio
| | - Joan Sanchez-Gurmaches
- Cincinnati Children’s Hospital Medical Center, Division of Endocrinology, Cincinnati, Ohio
- Cincinnati Children’s Hospital Medical Center, Division of Developmental Biology, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Basilia Zingarelli
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jennifer Kaplan
- Cincinnati Children’s Hospital Medical Center, Division of Critical Care Medicine, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
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11
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Maxwell ND, Smiley CE, Sadek AT, Loyo-Rosado FZ, Giles DC, Macht VA, Woodruff JL, Taylor DL, Wilson SP, Fadel JR, Reagan LP, Grillo CA. Leptin activation of dorsal raphe neurons inhibits feeding behavior. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.24.538086. [PMID: 37162932 PMCID: PMC10168215 DOI: 10.1101/2023.04.24.538086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Leptin is a homeostatic regulatory element that signals the presence of energy stores -in the form of adipocytes-which ultimately reduces food intake and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also regulates food intake. Here we use a combination of pharmacological manipulations, optogenetics, retrograde tracing, and in situ hybridization, combined with behavioral endpoints to physiologically and anatomically identify a novel leptin-mediated pathway between 5-HT neurons in the dorsal raphe nucleus (DRN) and hypothalamic arcuate nucleus (ARC) that controls food intake. In this study, we show that microinjecting leptin directly into the DRN reduces food intake in male Sprague-Dawley rats. This effect is mediated by leptin-receptor expressing neurons in the DRN as selective optogenetic activation of these neurons at either their ARC terminals or DRN cell bodies also reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing leptin receptors that send projections to the ARC. Finally, by utilizing in vivo microdialysis and high-performance liquid chromatography, we show that leptin administration to the DRN increases 5-HT efflux into the ARC. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, utilizing 5-HT as a mechanism to control feeding behavior. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders. Significance Leptin and serotonin both play a vital role in the regulation of food intake, yet there is still uncertainty in how these two molecules interact to control appetite. The purpose of this study is to further understand the anatomical and functional connections between leptin receptor expressing neurons in the dorsal raphe nucleus, the main source of serotonin, and the arcuate nucleus of the hypothalamus, and how serotonin plays a role in this pathway to reduce food intake. Insight gained from this study will contribute to a more thorough understanding of the networks that regulate food intake, and open alternative avenues for the development of treatments for obesity and eating disorders.
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12
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Wan Q, Calhoun C, Zahr T, Qiang L. Uncoupling Lipid Synthesis from Adipocyte Development. Biomedicines 2023; 11:biomedicines11041132. [PMID: 37189751 DOI: 10.3390/biomedicines11041132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/20/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
Obesity results from the expansion of adipose tissue, a versatile tissue regulating energy homeostasis, adipokine secretion, thermogenesis, and inflammation. The primary function of adipocytes is thought to be lipid storage through lipid synthesis, which is presumably intertwined with adipogenesis. However, during prolonged fasting, adipocytes are depleted of lipid droplets yet retain endocrine function and an instant response to nutrients. This observation led us to question whether lipid synthesis and storage can be uncoupled from adipogenesis and adipocyte function. By inhibiting key enzymes in the lipid synthesis pathway during adipocyte development, we demonstrated that a basal level of lipid synthesis is essential for adipogenesis initiation but not for maturation and maintenance of adipocyte identity. Furthermore, inducing dedifferentiation of mature adipocytes abrogated adipocyte identity but not lipid storage. These findings suggest that lipid synthesis and storage are not the defining features of adipocytes and raise the possibility of uncoupling lipid synthesis from adipocyte development to achieve smaller and healthier adipocytes for the treatment of obesity and related disorders.
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Affiliation(s)
- Qianfen Wan
- Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA
- Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
| | - Carmen Calhoun
- Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA
- Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
| | - Tarik Zahr
- Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA
- Molecular Pharmacology and Therapeutics, Columbia University, New York, NY 10032, USA
| | - Li Qiang
- Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA
- Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
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13
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Lutz TA. Mammalian models of diabetes mellitus, with a focus on type 2 diabetes mellitus. Nat Rev Endocrinol 2023; 19:350-360. [PMID: 36941447 DOI: 10.1038/s41574-023-00818-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2023] [Indexed: 03/23/2023]
Abstract
Although no single animal model replicates all aspects of diabetes mellitus in humans, animal models are essential for the study of energy balance and metabolism control as well as to investigate the reasons for their imbalance that could eventually lead to overt metabolic diseases such as type 2 diabetes mellitus. The most frequently used animal models in diabetes mellitus research are small rodents that harbour spontaneous genetic mutations or that can be manipulated genetically or by other means to influence their nutrient metabolism and nutrient handling. Non-rodent species, including pigs, cats and dogs, are also useful models in diabetes mellitus research. This Review will outline the advantages and disadvantages of selected animal models of diabetes mellitus to build a basis for their most appropriate use in biomedical research.
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Affiliation(s)
- Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland.
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14
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Li W, Twaddle NC, Spray B, Nounamo B, Monzavi-Karbassi B, Hakkak R. Feeding Soy Protein Concentrates with Low and High Isoflavones Alters 9 and 18 Weeks Serum Isoflavones and Inflammatory Protein Levels in Lean and Obese Zucker Rats. J Med Food 2023; 26:120-127. [PMID: 36720082 DOI: 10.1089/jmf.2022.0100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Soy's anti-inflammatory properties contribute to the health benefits of soy foods. This study was designed to investigate the bioavailability of soy isoflavones and whether the isoflavone content of soy protein concentrate diet would affect serum inflammatory proteins in an obese (fa/fa) Zucker rat model. Six-week-old male lean (L) and obese (O) Zucker rats were fed a casein control diet (C), soy protein concentrate with low isoflavones (SPC-LIF), or soy protein concentrate with high isoflavones (SPC-HIF) (7 rats/dietary group) before being killed at 9 and 18 weeks. Serum samples were analyzed for isoflavones and inflammatory proteins. At both time points, serum total (aglycone + conjugates) genistein, daidzein, and equol concentrations were significantly higher in L-SPC-HIF and O-SPC-HIF groups compared with L-SPC-LIF and O-SPC-LIF groups, respectively, and were not detectable in either L-C or O-C groups. At week 9, serum C-reactive protein (CRP) concentration was significantly lower in O-SPC-HIF group compared with O-C and O-SPC-LIF group, whereas proteins tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels did not differ between any groups. At week 18, serum CRP levels in both O-SPC-HIF and O-SPC-LIF groups were significantly lower compared with the O-C group. TNF-α level was higher in the O-SPC-LIF group compared with both O-C and O-SPC-HIF groups, whereas IL-6 levels were not different between any groups. Taken together, feeding Zucker rats SPC-LIF and SPC-HIF diets led to different serum isoflavone concentrations in both L and O Zucker rats and altered CRP and TNF-α levels in obese Zucker rats compared with controls.
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Affiliation(s)
- Wei Li
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Nathan C Twaddle
- Division of Biochemical Toxicology of National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA
| | - Beverly Spray
- Division of Biostatistics Core, Arkansas Children's Research Institute, Little Rock, Arkansas, USA
| | - Bernice Nounamo
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | | | - Reza Hakkak
- Department of Dietetics and Nutrition, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.,Division of Biostatistics Core, Arkansas Children's Research Institute, Little Rock, Arkansas, USA.,Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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15
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Gomes MFP, de Moura EDOC, Cardoso NM, da Silva GA, Dos Santos ACC, de Souza FS, Estadella D, Lambertucci RH, Lago JHG, Medeiros A. Supplementation with okra combined or not with exercise training is able to protect the heart of animals with metabolic syndrome. Sci Rep 2023; 13:1468. [PMID: 36702820 PMCID: PMC9879946 DOI: 10.1038/s41598-023-28072-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 01/12/2023] [Indexed: 01/27/2023] Open
Abstract
The metabolic syndrome (MetS) is a clinical manifestation strongly associated with cardiovascular disease, the main cause of death worldwide. In view of this scenario, many therapeutic proposals have appeared in order to optimize the treatment of individuals with MetS, including the practice of exercise training (ET) and the consumption of okra (O). The aim of the present study was to evaluate the effect of O consumption and/or ET in animals with MetS. In all, 32 male Zucker rats (fa/fa) at 10 weeks old were randomly distributed into four groups of 8 animals each: MetS, MetS+O, MetS+ET and MetS+ET+O, and 8 lean Zucker rats (fa/ +) comprised the control group. Okra was administered by orogastric gavage 2x/day (morning and night, 100 mg/kg), 5 days/week, for 6 weeks. The ET was performed on a treadmill 1x/day (afternoon), 5 days/week, 60 min/day, in an intensity of 70% of maximal capacity, for the same days of O treatment. It was found that, O consumption alone was able to promote improved insulin sensitivity (MetS 93.93 ± 8.54 mg/dL vs. MetS+O 69.95 ± 18.7 mg/dL, p ≤ 0.05, d = 1.65, CI = 50.32 -89.58, triglyceride reduction (MetS 492.9 ± 97.8 mg/dL vs. MetS+O 334.9 ± 98.0 mg/dL, p ≤ 0.05, d = 1.61, CI = 193.2-398.7). In addition, it promoted a reduction in systolic blood pressure (MetS 149.0 ± 9.3 mmHg vs. MetS+O 132.0 ± 11.4 mmHg, p ≤ 0.05, d = 1.63, CI = 120-140), prevented an increase in cardiac collagen (MetS 12.60 ± 2.08% vs. MetS+O 7.52 ± 0.77%, p ≤ 0.05, d = 3.24, CI = 6.56-8.49). When associated with ET, the results were similar. Thus, we conclude that O consumption combined or not with aerobic ET can have a protective effect on the cardiac tissue of rats with MetS.
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Affiliation(s)
- Moisés Felipe Pereira Gomes
- Department of Bioscience, Universidade Federal de São Paulo (UNIFESP), R. Silva Jardim, 136 - Vila Matias, Santos, SP, 11015-020, Brazil.
