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Freire-Agulleiro Ó, Estévez-Salguero Á, Ferreira V, Holleman CL, García-Currás J, González-García I, Nogueiras R, Tena-Sempere M, García-Cáceres C, Diéguez C, López M. SF1-specific deletion of the energy sensor AMPKγ2 induces obesity. Mol Metab 2025; 92:102091. [PMID: 39746605 PMCID: PMC11782900 DOI: 10.1016/j.molmet.2024.102091] [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: 11/29/2024] [Revised: 12/21/2024] [Accepted: 12/25/2024] [Indexed: 01/04/2025] Open
Abstract
OBJECTIVE AMP-activated protein kinase (AMPK) is a heterotrimer complex consisting of a catalytic α subunit (α1, α2) with a serine/threonine kinase domain, and two regulatory subunits, β (β1, β2) and γ (γ1, γ2, γ3), encoded by different genes. In the hypothalamus, AMPK plays a crucial role in regulating energy balance, including feeding, energy expenditure, peripheral glucose and lipid metabolism. However, most research on hypothalamic AMPK has concentrated on the catalytic subunits AMPKα1 and AMPKα2, with little focus on the regulatory subunits. METHODS To fill this gap of knowledge, we investigated the effects of selectively deleting the regulatory isoform AMPKγ2, which is a primary "energy sensor", in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH). Complete metabolic phenotyping and molecular analyses in brown adipose tissue (BAT), white adipose tissue (WAT) and liver were carried out. RESULTS Our findings reveal that, in contrast to the obesity-protective effect of the genetic deletion of AMPKα subunits, the loss of AMPKγ2 in SF1 neurons leads to a sex-independent and feeding-independent obesity-prone phenotype due to decreased thermogenesis in brown adipose tissue (BAT) and reduced browning of WAT, resulting in lower energy expenditure. Additionally, SF1-Cre AMPKγ2 mice exhibit hepatic lipid accumulation, but surprisingly maintain normal glucose homeostasis. CONCLUSIONS Overall, these results highlight the distinct roles of AMPK subunits within the hypothalamus.
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Affiliation(s)
- Óscar Freire-Agulleiro
- Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain
| | - Ánxela Estévez-Salguero
- Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain
| | - Vitor Ferreira
- Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain
| | - Cassie Lynn Holleman
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany
| | - Julia García-Currás
- Biostatech Advice, Training and Innovation in Biostatistics, S.L, Ames, 15895, Spain
| | - Ismael González-García
- Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain
| | - Rubén Nogueiras
- Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain
| | - Manuel Tena-Sempere
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, Córdoba, 14004, Spain
| | - Cristina García-Cáceres
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, 80336, Munich, Germany
| | - Carlos Diéguez
- Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain
| | - Miguel López
- Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain.
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Fitzpatrick MK, Szalanczy A, Beeson A, Vora A, Scott C, Grzybowski M, Klotz J, Der N, Chen R, Geurts AM, Solberg Woods LC. Protein-coding mutation in Adcy3 increases adiposity and alters emotional behaviors sex-dependently in rats. Obesity (Silver Spring) 2025; 33:91-103. [PMID: 39632398 DOI: 10.1002/oby.24178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 08/29/2024] [Accepted: 09/23/2024] [Indexed: 12/07/2024]
Abstract
OBJECTIVE Adenylate cyclase 3 (Adcy3) has been linked to both obesity and major depressive disorder. We identified a protein-coding variant in the transmembrane (TM) helix of Adcy3 in rats; similar obesity variants have been identified in humans. This study investigates the role of a TM variant in adiposity and behavior. METHODS We mutated the TM domain of Adcy3 (Adcy3mut/mut) and created a heterozygous knockout (Adcy3+/-) in Wistar Kyoto (WKY) rats. Wild-type, Adcy3+/-, and Adcy3mut/mut rats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, memory, and downstream proteins. RESULTS Adcy3+/- and Adcy3mut/mut rats weighed more than wild-type rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. Adcy3mut/mut males displayed increased passive coping and decreased memory, whereas Adcy3mut/mut females displayed increased anxiety-like behavior. Adcy3mut/mut males had decreased hypothalamic cAMP-response element binding protein (CREB) signaling, with decreased phospho-AMP-activated protein kinase (p-AMPK) signaling in both sexes. CONCLUSIONS The ADCY3 TM domain plays a role in protein function via p-AMPK and CREB signaling. Adcy3 may contribute to the relationship between obesity and major depressive disorder, and sex influences the relationships between Adcy3, metabolism, and behavior.
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Affiliation(s)
- Mackenzie K Fitzpatrick
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Alexandria Szalanczy
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Angela Beeson
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Anusha Vora
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Christina Scott
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Michael Grzybowski
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jason Klotz
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Nataley Der
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Rong Chen
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Aron M Geurts
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Leah C Solberg Woods
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
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Smiles WJ, Ovens AJ, Oakhill JS, Kofler B. The metabolic sensor AMPK: Twelve enzymes in one. Mol Metab 2024; 90:102042. [PMID: 39362600 PMCID: PMC11752127 DOI: 10.1016/j.molmet.2024.102042] [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: 08/02/2024] [Revised: 09/12/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of αβγ-subunits that in humans are encoded by seven individual genes (isoforms α1, α2, β1, β2, γ1, γ2 and γ3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined. SCOPE OF REVIEW Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the α-subunit), altogether highlighting opportunities for future and impactful research. MAJOR CONCLUSIONS Baseline activity of α1-AMPK is higher than its α2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. α2 complexes however, show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers α1 is a tumour promoter and α2 a suppressor. β1-AMPK activity is toggled by a 'myristoyl-switch' mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. β2-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the γ2 and γ3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in γ2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, γ3 complexes might be preferentially regulated by mTORC1 in response to physical exercise.
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Affiliation(s)
- William J Smiles
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria; Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia.
| | - Ashley J Ovens
- Protein Engineering in Immunity & Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia
| | - Jonathan S Oakhill
- Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia; Department of Medicine, University of Melbourne, Parkville, Australia
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
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Pollard AE. New concepts in the roles of AMPK in adipocyte stem cell biology. Essays Biochem 2024; 68:349-361. [PMID: 39175418 DOI: 10.1042/ebc20240008] [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: 05/31/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024]
Abstract
Obesity is a major risk factor for many life-threatening diseases. Adipose tissue dysfunction is emerging as a driving factor in the transition from excess adiposity to comorbidities such as metabolic-associated fatty liver disease, cardiovascular disease, Type 2 diabetes and cancer. However, the transition from healthy adipose expansion to the development of these conditions is poorly understood. Adipose stem cells, residing in the vasculature and stromal regions of subcutaneous and visceral depots, are responsible for the expansion and maintenance of organ function, and are now recognised as key mediators of pathological transformation. Impaired tissue expansion drives inflammation, dysregulation of endocrine function and the deposition of lipids in the liver, muscle and around vital organs, where it is toxic. Contrary to previous hypotheses, it is the promotion of healthy adipose tissue expansion and function, not inhibition of adipogenesis, that presents the most attractive therapeutic strategy in the treatment of metabolic disease. AMP-activated protein kinase, a master regulator of energy homeostasis, has been regarded as one such target, due to its central role in adipose tissue lipid metabolism, and its apparent inhibition of adipogenesis. However, recent studies utilising AMP-activated protein kinase (AMPK)-specific compounds highlight a more subtle, time-dependent role for AMPK in the process of adipogenesis, and in a previously unexplored repression of leptin, independent of adipocyte maturity. In this article, I discuss historic evidence for AMPK-mediated adipogenesis inhibition and the multi-faceted roles for AMPK in adipose tissue.
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Affiliation(s)
- Alice E Pollard
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, U.K
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Forner-Piquer I, Giommi C, Sella F, Lombó M, Montik N, Dalla Valle L, Carnevali O. Endocannabinoid System and Metabolism: The Influences of Sex. Int J Mol Sci 2024; 25:11909. [PMID: 39595979 PMCID: PMC11593739 DOI: 10.3390/ijms252211909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/30/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
The endocannabinoid system (ECS) is a lipid signaling system involved in numerous physiological processes, such as endocrine homeostasis, appetite control, energy balance, and metabolism. The ECS comprises endocannabinoids, their cognate receptors, and the enzymatic machinery that tightly regulates their levels within tissues. This system has been identified in various organs, including the brain and liver, in multiple mammalian and non-mammalian species. However, information regarding the sex-specific regulation of the ECS remains limited, even though increasing evidence suggests that interactions between sex steroid hormones and the ECS may ultimately modulate hepatic metabolism and energy homeostasis. Within this framework, we will review the sexual dimorphism of the ECS in various animal models, providing evidence of the crosstalk between endocannabinoids and sex hormones via different metabolic pathways. Additionally, we will underscore the importance of understanding how endocrine-disrupting chemicals and exogenous cannabinoids influence ECS-dependent metabolic pathways in a sex-specific manner.