- Center for Applied Social Sciences and Health, Universidade Católica de Santos (Unisantos), Av. Conselheiro Nébias, 300, Vila Matias, Santos, SP, 11015-002, Brazil.
| | | | - Naiara Magalhães Cardoso
- Department of Bioscience, Universidade Federal de São Paulo (UNIFESP), R. Silva Jardim, 136 - Vila Matias, Santos, SP, 11015-020, Brazil
| | - Graziele Aparecida da Silva
- Department of Bioscience, Universidade Federal de São Paulo (UNIFESP), R. Silva Jardim, 136 - Vila Matias, Santos, SP, 11015-020, Brazil
| | - Ana Carolina Cardoso Dos Santos
- Department of Bioscience, Universidade Federal de São Paulo (UNIFESP), R. Silva Jardim, 136 - Vila Matias, Santos, SP, 11015-020, Brazil
| | - Fernanda Samantha de Souza
- Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo (UNIFESP), Rua Prof. Artur Riedel, n° 275, Eldorado, Diadema, SP, 09972-270, Brazil
| | - Débora Estadella
- Department of Bioscience, Universidade Federal de São Paulo (UNIFESP), R. Silva Jardim, 136 - Vila Matias, Santos, SP, 11015-020, Brazil
| | - Rafael Herling Lambertucci
- Department of Bioscience, Universidade Federal de São Paulo (UNIFESP), R. Silva Jardim, 136 - Vila Matias, Santos, SP, 11015-020, Brazil
| | - João Henrique Ghilardi Lago
- Center of Natural and Human Sciences, Universidade Federal Do ABC, Av. Dos Estados, 500, Bangú, Santo André, SP, 09210-580, Brazil
| | - Alessandra Medeiros
- Department of Bioscience, Universidade Federal de São Paulo (UNIFESP), R. Silva Jardim, 136 - Vila Matias, Santos, SP, 11015-020, Brazil
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16
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Abend Bardagi A, Dos Santos Paschoal C, Favero GG, Riccetto L, Alexandrino Dias ML, Guerra Junior G, Degasperi G. Leptin's Immune Action: A Review Beyond Satiety. Immunol Invest 2023; 52:117-133. [PMID: 36278927 DOI: 10.1080/08820139.2022.2129381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The adipose tissue is an endocrine organ that secretes adipokines such as leptin, which is one of the most important hormones for controlling satiety, metabolism, and energy homeostasis. This hormone acts in the regulation of innate and adaptive immune responses since immune cells have leptin receptors from which this hormone initiates its biological action. These receptors have been identified in hematopoietic stem cells in the bone marrow and mature immune cells, inducing signaling pathways mediated by JAK/STAT, PI3K, and ERK 1/2. It is known that the bone marrow also contains leptin-producing adipocytes, which are crucial for regulating hematopoiesis through largely unknown mechanisms. Therefore, we have reviewed the roles of leptin inside and outside the bone marrow, going beyond its action in the control of satiety.
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Affiliation(s)
- Alice Abend Bardagi
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Clarissa Dos Santos Paschoal
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Giovanna Ganem Favero
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Luisa Riccetto
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Maria Luisa Alexandrino Dias
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
| | - Gil Guerra Junior
- Center for Investigation in Pediatrics (CIPED), School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, Brazil
| | - Giovanna Degasperi
- Center for Health Sciences, School of Medical Sciences, Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, Brazil
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17
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Ramms B, Pollow DP, Zhu H, Nora C, Harrington AR, Omar I, Gordts PL, Wortham M, Sander M. Systemic LSD1 Inhibition Prevents Aberrant Remodeling of Metabolism in Obesity. Diabetes 2022; 71:2513-2529. [PMID: 36162056 PMCID: PMC9750949 DOI: 10.2337/db21-1131] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 09/06/2022] [Indexed: 01/11/2023]
Abstract
The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates nonalcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting that LSD1 has a context-dependent role in promoting maladaptive changes in obesity. In analysis of insulin target tissues we identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD.
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Affiliation(s)
- Bastian Ramms
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA
| | - Dennis P. Pollow
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA
| | - Han Zhu
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA
| | - Chelsea Nora
- Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Austin R. Harrington
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA
| | - Ibrahim Omar
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA
| | - Philip L.S.M. Gordts
- Department of Medicine, University of California, San Diego, La Jolla, CA
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA
| | - Matthew Wortham
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA
| | - Maike Sander
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA
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18
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The Efficacy of HGF/VEGF Gene Therapy for Limb Ischemia in Mice with Impaired Glucose Tolerance: Shift from Angiogenesis to Axonal Growth and Oxidative Potential in Skeletal Muscle. Cells 2022; 11:cells11233824. [PMID: 36497083 PMCID: PMC9737863 DOI: 10.3390/cells11233824] [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: 11/03/2022] [Revised: 11/23/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Combined non-viral gene therapy (GT) of ischemia and cardiovascular disease is a promising tool for potential clinical translation. In previous studies our group has developed combined gene therapy by vascular endothelial growth factor 165 (VEGF165) + hepatocyte growth factor (HGF). Our recent works have demonstrated that a bicistronic pDNA that carries both human HGF and VEGF165 coding sequences has a potential for clinical application in peripheral artery disease (PAD). The present study aimed to test HGF/VEGF combined plasmid efficacy in ischemic skeletal muscle comorbid with predominant complications of PAD-impaired glucose tolerance and type 2 diabetes mellitus (T2DM). METHODS Male C57BL mice were housed on low-fat (LFD) or high-fat diet (HFD) for 10 weeks and metabolic parameters including FBG level, ITT, and GTT were evaluated. Hindlimb ischemia induction and plasmid administration were performed at 10 weeks with 3 weeks for post-surgical follow-up. Limb blood flow was assessed by laser Doppler scanning at 7, 14, and 21 days after ischemia induction. The necrotic area of m.tibialis anterior, macrophage infiltration, angio- and neuritogenesis were evaluated in tissue sections. The mitochondrial status of skeletal muscle (total mitochondria content, ETC proteins content) was assessed by Western blotting of muscle lysates. RESULTS At 10 weeks, the HFD group demonstrated impaired glucose tolerance in comparison with the LFD group. HGF/VEGF plasmid injection aggravated glucose intolerance in HFD conditions. Blood flow recovery was not changed by HGF/VEGF plasmid injection either in LFD or HFD conditions. GT in LFD, but not in HFD conditions, enlarged the necrotic area and CD68+ cells infiltration. However, HGF/VEGF plasmid enhanced neuritogenesis and enlarged NF200+ area on muscle sections. In HFD conditions, HGF/VEGF plasmid injection significantly increased mitochondria content and ETC proteins content. CONCLUSIONS The current study demonstrated a significant role of dietary conditions in pre-clinical testing of non-viral GT drugs. HGF/VEGF combined plasmid demonstrated a novel aspect of potential participation in ischemic skeletal muscle regeneration, through regulation of innervation and bioenergetics of muscle. The obtained results made HGF/VEGF combined plasmid a very promising tool for PAD therapy in impaired glucose tolerance conditions.
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19
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Speakman JR, Elmquist JK. Obesity: an evolutionary context. LIFE METABOLISM 2022; 1:10-24. [PMID: 36394061 PMCID: PMC9642988 DOI: 10.1093/lifemeta/loac002] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/21/2022] [Accepted: 03/09/2022] [Indexed: 05/07/2023]
Abstract
People completely lacking body fat (lipodystrophy/lipoatrophy) and those with severe obesity both show profound metabolic and other health issues. Regulating levels of body fat somewhere between these limits would, therefore, appear to be adaptive. Two different models might be contemplated. More traditional is a set point (SP) where the levels are regulated around a fixed level. Alternatively, dual-intervention point (DIP) is a system that tolerates fairly wide variation but is activated when critically high or low levels are breached. The DIP system seems to fit our experience much better than an SP, and models suggest that it is more likely to have evolved. A DIP system may have evolved because of two contrasting selection pressures. At the lower end, we may have been selected to avoid low levels of fat as a buffer against starvation, to avoid disease-induced anorexia, and to support reproduction. At the upper end, we may have been selected to avoid excess storage because of the elevated risks of predation. This upper limit of control seems to have malfunctioned because some of us deposit large fat stores, with important negative health effects. Why has evolution not protected us against this problem? One possibility is that the protective system slowly fell apart due to random mutations after we dramatically reduced the risk of being predated during our evolutionary history. By chance, it fell apart more in some people than others, and these people are now unable to effectively manage their weight in the face of the modern food glut. To understand the evolutionary context of obesity, it is important to separate the adaptive reason for storing some fat (i.e. the lower intervention point), from the nonadaptive reason for storing lots of fat (a broken upper intervention point). The DIP model has several consequences, showing how we understand the obesity problem and what happens when we attempt to treat it.
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Affiliation(s)
- John R Speakman
- Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- School of Biological Sciences, University of Aberdeen, Aberdeen, UK
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental biology, Chinese Academy of Sciences, Beijing, China
- CAS Center of Excellence in Animal Evolution and Genetics, Kunming, China
| | - Joel K Elmquist
- Departments of Internal Medicine and Pharmacology, Center for Hypothalamic Research, University of Texas Southwestern, Dallas, TX, USA
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20
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Cui J, Lee S, Sun Y, Zhang C, Hill MA, Li Y, Zhang H. Alternate Day Fasting Improves Endothelial Function in Type 2 Diabetic Mice: Role of Adipose-Derived Hormones. Front Cardiovasc Med 2022; 9:925080. [PMID: 35711339 PMCID: PMC9196729 DOI: 10.3389/fcvm.2022.925080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction Intermittent fasting, including alternate day fasting (ADF), has grown in popularity as it can produce clinically significant metabolic benefits and is often considered to be easier to adhere to than other types of diets such as chronic calorie restriction. However, the effects of ADF on diabetes-associated vascular dysfunction, and the role of adipose-derived hormones, i.e., adipokines, in mediating its effects, remain largely unknown. Objective We aimed to test the hypothesis that ADF protects against diabetes-associated endothelial dysfunction, at least partly through modulating adipokine profiles. Methods Control mice (m Lepr db ) and diabetic mice (Leprdb ) were treated with 12-weeks of ADF. Glucose metabolism, endothelial function, and adipokine profile were assessed. Results ADF reduced fasting blood glucose level and homeostatic model assessment for insulin resistance (HOMA-IR), and improved insulin sensitivity. ADF improved endothelium-dependent vasorelaxation of small mesenteric arteries (SMA) of Leprdb mice. The improvement in endothelial function was largely attenuated by incubation with the nitric oxide synthase inhibitor, L-NAME. These ADF-induced metabolic and vascular benefits were accompanied by increased circulating adiponectin. Adenovirus-mediated adiponectin supplementation improved endothelial function in Leprdb mice, supporting endothelial protective roles in diabetes-associated endothelial dysfunction. Protein tyrosine nitration is a post-translational modification that serves as a marker of oxidative stress. Nitrotyrosine protein levels in SMA and mesenteric adipose tissue (MAT) were elevated in Leprdb mice. ADF reduced nitrotyrosine protein in SMA, but not in MAT, of Leprdb mice. Conclusion ADF exerts metabolic and endothelial protective benefits. The improvement of endothelial function was partly mediated by increased adiponectin, representing an important mechanism for the beneficial vascular effects resulting from ADF.
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Affiliation(s)
- Jian Cui
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Dalton Cardiovascular Research Center, School of Medicine, University of Missouri, Columbia, MO, United States
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, United States
| | - Sewon Lee
- Dalton Cardiovascular Research Center, School of Medicine, University of Missouri, Columbia, MO, United States
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, United States
- Division of Sport Science, College of Arts and Physical Education, Incheon National University, Incheon, South Korea
| | - Yan Sun
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Cuihua Zhang
- Dalton Cardiovascular Research Center, School of Medicine, University of Missouri, Columbia, MO, United States
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, United States
| | - Michael A. Hill
- Dalton Cardiovascular Research Center, School of Medicine, University of Missouri, Columbia, MO, United States
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, United States
| | - Yuhang Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Hanrui Zhang
- Dalton Cardiovascular Research Center, School of Medicine, University of Missouri, Columbia, MO, United States
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, United States
- Department of Medicine, Division of Cardiology, Cardiometabolic Genomics Program, Columbia University Irving Medical Center, New York, NY, United States
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21
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Hyun U, Sohn JW. Autonomic control of energy balance and glucose homeostasis. Exp Mol Med 2022; 54:370-376. [PMID: 35474336 PMCID: PMC9076646 DOI: 10.1038/s12276-021-00705-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/07/2021] [Indexed: 11/21/2022] Open
Abstract
Neurons in the central nervous system (CNS) communicate with peripheral organs largely via the autonomic nervous system (ANS). Through such communications, the sympathetic and parasympathetic efferent divisions of the ANS may affect thermogenesis and blood glucose levels. In contrast, peripheral organs send feedback to the CNS via hormones and autonomic afferent nerves. These humoral and neural feedbacks, as well as neural commands from higher brain centers directly or indirectly shape the metabolic function of autonomic neurons. Notably, recent developments in mouse genetics have enabled more detailed studies of ANS neurons and circuits, which have helped elucidate autonomic control of metabolism. Here, we will summarize the functional organization of the ANS and discuss recent updates on the roles of neural and humoral factors in the regulation of energy balance and glucose homeostasis by the ANS. Cutting-edge techniques should be harnessed to unravel how metabolism is modulated by a key part of the body’s nervous system. The autonomic nervous system (ANS) regulates many involuntary physiological processes, such as heart rate, breathing, and blood pressure. Scientists now believe that the ANS is involved in regulating metabolism, but its precise roles are unclear. Jong-Woo Sohn and Uisu Hyun at the Korea Advanced Institute of Science and Technology, Daejeon, Korea, reviewed understanding of how the ANS regulates energy balance, appetite, and glucose homeostasis. Recently-developed mouse models have provided insights into how ANS neurons translate neuronal and hormonal signals into commands during feeding, sending instructions to the liver, and mediating blood glucose levels. Several hormones have been identified that may act on a specific part of the ANS to influence appetite and metabolism.
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Affiliation(s)
- Uisu Hyun
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea
| | - Jong-Woo Sohn
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea.
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22
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Watts AG, Kanoski SE, Sanchez-Watts G, Langhans W. The physiological control of eating: signals, neurons, and networks. Physiol Rev 2022; 102:689-813. [PMID: 34486393 PMCID: PMC8759974 DOI: 10.1152/physrev.00028.2020] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 08/30/2021] [Indexed: 02/07/2023] Open
Abstract
During the past 30 yr, investigating the physiology of eating behaviors has generated a truly vast literature. This is fueled in part by a dramatic increase in obesity and its comorbidities that has coincided with an ever increasing sophistication of genetically based manipulations. These techniques have produced results with a remarkable degree of cell specificity, particularly at the cell signaling level, and have played a lead role in advancing the field. However, putting these findings into a brain-wide context that connects physiological signals and neurons to behavior and somatic physiology requires a thorough consideration of neuronal connections: a field that has also seen an extraordinary technological revolution. Our goal is to present a comprehensive and balanced assessment of how physiological signals associated with energy homeostasis interact at many brain levels to control eating behaviors. A major theme is that these signals engage sets of interacting neural networks throughout the brain that are defined by specific neural connections. We begin by discussing some fundamental concepts, including ones that still engender vigorous debate, that provide the necessary frameworks for understanding how the brain controls meal initiation and termination. These include key word definitions, ATP availability as the pivotal regulated variable in energy homeostasis, neuropeptide signaling, homeostatic and hedonic eating, and meal structure. Within this context, we discuss network models of how key regions in the endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, and spinal cord work together with the gastrointestinal tract to enable the complex motor events that permit animals to eat in diverse situations.
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Affiliation(s)
- Alan G Watts
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Scott E Kanoski
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Graciela Sanchez-Watts
- The Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Eidgenössische Technische Hochschule-Zürich, Schwerzenbach, Switzerland
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23
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Sato M, Nakamura S, Inada E, Takabayashi S. Recent Advances in the Production of Genome-Edited Rats. Int J Mol Sci 2022; 23:ijms23052548. [PMID: 35269691 PMCID: PMC8910656 DOI: 10.3390/ijms23052548] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/17/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
The rat is an important animal model for understanding gene function and developing human disease models. Knocking out a gene function in rats was difficult until recently, when a series of genome editing (GE) technologies, including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the type II bacterial clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated Cas9 (CRISPR/Cas9) systems were successfully applied for gene modification (as exemplified by gene-specific knockout and knock-in) in the endogenous target genes of various organisms including rats. Owing to its simple application for gene modification and its ease of use, the CRISPR/Cas9 system is now commonly used worldwide. The most important aspect of this process is the selection of the method used to deliver GE components to rat embryos. In earlier stages, the microinjection (MI) of GE components into the cytoplasm and/or nuclei of a zygote was frequently employed. However, this method is associated with the use of an expensive manipulator system, the skills required to operate it, and the egg transfer (ET) of MI-treated embryos to recipient females for further development. In vitro electroporation (EP) of zygotes is next recognized as a simple and rapid method to introduce GE components to produce GE animals. Furthermore, in vitro transduction of rat embryos with adeno-associated viruses is potentially effective for obtaining GE rats. However, these two approaches also require ET. The use of gene-engineered embryonic stem cells or spermatogonial stem cells appears to be of interest to obtain GE rats; however, the procedure itself is difficult and laborious. Genome-editing via oviductal nucleic acids delivery (GONAD) (or improved GONAD (i-GONAD)) is a novel method allowing for the in situ production of GE zygotes existing within the oviductal lumen. This can be performed by the simple intraoviductal injection of GE components and subsequent in vivo EP toward the injected oviducts and does not require ET. In this review, we describe the development of various approaches for producing GE rats together with an assessment of their technical advantages and limitations, and present new GE-related technologies and current achievements using those rats in relation to human diseases.
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Affiliation(s)
- Masahiro Sato
- Department of Genome Medicine, National Center for Child Health and Development, Tokyo 157-8535, Japan
- Correspondence: (M.S.); (S.T.); Tel.: +81-3-3416-0181 (M.S.); +81-53-435-2001 (S.T.)
| | - Shingo Nakamura
- Division of Biomedical Engineering, National Defense Medical College Research Institute, Saitama 359-8513, Japan;
| | - Emi Inada
- Department of Pediatric Dentistry, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan;
| | - Shuji Takabayashi
- Laboratory Animal Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
- Correspondence: (M.S.); (S.T.); Tel.: +81-3-3416-0181 (M.S.); +81-53-435-2001 (S.T.)
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24
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Carpéné C, Marti L, Morin N. Increased monoamine oxidase activity and imidazoline binding sites in insulin-resistant adipocytes from obese Zucker rats. World J Biol Chem 2022; 13:15-34. [PMID: 35126867 PMCID: PMC8790288 DOI: 10.4331/wjbc.v13.i1.15] [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: 03/26/2021] [Revised: 07/09/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite overt insulin resistance, adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.
AIM To investigate whether factors can replace or reinforce insulin lipogenic action by exploring glucose uptake activation by hydrogen peroxide, since it is produced by monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) in adipocytes.
METHODS 3H-2-deoxyglucose uptake (2-DG) was determined in adipocytes from obese and lean rats in response to insulin or MAO and SSAO substrates such as tyramine and benzylamine. 14C-tyramine oxidation and binding of imidazolinic radioligands [3H-Idazoxan, 3H-(2-benzofuranyl)-2-imidazoline] were studied in adipocytes, the liver, and muscle. The influence of in vivo administration of tyramine + vanadium on glucose handling was assessed in lean and obese rats.