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Affiliation(s)
- Isabel Forner-Piquer
- Centre for Pollution Research and Policy, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK;
| | - Christian Giommi
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (C.G.); (F.S.)
- INBB—Biostructures and Biosystems National Institute, 00136 Roma, Italy
| | - Fiorenza Sella
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (C.G.); (F.S.)
- INBB—Biostructures and Biosystems National Institute, 00136 Roma, Italy
| | - Marta Lombó
- INBB—Biostructures and Biosystems National Institute, 00136 Roma, Italy
- Department of Molecular Biology, Universidad de León, 24071 León, Spain
| | - Nina Montik
- Department of Odontostomatological and Specialized Clinical Sciences, Polytechnic University of Marche, 60020 Ancona, Italy;
| | | | - Oliana Carnevali
- Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy; (C.G.); (F.S.)
- INBB—Biostructures and Biosystems National Institute, 00136 Roma, Italy
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Ashraf N, Van Nostrand JL. Fine-tuning AMPK in physiology and disease using point-mutant mouse models. Dis Model Mech 2024; 17:dmm050798. [PMID: 39136185 PMCID: PMC11340815 DOI: 10.1242/dmm.050798] [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: 08/17/2024] Open
Abstract
AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that monitors the cellular energy status to adapt it to the fluctuating nutritional and environmental conditions in an organism. AMPK plays an integral part in a wide array of physiological processes, such as cell growth, autophagy and mitochondrial function, and is implicated in diverse diseases, including cancer, metabolic disorders, cardiovascular diseases and neurodegenerative diseases. AMPK orchestrates many different physiological outcomes by phosphorylating a broad range of downstream substrates. However, the importance of AMPK-mediated regulation of these substrates in vivo remains an ongoing area of investigation to better understand its precise role in cellular and metabolic homeostasis. Here, we provide a comprehensive overview of our understanding of the kinase function of AMPK in vivo, as uncovered from mouse models that harbor phosphorylation mutations in AMPK substrates. We discuss some of the inherent limitations of these mouse models, highlight the broader implications of these studies for understanding human health and disease, and explore the valuable insights gained that could inform future therapeutic strategies for the treatment of metabolic and non-metabolic disorders.
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Affiliation(s)
- Naghmana Ashraf
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jeanine L. Van Nostrand
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Castro G, Mendes NF, Weissmann L, Quaresma PGF, Saad MJA, Prada PO. Multiple metabolic signals in the CeA regulate feeding: The role of AMPK. Mol Cell Endocrinol 2024; 589:112232. [PMID: 38604549 DOI: 10.1016/j.mce.2024.112232] [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: 10/03/2023] [Revised: 03/30/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024]
Abstract
BACKGROUND The central nucleus of the amygdala (CeA) is part of the dopaminergic reward system and controls energy balance. Recently, a cluster of neurons was identified as responsive to the orexigenic effect of ghrelin and fasting. However, the signaling pathway by which ghrelin and fasting induce feeding is unknown. AMP-activated protein kinase (AMPK) is a cellular energy sensor, and its Thr172 phosphorylation (AMPKThr172) in the mediobasal hypothalamus regulates food intake. However, whether the expression and activation of AMPK in CeA could be one of the intracellular signaling activated in response to ghrelin and fasting eliciting food intake is unknown. AIM To evaluate the activation of AMPK into CeA in response to ghrelin, fasting, and 2-deoxy-D-glucose (2DG) and whether feeding accompanied these changes. In addition, to investigate whether the inhibition of AMPK into CeA could decrease food intake. METHODS On a chow diet, eight-week-old Wistar male rats were stereotaxically implanted with a cannula in the CeA to inject several modulators of AMPKα1/2Thr172 phosphorylation, and we performed physiological and molecular assays. KEY FINDINGS Fasting increased, and refeeding reduced AMPKThr172 in the CeA. Intra-CeA glucose injection decreased feeding, whereas injection of 2DG, a glucoprivation inductor, in the CeA, increased food intake and blood glucose, despite faint increases in AMPKThr172. Intra-CeA ghrelin injection increased food intake and AMPKThr172. To further confirm the role of AMPK in the CeA, chronic injection of Melanotan II (MTII) in CeA reduced body mass and food intake over seven days together with a slight decrease in AMPKThr172. SIGNIFICANCE Our findings identified that AMPK might be part of the signaling machinery in the CeA, which responds to nutrients and hormones contributing to feeding control. The results can contribute to understanding the pathophysiological mechanisms of altered feeding behavior/consumption, such as binge eating of caloric-dense, palatable food.