RESULTS 2-DG uptake and lipogenesis stimulation by insulin were dampened in adipocytes from obese rats, when compared to their lean littermates. Tyramine and benzylamine activation of hexose uptake was vanadate-dependent and was also limited, while MAO was increased and SSAO decreased. These changes were adipocyte-specific and accompanied by a greater number of imidazoline I2 binding sites in the obese rat, when compared to the lean. In vitro, tyramine precluded the binding to I2 sites, while in vivo, its administration together with vanadium lowered fasting plasma levels of glucose and triacylglycerols in obese rats.
CONCLUSION The adipocytes from obese Zucker rats exhibit increased MAO activity and imidazoline binding site number. However, probably as a consequence of SSAO down-regulation, the glucose transport stimulation by tyramine is decreased as much as that of insulin in these insulin-resistant adipocytes. The adipocyte amine oxidases deserve more studies with respect to their putative contribution to the management of glucose and lipid handling.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
| | - Luc Marti
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
| | - Nathalie Morin
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM, Toulouse 31342, France
- Faculté de Pharmacie de Paris, Paris University, Paris 75270, France
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25
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Metabolic Status of Lean and Obese Zucker Rats Based on Untargeted and Targeted Metabolomics Analysis of Serum. Biomedicines 2022; 10:biomedicines10010153. [PMID: 35052832 PMCID: PMC8773868 DOI: 10.3390/biomedicines10010153] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/04/2022] [Accepted: 01/10/2022] [Indexed: 01/02/2023] Open
Abstract
Obesity is growing worldwide epidemic. Animal models can provide some clues about the etiology, development, prevention, and treatment of obesity. We examined and compared serum metabolites between seven lean (L) and seven obese (O) female Zucker rats to investigate the individual serum metabolic profile. A combination of HPLC-UV, HPLC-ECD, and LC-MS revealed more than 400 peaks. The 50 highest quality peaks were selected as the focus of our study. Untargeted metabolomics analysis showed significantly higher mean peak heights for 20 peaks in L rats, generally distributed randomly, except for a cluster (peaks 44–50) where L showed stable dominancy over O. Only eight peaks were significantly higher in O rats. Peak height ratios between pairs of L and O rats were significantly higher at 199 positions in L rats and at 123 positions in O rats. Targeted metabolomics analysis showed significantly higher levels of methionine, cysteine, tryptophan, kynurenic acid, and cysteine/cystine ratio in L rats and significantly higher levels of cystine and tyrosine in O rats. These results contribute to a better understanding of systemic metabolic perturbations in the obese Zucker rat model, emphasizing the value of both whole metabolome and individual metabolic profiles in the design and interpretation of studies using animal models.
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26
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Leptin enhances social motivation and reverses chronic unpredictable stress-induced social anhedonia during adolescence. Mol Psychiatry 2022; 27:4948-4958. [PMID: 36138127 PMCID: PMC9763124 DOI: 10.1038/s41380-022-01778-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/12/2022] [Accepted: 09/02/2022] [Indexed: 01/19/2023]
Abstract
Social anhedonia, a loss of interest and pleasure in social interactions, is a common symptom of major depression as well as other psychiatric disorders. Depression can occur at any age, but typically emerges in adolescence or early adulthood, which represents a sensitive period for social interaction that is vulnerable to stress. In this study, we evaluated social interaction reward using a conditioned place preference (CPP) paradigm in adolescent male and female mice. Adolescent mice of both sexes exhibited a preference for the social interaction-associated context. Chronic unpredictable stress (CUS) impaired the development of CPP for social interaction, mimicking social anhedonia in depressed adolescents. Conversely, administration of leptin, an adipocyte-derived hormone, enhanced social interaction-induced CPP in non-stressed control mice and reversed social anhedonia in CUS mice. By dissecting the motivational processes of social CPP into social approach and isolation avoidance components, we demonstrated that leptin treatment increased isolation aversion without overt social reward effect. Further mechanistic exploration revealed that leptin stimulated oxytocin gene transcription in the paraventricular nucleus of the hypothalamus, while oxytocin receptor blockade abolished the leptin-induced enhancement of socially-induced CPP. These results establish that chronic unpredictable stress can be used to study social anhedonia in adolescent mice and provide evidence that leptin modulates social motivation possibly via increasing oxytocin synthesis and oxytocin receptor activation.
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27
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Cai L, Li W, Zeng R, Cao Z, Guo Q, Huang Q, Liu X. Valsartan alleviates the blood-brain barrier dysfunction in db/db diabetic mice. Bioengineered 2021; 12:9070-9080. [PMID: 34697992 PMCID: PMC8806495 DOI: 10.1080/21655979.2021.1981799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Type 2 diabetes (T2D)-related neurological complication is the risk factor for neurodegenerative disorders. The pathological changes from T2D-caused blood–brain barrier (BBB) dysfunction plays a critical role in developing neurodegeneration. The hyper-activation of the Angiotensin II type 1 receptor (AT1R) in the brain is associated with neurovascular impairment. The AT1R antagonist Valsartan is commonly prescribed to control high blood pressure, heart failure, and diabetic kidney diseases. In this study, we investigated the beneficial effects of Valsartan in db/db diabetic mice and isolated brain endothelial cells. We showed that 2 weeks of Valsartan administration (30 mg/Kg body weight) mitigated the increased permeability of the brain-blood barrier and the reduction of gap junction proteins VE-Cadherin and Claudin 2. In human brain microvascular cells (HBMVECs), we found that Valsartan treatment ameliorated high glucose-induced hyperpermeability by measuring Dextran uptake and transendothelial electrical resistance (TEER). Furthermore, Valsartan treatment recovered high glucose-repressed endothelial VE-Cadherin and Claudin 2 expression. Moreover, Valsartan significantly suppressed the expressions of pro-inflammatory cytokines such as macrophage chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) against high glucose. Mechanistically, Valsartan ameliorated high glucose-repressed endothelial cAMP-responsive element-binding protein (CREB) signaling activation. The blockage of CREB activation by PKA inhibitor H89 abolished the action of Valsartan, suggesting its dependence on CREB signaling. In conclusion, Valsartan shows a neuroprotective effect in diabetic mice by ameliorating BBB dysfunction. These effects of Valsartan require cellular CREB signaling in brain endothelial cells.
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Affiliation(s)
- Longxue Cai
- Department of Emergency, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Wenfeng Li
- Department of Cardiology, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, China
| | - Renqing Zeng
- Department of Emergency, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Zuohong Cao
- Department of Emergency, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Qicai Guo
- Department of Emergency, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Qi Huang
- Department of Emergency, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
| | - Xianfa Liu
- Department of Emergency, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China
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Cutaneous innervation in impaired diabetic wound healing. Transl Res 2021; 236:87-108. [PMID: 34029747 PMCID: PMC8380642 DOI: 10.1016/j.trsl.2021.05.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, which communicate with epidermal keratinocytes and dermal fibroblasts bidirectionally to effect normal wound healing after trauma. However, the mechanisms through which cutaneous innervation modulates wound healing are poorly understood, especially in humans. Better understanding of these mechanisms may provide the basis for targeted treatments for chronic diabetic wounds. This review provides an overview of wound healing pathophysiology with a focus on neural involvement in normal and diabetic wound healing, as well as future therapeutic perspectives to address the unmet needs of diabetic patients with chronic wounds.
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29
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De Rosa MC, Glover HJ, Stratigopoulos G, LeDuc CA, Su Q, Shen Y, Sleeman MW, Chung WK, Leibel RL, Altarejos JY, Doege CA. Gene expression atlas of energy balance brain regions. JCI Insight 2021; 6:e149137. [PMID: 34283813 PMCID: PMC8409984 DOI: 10.1172/jci.insight.149137] [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] [Indexed: 01/03/2023] Open
Abstract
Energy balance is controlled by interconnected brain regions in the hypothalamus, brainstem, cortex, and limbic system. Gene expression signatures of these regions can help elucidate the pathophysiology underlying obesity. RNA sequencing was conducted on P56 C57BL/6NTac male mice and E14.5 C57BL/6NTac embryo punch biopsies in 16 obesity-relevant brain regions. The expression of 190 known obesity-associated genes (monogenic, rare, and low-frequency coding variants; GWAS; syndromic) was analyzed in each anatomical region. Genes associated with these genetic categories of obesity had localized expression patterns across brain regions. Known monogenic obesity causal genes were highly enriched in the arcuate nucleus of the hypothalamus and developing hypothalamus. The obesity-associated genes clustered into distinct “modules” of similar expression profile, and these were distinct from expression modules formed by similar analysis with genes known to be associated with other disease phenotypes (type 1 and type 2 diabetes, autism, breast cancer) in the same energy balance–relevant brain regions.
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Affiliation(s)
- Maria Caterina De Rosa
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,Columbia Stem Cell Initiative, and
| | - Hannah J Glover
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,Columbia Stem Cell Initiative, and
| | - George Stratigopoulos
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons
| | - Charles A LeDuc
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,New York Obesity Nutrition Research Center, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Qi Su
- Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
| | - Yufeng Shen
- Department of Systems Biology.,Department of Biomedical Informatics
| | - Mark W Sleeman
- Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
| | - Wendy K Chung
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,Department of Medicine.,Herbert Irving Comprehensive Cancer Center.,Institute of Human Nutrition
| | - Rudolph L Leibel
- Department of Pediatrics and Molecular Genetics.,Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,New York Obesity Nutrition Research Center, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Institute of Human Nutrition
| | | | - Claudia A Doege
- Naomi Berrie Diabetes Center, College of Physicians and Surgeons.,Columbia Stem Cell Initiative, and.,New York Obesity Nutrition Research Center, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.,Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
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30
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Quiroz J, Yazdanyar A. Animal models of diabetic retinopathy. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1272. [PMID: 34532409 PMCID: PMC8421981 DOI: 10.21037/atm-20-6737] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 12/23/2020] [Indexed: 12/16/2022]
Abstract
The retina is the posterior neuro-integrated layer of the eye that conducts impulses induced by light to the optic nerve for human vision. Diseases of the retina often leads to diminished vision and in some cases blindness. Diabetes mellitus (DM) is a worldwide public health issue and globally, there is an estimated 463 million people that are affected by DM and its consequences. Diabetic retinopathy (DR) is a blinding complication of chronic uncontrolled DM and is the most common cause of blindness in the United States between the ages 24-75. It is estimated that the global prevalence of DR will increase to 191.0 million by 2030, of those 56.3 million possessing vision-threatening diabetic retinopathy (VTDR). For the most part, current treatment modalities control the complications of DR without addressing the underlying pathophysiology of the disease. Therefore, there is an unmet need for new therapeutics that not only repair the damaged retinal tissue, but also reverse the course of DR. The key element in developing these treatments is expanding our basic knowledge by studying DR pathogenesis in animal models of proliferative and non-proliferative DR (PDR and NPDR). There are numerous models available for the research of both PDR and NPDR with substantial overlap. Animal models available include those with genetic backgrounds prone to hyperglycemic states, immunologic etiologies, or environmentally induced disease. In this review we aimed to comprehensively summarize the available animal models for DR while also providing insight to each model's ocular therapeutic potential for drug discovery.
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Affiliation(s)
- Jose Quiroz
- Medical Scientist Training Program, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Amirfarbod Yazdanyar
- Department of Ophthalmology and Visual Sciences, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
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31
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Li C, Meng F, Lei Y, Liu J, Liu J, Zhang J, Liu F, Liu C, Guo M, Lu XY. Leptin regulates exon-specific transcription of the Bdnf gene via epigenetic modifications mediated by an AKT/p300 HAT cascade. Mol Psychiatry 2021; 26:3701-3722. [PMID: 33106599 PMCID: PMC8550971 DOI: 10.1038/s41380-020-00922-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/07/2020] [Accepted: 10/08/2020] [Indexed: 01/17/2023]
Abstract
Leptin is an adipocyte-derived hormone with pleiotropic functions affecting appetite and mood. While leptin's role in the regulation of appetite has been extensively studied in hypothalamic neurons, its function in the hippocampus, where it regulates mood-related behaviors, is poorly understood. Here, we show that the leptin receptor (LepRb) colocalizes with brain-derived neurotrophic factor (BDNF), a key player in the pathophysiology of major depression and the action of antidepressants, in the dentate gyrus of the hippocampus. Leptin treatment increases, whereas deficiency of leptin or leptin receptors decreases, total Bdnf mRNA levels, with distinct expression profiles of specific exons, in the hippocampus. Epigenetic analyses reveal that histone modifications, but not DNA methylation, underlie exon-specific transcription of the Bdnf gene induced by leptin. This is mediated by stimulation of AKT signaling, which in turn activates histone acetyltransferase p300 (p300 HAT), leading to changes in histone H3 acetylation and methylation at specific Bdnf promoters. Furthermore, deletion of Bdnf in the dentate gyrus, or specifically in LepRb-expressing neurons, abolishes the antidepressant-like effects of leptin. These findings indicate that leptin, acting via an AKT-p300 HAT epigenetic cascade, induces exon-specific Bdnf expression, which in turn is indispensable for leptin-induced antidepressant-like effects.
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Affiliation(s)
- Chen Li
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Shandong, China.
- Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA.
| | - Fantao Meng
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Shandong, China
| | - Yun Lei
- Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Jing Liu
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jing Liu
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Shandong, China
| | - Jingyan Zhang
- Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Fang Liu
- Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Cuilan Liu
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Shandong, China
| | - Ming Guo
- Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Xin-Yun Lu
- Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA.
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
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32
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Marques Miranda C, de Lima Campos M, Leite-Almeida H. Diet, body weight and pain susceptibility - A systematic review of preclinical studies. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2021; 10:100066. [PMID: 34195483 PMCID: PMC8237587 DOI: 10.1016/j.ynpai.2021.100066] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/26/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Obesity has been associated with increased chronic pain susceptibility but causes are unclear. In this review, we systematize and analyze pain outcomes in rodent models of obesity as these can be important tools for mechanistic studies. Studies were identified using MEDLINE/PubMed and Scopus databases using the following search query: (((pain) OR (nociception)) AND (obesity)) AND (rat OR (mouse) OR (rodent))). From each eligible record we extracted the following data: species, strain, sex, pain/obesity model and main behavioral readouts. Out of 695 records 33 were selected for inclusion. 27 studies assessed nociception/acute pain and 17 studies assessed subacute or chronic pain. Overall genetic and dietary models overlapped in pain-related outcomes. Most acute pain studies reported either decreased or unaltered responses to noxious painful stimuli. However, decreased thresholds to mechanical innocuous stimuli, i.e. allodynia, were frequently reported. In most studies using subacute and chronic pain models, namely of subcutaneous inflammation, arthritis and perineural inflammation, decreased thresholds and/or prolonged pain manifestations were reported in obesity models. Strain comparisons and longitudinal observations indicate that genetic factors and the time course of the pathology might account for some of the discrepancies observed across studies. Two studies reported increased pain in animals subjected to high fat diet in the absence of weight gain. Pain-related outcomes in experimental models and clinical obesity are aligned indicating that the rodent can be an useful tool to study the interplay between diet, obesity and pain. In both cases weight gain might represent only a minor contribution to abnormal pain manifestation.
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Affiliation(s)
- Carolina Marques Miranda
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Mariana de Lima Campos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Hugo Leite-Almeida
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
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33
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Ryan G, Magony R, Gortler H, Godbout C, Schemitsch EH, Nauth A. Systemically impaired fracture healing in small animal research: A review of fracture repair models. J Orthop Res 2021; 39:1359-1367. [PMID: 33580554 DOI: 10.1002/jor.25003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/09/2020] [Accepted: 02/10/2021] [Indexed: 02/04/2023]
Abstract
Fracture healing is a complex process requiring mechanical stability, an osteoconductive matrix, and osteoinductive and osteogenic biology. This intricate process is easily disrupted by various patient factors such as chronic disease and lifestyle. As the medical complexity and age of patients with fractures continue to increase, the importance of developing relevant experimental models is becoming paramount in preclinical research. The objective of this review is to describe the most common small animal models of systemically impaired fracture healing used in the orthopedic literature including osteoporosis, diabetes mellitus, smoking, alcohol use, obesity, and ageing. This review will provide orthopedic researchers with a summary of current models of systemically impaired fracture healing used in small animals and present an overview of the methods of induction for each condition.
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Affiliation(s)
- Gareth Ryan
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Richard Magony
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Hilary Gortler
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Charles Godbout
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
| | - Emil H Schemitsch
- Department of Surgery, Division of Orthopaedic Surgery, University of Western Ontario, London, Ontario, Canada
| | - Aaron Nauth
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada.,Department of Surgery, Division of Orthopaedic Surgery, St. Michael's Hospital - Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
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34
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Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine? Int J Mol Sci 2021; 22:ijms22126445. [PMID: 34208585 PMCID: PMC8235268 DOI: 10.3390/ijms22126445] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/03/2021] [Accepted: 06/10/2021] [Indexed: 12/17/2022] Open
Abstract
Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.
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35
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Kennon AM, Stewart JA. RAGE Differentially Altered in vitro Responses in Vascular Smooth Muscle Cells and Adventitial Fibroblasts in Diabetes-Induced Vascular Calcification. Front Physiol 2021; 12:676727. [PMID: 34163373 PMCID: PMC8215351 DOI: 10.3389/fphys.2021.676727] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
The Advanced Glycation End-Products (AGE)/Receptor for AGEs (RAGE) signaling pathway exacerbates diabetes-mediated vascular calcification (VC) in vascular smooth muscle cells (VSMCs). Other cell types are involved in VC, such as adventitial fibroblasts (AFBs). We hope to elucidate some of the mechanisms responsible for differential signaling in diabetes-mediated VC with this work. This work utilizes RAGE knockout animals and in vitro calcification to measure calcification and protein responses. Our calcification data revealed that VSMCs calcification was AGE/RAGE dependent, yet AFBs calcification was not an AGE-mediated RAGE response. Protein expression data showed VSMCs lost their phenotype marker, α-smooth muscle actin, and had a higher RAGE expression over non-diabetics. RAGE knockout (RKO) VSMCs did not show changes in phenotype markers. P38 MAPK, a downstream RAGE-associated signaling molecule, had significantly increased activation with calcification in both diabetic and diabetic RKO VSMCs. AFBs showed a loss in myofibroblast marker, α-SMA, due to calcification treatment. RAGE expression decreased in calcified diabetic AFBs, and P38 MAPK activation significantly increased in diabetic and diabetic RKO AFBs. These findings point to potentially an alternate receptor mediating the calcification response in the absence of RAGE. Overall, VSMCs and AFBs respond differently to calcification and the application of AGEs.
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Affiliation(s)
- Amber M Kennon
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Mississippi, MS, United States
| | - James A Stewart
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Mississippi, MS, United States
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36
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McKimpson WM, Chen Y, Irving JA, Zheng M, Weinberger J, Tan WLW, Tiang Z, Jagger AM, Chua SC, Pessin JE, Foo RSY, Lomas DA, Kitsis RN. Conversion of the death inhibitor ARC to a killer activates pancreatic β cell death in diabetes. Dev Cell 2021; 56:747-760.e6. [PMID: 33667344 DOI: 10.1016/j.devcel.2021.02.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 12/28/2020] [Accepted: 02/09/2021] [Indexed: 01/06/2023]
Abstract
Loss of insulin-secreting pancreatic β cells through apoptosis contributes to the progression of type 2 diabetes, but underlying mechanisms remain elusive. Here, we identify a pathway in which the cell death inhibitor ARC paradoxically becomes a killer during diabetes. While cytoplasmic ARC maintains β cell viability and pancreatic architecture, a pool of ARC relocates to the nucleus to induce β cell apoptosis in humans with diabetes and several pathophysiologically distinct mouse models. β cell death results through the coordinate downregulation of serpins (serine protease inhibitors) not previously known to be synthesized and secreted by β cells. Loss of the serpin α1-antitrypsin from the extracellular space unleashes elastase, triggering the disruption of β cell anchorage and subsequent cell death. Administration of α1-antitrypsin to mice with diabetes prevents β cell death and metabolic abnormalities. These data uncover a pathway for β cell loss in type 2 diabetes and identify an FDA-approved drug that may impede progression of this syndrome.