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Affiliation(s)
- Gisele Castro
- Department of Internal Medicine, School of Medical Science, State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Natália Ferreira Mendes
- Department of Translational Medicine (Section of Pharmacology), School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Laís Weissmann
- Department of Internal Medicine, School of Medical Science, State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | | | - Mario Jose Abdalla Saad
- Department of Internal Medicine, School of Medical Science, State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Patricia Oliveira Prada
- Department of Internal Medicine, School of Medical Science, State University of Campinas (UNICAMP), Campinas, SP, Brazil; School of Applied Sciences, State University of Campinas (UNICAMP), Limeira, SP, Brazil; Biology Institute, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
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Kakoti BB, Alom S, Deka K, Halder RK. AMPK pathway: an emerging target to control diabetes mellitus and its related complications. J Diabetes Metab Disord 2024; 23:441-459. [PMID: 38932895 PMCID: PMC11196491 DOI: 10.1007/s40200-024-01420-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 03/07/2024] [Indexed: 06/28/2024]
Abstract
Purpose In this extensive review work, the important role of AMP-activated protein kinase (AMPK) in causing of diabetes mellitus has been highlighted. Structural feature of AMPK as well its regulations and roles are described nicely, and the association of AMPK with the diabetic complications like nephropathy, neuropathy and retinopathy are also explained along with the connection between AMPK and β-cell function, insulin resistivity, mTOR, protein metabolism, autophagy and mitophagy and effect on protein and lipid metabolism. Methods Published journals were searched on the database like PubMed, Medline, Scopus and Web of Science by using keywords such as AMPK, diabetes mellitus, regulation of AMPK, complications of diabetes mellitus, autophagy, apoptosis etc. Result After extensive review, it has been found that, kinase enzyme like AMPK is having vital role in management of type II diabetes mellitus. AMPK involve in enhance the concentration of glucose transporter like GLUT 1 and GLUT 4 which result in lowering of blood glucose level in influx of blood glucose into the cells; AMPK increases the insulin sensitivity and decreases the insulin resistance and further AMPK decreases the apoptosis of β-cells which result into secretion of insulin and AMPK is also involve in declining of oxidative stress, lipotoxicity and inflammation, owing to which organ damage due to diabetes mellitus can be lowered by activation of AMPK. Conclusion As AMPK activation leads to overall control of diabetes mellitus, designing and developing of small molecules or peptide that can act as AMPK agonist will be highly beneficial for control or manage diabetes mellitus.
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Affiliation(s)
- Bibhuti B. Kakoti
- Department of Pharmaceutical Sciences, Dibrugarh University, 786004 Dibrugarh, Assam India
| | - Shahnaz Alom
- Department of Pharmaceutical Sciences, Dibrugarh University, 786004 Dibrugarh, Assam India
- Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Sciences, Girijananda Chowdhury University- Tezpur campus, 784501 Sonitpur, Assam India
| | - Kangkan Deka
- Department of Pharmaceutical Sciences, Dibrugarh University, 786004 Dibrugarh, Assam India
- Department of Pharmacognosy, NETES Institute of Pharmaceutical Science, NEMCARE Group of Institutions, 781125 Mirza, Kamrup, Assam India
| | - Raj Kumar Halder
- Ruhvenile Biomedical, Plot -8 OCF Pocket Institution, Sarita Vihar, 110076 Delhi, India
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Achanta LB, Thomas DS, Housley GD, Rae CD. AMP-activated protein kinase activators have compound and concentration-specific effects on brain metabolism. J Neurochem 2024; 168:677-692. [PMID: 36977628 DOI: 10.1111/jnc.15815] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/18/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023]
Abstract
AMP-activated protein kinase (AMPK) is a key sensor of energy balance playing important roles in the balancing of anabolic and catabolic activities. The high energy demands of the brain and its limited capacity to store energy indicate that AMPK may play a significant role in brain metabolism. Here, we activated AMPK in guinea pig cortical tissue slices, both directly with A769662 and PF 06409577 and indirectly with AICAR and metformin. We studied the resultant metabolism of [1-13C]glucose and [1,2-13C]acetate using NMR spectroscopy. We found distinct activator concentration-dependent effects on metabolism, which ranged from decreased metabolic pool sizes at EC50 activator concentrations with no expected stimulation in glycolytic flux to increased aerobic glycolysis and decreased pyruvate metabolism with certain activators. Further, activation with direct versus indirect activators produced distinct metabolic outcomes at both low (EC50) and higher (EC50 × 10) concentrations. Specific direct activation of β1-containing AMPK isoforms with PF 06409577 resulted in increased Krebs cycle activity, restoring pyruvate metabolism while A769662 increased lactate and alanine production, as well as labelling of citrate and glutamine. These results reveal a complex metabolic response to AMPK activators in brain beyond increased aerobic glycolysis and indicate that further research is warranted into their concentration- and mechanism-dependent impact.