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Affiliation(s)
- Wendy M McKimpson
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Yun Chen
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - James A Irving
- UCL Respiratory Medicine, University College London, London WC1E 6BN, UK; Institute of Structural and Molecular Biology/Birkbeck, University of London, London WC1E 7HX, UK
| | - Min Zheng
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Jeremy Weinberger
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Wilson Lek Wen Tan
- Cardiovascular Research Institute, National University Health Systems, Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Zenia Tiang
- Cardiovascular Research Institute, National University Health Systems, Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Alistair M Jagger
- UCL Respiratory Medicine, University College London, London WC1E 6BN, UK; Institute of Structural and Molecular Biology/Birkbeck, University of London, London WC1E 7HX, UK
| | - Streamson C Chua
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Jeffrey E Pessin
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Roger S-Y Foo
- Cardiovascular Research Institute, National University Health Systems, Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - David A Lomas
- UCL Respiratory Medicine, University College London, London WC1E 6BN, UK; Institute of Structural and Molecular Biology/Birkbeck, University of London, London WC1E 7HX, UK
| | - Richard N Kitsis
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Voigtmann F, Wolf P, Landgraf K, Stein R, Kratzsch J, Schmitz S, Abou Jamra R, Blüher M, Meiler J, Beck-Sickinger AG, Kiess W, Körner A. Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity. Metabolism 2021; 116:154438. [PMID: 33221380 DOI: 10.1016/j.metabol.2020.154438] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/13/2020] [Accepted: 11/17/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Deficiency in the leptin-leptin receptor (LEPR) axis leads to severe, and potentially treatable, obesity in humans. To guide clinical decision-making, the functional relevance of variants in the LEPR gene needs to be carefully investigated. CASES AND METHODS We characterized the functional impact of LEPR variants identified in two patients with severe early-onset obesity (1: compound heterozygous for the novel variant p.Tyr411del and p.Trp664Arg; 2: heterozygous for p.Arg612His) by investigating leptin-mediated signaling, leptin binding, receptor expression on cell surfaces, and receptor dimerization and activation for either wild-type and/or mutant LEPR. RESULTS Leptin-induced STAT3-phosphorylation was blunted the novel p.Tyr411del or the p.Trp664Arg variant and mildly reduced with the p.Arg612His variant. Computational structure prediction suggested impaired leptin binding for all three LEPR variants. Experimentally, reduced leptin binding of all mutant proteins was due to diminished LEPR expression on the cell surface, with the p.Trp664Arg mutations being the most affected. Considering the heterozygosity in our patients, we assessed the heterodimerization capacity with the wild-type LEPR, which was retained for the p.Tyr411del and p.Arg612His variants. Finally, mimicking (compound) heterozygosity, we confirmed abolished STAT3-phosphorylation for the variant combination [p.Tyr411del + p.Trp664Arg] as found in patient 1, whereas it was retained for [p.Arg612His + wilde type] as found in patient 2. CONCLUSIONS The novel p.Tyr411del mutation causes complete loss of function alone (and combined with p.Trp664Arg) and is likely the cause for the early onset obesity, qualifying the patient for pharmacologic treatment. Heterozygosity for the p.Arg612His variant, however, appears unlikely to be solely responsible for the phenotype.
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Affiliation(s)
- Franziska Voigtmann
- Center of Pediatric Research Leipzig, University Hospital for Children & Adolescents, Medical Faculty, University of Leipzig, Germany
| | - Philipp Wolf
- Institute of Biochemistry, Faculty of Life Sciences, Pharmacy and Psychology, University of Leipzig, Germany
| | - Kathrin Landgraf
- Center of Pediatric Research Leipzig, University Hospital for Children & Adolescents, Medical Faculty, University of Leipzig, Germany
| | - Robert Stein
- Center of Pediatric Research Leipzig, University Hospital for Children & Adolescents, Medical Faculty, University of Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Germany
| | - Jürgen Kratzsch
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnosis, University Medical Center Leipzig, Medical Faculty, University of Leipzig, Germany
| | - Samuel Schmitz
- Department of Chemistry and Center for Structural Biology, Vanderbilt University, TN, USA
| | - Rami Abou Jamra
- Institute of Human Genetics, University Medical Center Leipzig, Medical Faculty, University of Leipzig, Germany
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Germany; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig, Germany
| | - Jens Meiler
- Department of Chemistry and Center for Structural Biology, Vanderbilt University, TN, USA; Institute of Drug Discovery, Medical Faculty, University of Leipzig, Germany
| | - Annette G Beck-Sickinger
- Institute of Biochemistry, Faculty of Life Sciences, Pharmacy and Psychology, University of Leipzig, Germany
| | - Wieland Kiess
- Center of Pediatric Research Leipzig, University Hospital for Children & Adolescents, Medical Faculty, University of Leipzig, Germany
| | - Antje Körner
- Center of Pediatric Research Leipzig, University Hospital for Children & Adolescents, Medical Faculty, University of Leipzig, Germany.
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38
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Zaghlool SB, Sharma S, Molnar M, Matías-García PR, Elhadad MA, Waldenberger M, Peters A, Rathmann W, Graumann J, Gieger C, Grallert H, Suhre K. Revealing the role of the human blood plasma proteome in obesity using genetic drivers. Nat Commun 2021; 12:1279. [PMID: 33627659 PMCID: PMC7904950 DOI: 10.1038/s41467-021-21542-4] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 01/29/2021] [Indexed: 12/21/2022] Open
Abstract
Blood circulating proteins are confounded readouts of the biological processes that occur in different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets further elucidating the role of these proteins in obesity associated pathologies.
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Affiliation(s)
- Shaza B Zaghlool
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Sapna Sharma
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Megan Molnar
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
| | - Pamela R Matías-García
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- TUM School of Medicine, Technical University of Munich, Munich, Germany
| | - Mohamed A Elhadad
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Melanie Waldenberger
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- German Research Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- German Research Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Wolfgang Rathmann
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Biometrics and Epidemiology, German Diabetes Center, Düsseldorf, Germany
| | - Johannes Graumann
- Scientific Service Group Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, Bad Nauheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Max Planck Institute of Heart and Lung Research, Bad Nauheim, Germany
| | - Christian Gieger
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Harald Grallert
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Karsten Suhre
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar.
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Hosszu A, Kaucsar T, Seeliger E, Fekete A. Animal Models of Renal Pathophysiology and Disease. Methods Mol Biol 2021; 2216:27-44. [PMID: 33475992 DOI: 10.1007/978-1-0716-0978-1_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Renal diseases remain devastating illnesses with unacceptably high rates of mortality and morbidity worldwide. Animal models are essential tools to better understand the pathomechanisms of kidney-related illnesses and to develop new, successful therapeutic strategies. Magnetic resonance imaging (MRI) has been actively explored in the last decades for assessing renal function, perfusion, tissue oxygenation as well as the degree of fibrosis and inflammation. This chapter aims to provide a comprehensive overview of animal models of acute and chronic kidney diseases, highlighting MRI-specific considerations, advantages, and pitfalls, and thus assisting the researcher in experiment planning.This publication is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.
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Affiliation(s)
- Adam Hosszu
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Tamas Kaucsar
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Erdmann Seeliger
- Working Group Integrative Kidney Physiology, Institute of Physiology, Charité-University Medicine Berlin, Berlin, Germany
| | - Andrea Fekete
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
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Sawczyn T, Stygar D, Nabrdalik K, Kukla M, Masri O, Magrowski Ł, Karcz W, Jochem J. Effect of Ileal Transposition (IT) on Angiopoietin-Like Protein-8 (ANGPTL8) and Pentraxin (PTX3) Plasma Level in Sprague-Dawley Rats Fed High-Fat Diet (HFD). Int J Endocrinol 2021; 2021:6699923. [PMID: 34035808 PMCID: PMC8118740 DOI: 10.1155/2021/6699923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/09/2021] [Accepted: 04/30/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Metabolic surgery procedures are designed not only for sustained weight loss but also for achieving positive metabolic changes, including improved glucose tolerance and insulin sensitivity, along with an increase in energy expenditure. Based on recent findings, the present study focuses on the relationship between the effects of ileal transposition (IT), high-fat diet (HFD), and selected markers of lipid metabolism and inflammation. METHODS Forty-eight male rats were divided into two groups: HFD and control diet (CD) fed rats. After eight weeks, animals in each group were randomly assigned to two types of surgery: IT and SHAM. Thereafter, fifty percent of the animals in the HFD and CD groups had their diets changed, while the remaining half maintained their presurgery diets. Eight weeks after surgery, plasma levels of ANGPTL8, PTX3, leptin, and adiponectin were assessed. RESULTS The IT group pre- and postoperatively maintained on the HFD showed higher ANGPTL8 level compared to SHAM operated animals (p=0.0041). The effect of IT on PTX3 level in the group pre- and postoperatively maintained on a CD was not significant, and there were no differences compared to SHAM. Only the postoperative diet change to HFD increased PTX3 level in the IT operated animals (p=0.0002). The IT group had increased plasma adiponectin (p=0.026) and leptin (p=0.0027) levels after dietary change to HFD compared to IT rats fed CD. CONCLUSIONS This study indicates that the outcomes of metabolic surgery can be greatly modified by HFD. The effects of the IT procedure in this experiment are ambiguous and do not provide a clear answer as to whether or not they are beneficial.
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Affiliation(s)
- Tomasz Sawczyn
- Department of Physiology, Faculty of Medical Sciences, Zabrze, Medical University of Silesia, Katowice, Poland
| | - Dominika Stygar
- Department of Physiology, Faculty of Medical Sciences, Zabrze, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Nabrdalik
- Department of Internal Medicine, Diabetology and Nephrology, Zabrze, Medical University of Silesia, Katowice, Poland
| | - Michał Kukla
- Department of Internal Medicine and Geriatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Oliwia Masri
- Department of Physiology, Faculty of Medical Sciences, Zabrze, Medical University of Silesia, Katowice, Poland
| | - Łukasz Magrowski
- Department of Physiology, Faculty of Medical Sciences, Zabrze, Medical University of Silesia, Katowice, Poland
| | - Wojciech Karcz
- Department of General, Visceral, Transplantation and Vascular Surgery, Hospital of the Ludwig Maximilian University, Munich, Germany
| | - Jerzy Jochem
- Department of Physiology, Faculty of Medical Sciences, Zabrze, Medical University of Silesia, Katowice, Poland
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Pruszynska-Oszmalek E, Sassek M, Szczepankiewicz D, Nowak KW, Kolodziejski PA. Short-term administration of spexin in rats reduces obesity by affecting lipolysis and lipogenesis: An in vivo and in vitro study. Gen Comp Endocrinol 2020; 299:113615. [PMID: 32950584 DOI: 10.1016/j.ygcen.2020.113615] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/12/2020] [Accepted: 09/09/2020] [Indexed: 12/31/2022]
Abstract
The present study aimed to characterize the role of spexin (SPX) in maintaining glucose and lipid homeostasis in vivo in rats with diet-induced obesity. The in vitro effect of spexin on metabolic and endocrine functions of adipocytes isolated from obese rats was also investigated. The in vivo experiment was conducted on rats with diet-induced obesity and administered with SPX for 7 days. Lipid and carbohydrate parameters, liver markers, and hormonal profile were measured. In in vitro studies, adipocytes isolated from obese rats were used. The effect of SPX on lipolysis, lipogenesis, and leptin secretion from fat cells was assessed. The results showed that short-term administration of SPX causes weight loss, increases insulin sensitivity, and improves the metabolic state of obese rats. The in vitro experiments showed that spexin and its receptors, namely galanin receptor 2 (GALR2) and galanin receptor 3 (GALR3), were expressed in various fat depots and in adipocytes from obese rats. We also found that the addition of spexin increased the basal and isoproterenol-stimulated lipolysis and reduced the basal and insulin-stimulated lipogenesis in adipocytes isolated from obese rats. Molecular analysis showed that SPX activated hormone-sensitive lipase (HSL) phosphorylation and upregulated perilipin and HSL mRNA expression. These results suggest that SPX regulates metabolism of obese rats by affecting lipolysis and lipogenesis in adipocytes. Moreover, the present study for the first time demonstrates that SPX modulates leptin synthesis and secretion from isolated adipocytes.
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Affiliation(s)
- Ewa Pruszynska-Oszmalek
- Department of Animal Physiology, Biochemistry and Biostructure, Poznan University of Life Sciences, Poznan, Poland.
| | - Maciej Sassek
- Department of Animal Physiology, Biochemistry and Biostructure, Poznan University of Life Sciences, Poznan, Poland
| | - Dawid Szczepankiewicz
- Department of Animal Physiology, Biochemistry and Biostructure, Poznan University of Life Sciences, Poznan, Poland
| | - Krzysztof W Nowak
- Department of Animal Physiology, Biochemistry and Biostructure, Poznan University of Life Sciences, Poznan, Poland
| | - Pawel Antoni Kolodziejski
- Department of Animal Physiology, Biochemistry and Biostructure, Poznan University of Life Sciences, Poznan, Poland
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Shin SJ, Chen CH, Kuo WC, Chan HC, Chan HC, Lin KD, Ke LY. Disruption of retinoid homeostasis induces RBP4 overproduction in diabetes: O-GlcNAcylation involved. Metabolism 2020; 113:154403. [PMID: 33065162 DOI: 10.1016/j.metabol.2020.154403] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/10/2020] [Accepted: 10/09/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Retinol-binding protein 4 (RBP4) is elevated and associated with inflammation in metabolic diseases. Disruption of the retinol cascade and O-GlcNAcylation of the RBP4 receptor (STRA6) are found in diabetic kidneys. OBJECTIVES We investigated whether the disruption of the retinol cascade induces RBP4 overproduction and if O-linked GlcNAc modification targets RBPR2 and contributes to the disruption of retinol cascades in diabetic livers. METHODS Western blot or immunohistochemistry for RBPR2, CRBP1, LRAT, RALDH, RARα, RARγ, RXRα, RBP4, GFAT, OGT, OGA and inflammatory markers, as well as ELISA for RBP4, were performed in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. Immunoprecipitation and dual fluorescence staining were used to explore O-GlcNAc-modified RBPR2 and RBP4 binding activity on RBPR2. Transfection of the CRBP1 gene was done to verify whether a disrupted retinol cascade induces RBP4 overproduction. OGT silencing was done to investigate the association of O-GlcNAcylation with the disruption of retinol cascade. RESULTS Disruption of retinol cascade, RBP4 overproduction, O-GlcNAcylation of RBPR2, decreased RBP4 binding activity on RBPR2 and inflammation were found in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. CRBP1 gene transfection reversed the suppression of the cellular retinol cascade and simultaneously attenuated the RBP4 overproduction and inflammation in high glucose-treated hepatocytes. The silencing of OGT reversed the disruption of the cellular retinol cascade, RBP4 overproduction and inflammation induced by high glucose in hepatocytes. CONCLUSIONS This study indicates that the disruption of cellular retinol cascade is strongly associated with RBP4 overproduction and inflammation in diabetic livers. RBPR2 is one target for high glucose-mediated O-linked GlcNAc modification, which causes liver retinol dyshomeostasis.
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Affiliation(s)
- Shyi-Jang Shin
- Grander Clinic, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Hung Chen
- The Graduate Institute of Animal Vaccine Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan; General Research Service Center, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Wen-Chen Kuo
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hua-Chen Chan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hsiu-Chuan Chan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Kun-Der Lin
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Liang-Yin Ke
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Jiang Q, Maresch CC, Petry SF, Paradowska-Dogan A, Bhushan S, Chang Y, Wrenzycki C, Schuppe HC, Houska P, Hartmann MF, Wudy SA, Shi L, Linn T. Elevated CCL2 causes Leydig cell malfunction in metabolic syndrome. JCI Insight 2020; 5:134882. [PMID: 33148888 PMCID: PMC7710294 DOI: 10.1172/jci.insight.134882] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 09/30/2020] [Indexed: 01/22/2023] Open
Abstract
Metabolic syndrome (MetS), which is associated with chronic inflammation, predisposes males to hypogonadism and subfertility. The underlying mechanism of these pathologies remains poorly understood. Homozygous leptin-resistant obese db/db mice are characterized by small testes, low testicular testosterone, and a reduced number of Leydig cells. Here we report that IL-1β, CCL2 (also known as MCP-1), and corticosterone concentrations were increased in the testes of db/db mice relative to those in WT controls. Cultured murine and human Leydig cells responded to cytokine stress with increased CCL2 release and apoptotic signals. Chemical inhibition of CCL2 rescued Leydig cell function in vitro and in db/db mice. Consistently, we found that Ccl2-deficient mice fed with a high-energy diet were protected from testicular dysfunction compared with similarly fed WT mice. Finally, a cohort of infertile men with a history of MetS showed that reduction of CCL2 plasma levels could be achieved by weight loss and was clearly associated with recovery from hypogonadism. Taken together, we conclude that CCL2-mediated chronic inflammation is, to a large extent, responsible for the subfertility in MetS by causing damage to Leydig cells. MCP-1/CCL2 upregulation associates with metabolic syndrome–induced male subfertility in both mice and men.
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Affiliation(s)
- Qingkui Jiang
- Clinical Research Unit, Centre of Internal Medicine, Justus-Liebig-University (JLU), Giessen, Germany
| | - Constanze C Maresch
- Clinical Research Unit, Centre of Internal Medicine, Justus-Liebig-University (JLU), Giessen, Germany
| | - Sebastian Friedrich Petry
- Clinical Research Unit, Centre of Internal Medicine, Justus-Liebig-University (JLU), Giessen, Germany
| | - Agnieszka Paradowska-Dogan
- Department of Gynecological Endocrinology and Reproductive Medicine, University Clinic Bonn, Bonn, Germany
| | - Sudhanshu Bhushan
- Institute of Anatomy and Cell Biology, Department of Reproductive Biology, JLU, Giessen, Germany
| | - Yongsheng Chang
- Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Christine Wrenzycki
- Department of Molecular Reproductive Medicine, Clinic for Veterinary Obstetrics, Gynecology and Andrology, and
| | | | - Petr Houska
- Clinical Research Unit, Centre of Internal Medicine, Justus-Liebig-University (JLU), Giessen, Germany.,ANOVA, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Michaela F Hartmann
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, JLU, Giessen, Germany
| | - Stefan A Wudy
- Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, JLU, Giessen, Germany
| | - Lanbo Shi
- Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, New Jersey, USA
| | - Thomas Linn
- Clinical Research Unit, Centre of Internal Medicine, Justus-Liebig-University (JLU), Giessen, Germany
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Yang Y, Xu Y. The central melanocortin system and human obesity. J Mol Cell Biol 2020; 12:785-797. [PMID: 32976556 PMCID: PMC7816681 DOI: 10.1093/jmcb/mjaa048] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/04/2020] [Accepted: 08/14/2020] [Indexed: 12/13/2022] Open
Abstract
The prevalence of obesity and the associated comorbidities highlight the importance of understanding the regulation of energy homeostasis. The central melanocortin system plays a critical role in controlling body weight balance. Melanocortin neurons sense and integrate the neuronal and hormonal signals, and then send regulatory projections, releasing anorexigenic or orexigenic melanocortin neuropeptides, to downstream neurons to regulate the food intake and energy expenditure. This review summarizes the latest progress in our understanding of the role of the melanocortin pathway in energy homeostasis. We also review the advances in the identification of human genetic variants that cause obesity via mechanisms that affect the central melanocortin system, which have provided rational targets for treatment of genetically susceptible patients.