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Affiliation(s)
- Lavanya B Achanta
- Neuroscience Research Australia, Barker St, Randwick, New South Wales, 2031, Australia
- Translational Neuroscience Facility, School of Biomedical Sciences, UNSW, Sydney, New South Wales, 2052, Australia
| | - Donald S Thomas
- Mark Wainwright Analytical Centre, UNSW, Sydney, New South Wales, 2052, Australia
| | - Gary D Housley
- Translational Neuroscience Facility, School of Biomedical Sciences, UNSW, Sydney, New South Wales, 2052, Australia
| | - Caroline D Rae
- Neuroscience Research Australia, Barker St, Randwick, New South Wales, 2031, Australia
- School of Psychology, UNSW, Sydney, New South Wales, 2052, Australia
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Bustraan S, Bennett J, Whilding C, Pennycook BR, Smith D, Barr AR, Read J, Carling D, Pollard A. AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes. Biochem J 2024; 481:345-362. [PMID: 38314646 PMCID: PMC11088909 DOI: 10.1042/bcj20240003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 02/01/2024] [Accepted: 02/04/2024] [Indexed: 02/06/2024]
Abstract
Adipogenesis, defined as the development of mature adipocytes from stem cell precursors, is vital for the expansion, turnover and health of adipose tissue. Loss of adipogenic potential in adipose stem cells, or impairment of adipogenesis is now recognised as an underlying cause of adipose tissue dysfunction and is associated with metabolic disease. In this study, we sought to determine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved master regulator of energy homeostasis, in adipogenesis. Primary murine adipose-derived stem cells were treated with a small molecule AMPK activator (BI-9774) during key phases of adipogenesis, to determine the effect of AMPK activation on adipocyte commitment, maturation and function. To determine the contribution of the repression of lipogenesis by AMPK in these processes, we compared the effect of pharmacological inhibition of acetyl-CoA carboxylase (ACC). We show that AMPK activation inhibits adipogenesis in a time- and concentration-dependent manner. Transient AMPK activation during adipogenic commitment leads to a significant, ACC-independent, repression of adipogenic transcription factor expression. Furthermore, we identify a striking, previously unexplored inhibition of leptin gene expression in response to both short-term and chronic AMPK activation irrespective of adipogenesis. These findings reveal that in addition to its effect on adipogenesis, AMPK activation switches off leptin gene expression in primary mouse adipocytes independently of adipogenesis. Our results identify leptin expression as a novel target of AMPK through mechanisms yet to be identified.
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Affiliation(s)
- Sophia Bustraan
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, U.K
- Medical Research Council Laboratory of Medical Sciences, London, U.K
| | - Jane Bennett
- Medical Research Council Laboratory of Medical Sciences, London, U.K
| | - Chad Whilding
- Medical Research Council Laboratory of Medical Sciences, London, U.K
| | | | - David Smith
- Emerging Innovations Unit, Discovery Sciences, R&D, AstraZeneca, Cambridge, U.K
| | - Alexis R. Barr
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, U.K
- Medical Research Council Laboratory of Medical Sciences, London, U.K
| | - Jon Read
- Mechanistic and Structural Biology, Biopharmaceuticals R&D, AstraZeneca, Cambridge, U.K
| | - David Carling
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, U.K
- Medical Research Council Laboratory of Medical Sciences, London, U.K
| | - Alice Pollard
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, U.K
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11
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Abasubong KP, Jiang GZ, Guo HX, Wang X, Huang YY, Li XF, Yan-Zou D, Liu WB, Desouky HE. Effects of a high-fat and high-carbohydrate diet on appetite regulation and central AMPK in the hypothalamus of blunt snout bream (Megalobrama amblycephala). J Anim Physiol Anim Nutr (Berl) 2024; 108:480-492. [PMID: 38014877 DOI: 10.1111/jpn.13908] [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: 04/16/2023] [Revised: 11/06/2023] [Accepted: 11/10/2023] [Indexed: 11/29/2023]