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Affiliation(s)
- Yongjie Yang
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Yong Xu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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45
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Sergi D, Williams LM. Potential relationship between dietary long-chain saturated fatty acids and hypothalamic dysfunction in obesity. Nutr Rev 2020; 78:261-277. [PMID: 31532491 DOI: 10.1093/nutrit/nuz056] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Diet-induced hypothalamic inflammation, which leads to hypothalamic dysfunction and a loss of regulation of energy balance, is emerging as a potential driver of obesity. Excessive intake of long-chain saturated fatty acids is held to be the causative dietary component in hypothalamic inflammation. This review summarizes current evidence on the role of long-chain saturated fatty acids in promoting hypothalamic inflammation and the related induction of central insulin and leptin insensitivity. Particularly, the present review focuses on the molecular mechanisms linking long-chain saturated fatty acids and hypothalamic inflammation, emphasizing the metabolic fate of fatty acids and the resulting lipotoxicity, which is a key driver of hypothalamic dysfunction. In conclusion, long-chain saturated fatty acids are key nutrients that promote hypothalamic inflammation and dysfunction by fostering the build-up of lipotoxic lipid species, such as ceramide. Furthermore, when long-chain saturated fatty acids are consumed in combination with high levels of refined carbohydrates, the proinflammatory effects are exacerbated via a mechanism that relies on the formation of advanced glycation end products.
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Affiliation(s)
- Domenico Sergi
- Nutrition and Health Substantiation Group, Nutrition and Health Program, Health and Biosecurity, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Adelaide, South Australia, Australia
| | - Lynda M Williams
- Rowett Institute, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
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Clinical Evidence of Antidepressant Effects of Insulin and Anti-Hyperglycemic Agents and Implications for the Pathophysiology of Depression-A Literature Review. Int J Mol Sci 2020; 21:ijms21186969. [PMID: 32971941 PMCID: PMC7554794 DOI: 10.3390/ijms21186969] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/21/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023] Open
Abstract
Close connections between depression and type 2 diabetes (T2DM) have been suggested by many epidemiological and experimental studies. Disturbances in insulin sensitivity due to the disruption of various molecular pathways cause insulin resistance, which underpins many metabolic disorders, including diabetes, as well as depression. Several anti-hyperglycemic agents have demonstrated antidepressant properties in clinical trials, probably due to their action on brain targets based on the shared pathophysiology of depression and T2DM. In this article, we review reports of clinical trials examining the antidepressant effect of these medications, including insulin, metformin, glucagon like peptide-1 receptor agonists (GLP-1RA), and peroxisome proliferator-activated receptor (PPAR)-γ agonists, and briefly consider possible molecular mechanisms underlying the associations between amelioration of insulin resistance and improvement of depressive symptoms. In doing so, we intend to suggest an integrative perspective for understanding the pathophysiology of depression.
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Martínez-Sánchez N. There and Back Again: Leptin Actions in White Adipose Tissue. Int J Mol Sci 2020; 21:ijms21176039. [PMID: 32839413 PMCID: PMC7503240 DOI: 10.3390/ijms21176039] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/17/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022] Open
Abstract
Leptin is a hormone discovered almost 30 years ago with important implications in metabolism. It is primarily produced by white adipose tissue (WAT) in proportion to the amount of fat. The discovery of leptin was a turning point for two principle reasons: on one hand, it generated promising expectations for the treatment of the obesity, and on the other, it changed the classical concept that white adipose tissue was simply an inert storage organ. Thus, adipocytes in WAT produce the majority of leptin and, although its primary role is the regulation of fat stores by controlling lipolysis and lipogenesis, this hormone also has implications in other physiological processes within WAT, such as apoptosis, browning and inflammation. Although a massive number of questions related to leptin actions have been answered, the necessity for further clarification facilitates constantly renewing interest in this hormone and its pathways. In this review, leptin actions in white adipose tissue will be summarized in the context of obesity.
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DeBari MK, Abbott RD. Adipose Tissue Fibrosis: Mechanisms, Models, and Importance. Int J Mol Sci 2020; 21:ijms21176030. [PMID: 32825788 PMCID: PMC7503256 DOI: 10.3390/ijms21176030] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/15/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Increases in adipocyte volume and tissue mass due to obesity can result in inflammation, further dysregulation in adipose tissue function, and eventually adipose tissue fibrosis. Like other fibrotic diseases, adipose tissue fibrosis is the accumulation and increased production of extracellular matrix (ECM) proteins. Adipose tissue fibrosis has been linked to decreased insulin sensitivity, poor bariatric surgery outcomes, and difficulty in weight loss. With the rising rates of obesity, it is important to create accurate models for adipose tissue fibrosis to gain mechanistic insights and develop targeted treatments. This article discusses recent research in modeling adipose tissue fibrosis using in vivo and in vitro (2D and 3D) methods with considerations for biomaterial selections. Additionally, this article outlines the importance of adipose tissue in treating other fibrotic diseases and methods used to detect and characterize adipose tissue fibrosis.
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Affiliation(s)
- Megan K. DeBari
- Department of Materials Science and Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA;
| | - Rosalyn D. Abbott
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
- Correspondence:
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Sims NA. The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology. Exp Mol Med 2020; 52:1185-1197. [PMID: 32788655 PMCID: PMC8080635 DOI: 10.1038/s12276-020-0445-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/03/2020] [Accepted: 04/20/2020] [Indexed: 12/15/2022] Open
Abstract
Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation through an IL-6-dependent pathway. In growth plate chondrocytes, STAT3 signaling promotes the normal differentiation process that leads to bone lengthening. Within the osteoblast lineage, STAT3 signaling promotes bone formation in normal physiology and in response to mechanical loading through direct signaling in osteocytes. This activity, particularly that of the IL-6/gp130 family of cytokines, must be suppressed by SOCS3 for the normal formation of cortical bone. Maintaining normal bone structure and strength depends on a group of signaling proteins called cytokines that bind to receptor molecules on cell surfaces. Natalie Sims at St. Vincent’s Institute of Medical Research and The University of Melbourne in Australia reviews the role of cytokines in a specific signaling pathway in bone development and disease. Two of the proteins in this pathway respond to cytokine activity, whereas the third inhibits the cytokines’ effects. Studies in mice and humans have identified links between specific bone defects and spontaneous or experimentally induced mutations in the genes that code for the three proteins. The review covers the significance of recent findings to several types of cells that form new bone, degrade bone as part of normal bone turnover, and sustain the structure of bone and cartilage.
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Affiliation(s)
- Natalie A Sims
- St. Vincent's Institute of Medical Research, and Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Parkville, VIC, Australia.
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50
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Bains V, Kaur H, Badaruddoza B. Association analysis of polymorphisms in LEP (rs7799039 and rs2167270) and LEPR (rs1137101) gene towards the development of type 2 diabetes in North Indian Punjabi population. Gene 2020; 754:144846. [PMID: 32512158 DOI: 10.1016/j.gene.2020.144846] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Obesity is a major risk factor in aetiology of type 2 diabetes mellitus (T2DM). Leptin (LEP) is an anti-obesity hormone which regulates food intake, energy expenditure and glucose metabolism. The genetic variants in leptin and leptin receptor gene (LEPR) may play major role in the pathogenesis of T2DM and obesity. The current study aimed to investigate the association of polymorphisms in LEP (rs7799039, -2548G/A and rs2167270, 19G/A) and LEPR (rs1137101, 668A/G) gene with type 2 diabetes in North Indian Punjabi population. METHODS A total of 817 subjects were included for the present case-control study, consisting of 417 T2DM patients and 400 healthy controls. The anthropometric, physiometric and biochemical measurements were taken from all the subjects. The genotyping of LEP and LEPR gene variants were carried out by polymerase chain reaction based restriction fragment length polymorphism method (PCR-RFLP), followed by genotyping of 10% of the samples for each polymorphism by Sanger sequencing method for quality control measurement. RESULTS The risk genotype frequencies were found to be significantly higher in T2DM cases than control subjects (rs7799039, p = 0.001; rs2167270, p = 0.019 and rs1137101, p = 0.003). Under recessive genetic model LEPrs7799039 and LEPRrs1137101 polymorphism conferred 3.4 and 2.1 fold risk towards the development of T2DM after adjustment of various covariates (OR = 3.44, 95%CI: 1.768-6.681, p = 0.001 and OR: 2.12, 95%CI: 1.256-3.569, p = 0.005, respectively). In the stratified analysis of LEP variant rs7799039 by age, gender, BMI and alcohol use, a significantly increased risk of T2DM was found in female, BMI ≥ 23 and never drinking subgroups. However, in the LEPR variant rs1137101, significantly increased risk of T2DM was observed in age <50, male, BMI ≥ 23 and never drinking subgroup. The A-G haplotype combination of rs7799039A and rs2167270G conferred significant 2 fold risk towards T2DM (OR = 2.35, 95%CI: 1.34-4.12, p = 0.002). In control group, the genetic variants rs7799039 and rs1137101 were significantly associated with levels of random blood sugar and low density lipoprotein cholesterol levels. CONCLUSION The present study revealed the association of LEP rs7799039 and LEPR rs1137101 with type 2 diabetes mellitus, which suggest its predominant role in the estimation of type 2 diabetes mellitus in North Indian Punjabi population.
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Affiliation(s)
- Veena Bains
- Department of Human Genetics, Guru Nanak Dev University (GNDU), Amritsar 143 005, Punjab, India
| | - Harjit Kaur
- Department of Human Genetics, Guru Nanak Dev University (GNDU), Amritsar 143 005, Punjab, India
| | - Badaruddoza Badaruddoza
- Department of Human Genetics, Guru Nanak Dev University (GNDU), Amritsar 143 005, Punjab, India.
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