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is a sensor of cellular energy changes and controls food intake. This study investigates the effect of a high-calorie diet (high fat diet [HFD], high carbohydrate diet [HCD] and high energy diet [HED]) on appetite and central AMPK in blunt snout bream. In the present study, fish (average initial weight 45.84 ± 0.07 g) were fed the control, HFD, HCD and HED in four replicates for 12 weeks. At the end of the feeding trial, the result showed that body mass index, specific growth rate, feed efficiency ratio and feed intake were not affected (p > 0.05) by dietary treatment. However, fish fed the HFD obtained a significantly higher (p < 0.05) lipid productive value, lipid gain and lipid intake than those fed the control diet, but no significant difference was attributed to others. Also, a significantly higher (p < 0.05) energy intake content was found in fish-fed HFD, HCD and HED than those given the control diet. Long-term HFD and HCD feeding significantly increased (p < 0.05) plasma glucose, glycated serum protein, advanced glycation end product, insulin and leptin content levels than the control group. Moreover, a significantly lower (p < 0.05) complex 1, 2 and 3 content was found in fish-fed HFD and HCD than in the control, but no differences (p > 0.05) were attributed to those in HED. Fish-fed HED significantly upregulated (p < 0.05) hypothalamic ampα 1 and ampα 2 expression, whereas the opposite trend was observed in the hypothalamic mammalian target of rapamycin than those in HFD and HCD compared to the control. However, hypothalamic neuropeptide y, peroxisome proliferator-activated receptor α (pparα), acetyl-coa oxidase and carnitine palmitoyltransferase 1 were significantly upregulated (p < 0.05) in the HCD group, while the opposite was seen in cholecystokinin expression compared to those in the control group. Our findings indicated that the central AMPK signal pathway and appetite were modulated according to the diet's energy level to regulate nutritional status and maintain energy homoeostasis in fish.
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Affiliation(s)
- Kenneth Prudence Abasubong
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
| | - Guang-Zhen Jiang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
| | - Hui-Xing Guo
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
| | - Xi Wang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
| | - Yang-Yang Huang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
| | - Xiang-Fei Li
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
| | - Dong Yan-Zou
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
| | - Wen-Bin Liu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
| | - Hesham Eed Desouky
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, People's Republic of China
- National Laboratory of Animal Science, Nanjing Agricultural University, Nanjing, People's Republic of China
- Department of Animal and Poultry Production, Faculty of Agriculture, Damanhour University, Damanhour, Egypt
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12
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Min SH, Song DK, Lee CH, Roh E, Kim MS. Hypothalamic AMP-Activated Protein Kinase as a Whole-Body Energy Sensor and Regulator. Endocrinol Metab (Seoul) 2024; 39:1-11. [PMID: 38356211 PMCID: PMC10901667 DOI: 10.3803/enm.2024.1922] [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: 01/02/2024] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 02/16/2024] Open
Abstract
5´-Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a cellular energy sensor, is an essential enzyme that helps cells maintain stable energy levels during metabolic stress. The hypothalamus is pivotal in regulating energy balance within the body. Certain neurons in the hypothalamus are sensitive to fluctuations in food availability and energy stores, triggering adaptive responses to preserve systemic energy equilibrium. AMPK, expressed in these hypothalamic neurons, is instrumental in these regulatory processes. Hypothalamic AMPK activity is modulated by key metabolic hormones. Anorexigenic hormones, including leptin, insulin, and glucagon-like peptide 1, suppress hypothalamic AMPK activity, whereas the hunger hormone ghrelin activates it. These hormonal influences on hypothalamic AMPK activity are central to their roles in controlling food consumption and energy expenditure. Additionally, hypothalamic AMPK activity responds to variations in glucose concentrations. It becomes active during hypoglycemia but is deactivated when glucose is introduced directly into the hypothalamus. These shifts in AMPK activity within hypothalamic neurons are critical for maintaining glucose balance. Considering the vital function of hypothalamic AMPK in the regulation of overall energy and glucose balance, developing chemical agents that target the hypothalamus to modulate AMPK activity presents a promising therapeutic approach for metabolic conditions such as obesity and type 2 diabetes mellitus.
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Affiliation(s)
- Se Hee Min
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Do Kyeong Song
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Chan Hee Lee
- Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon, Korea
| | - Eun Roh
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, Korea
| | - Min-Seon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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13
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Cantacorps L, Zhu J, Yagoub S, Coull BM, Falck J, Chesters RA, Ritter K, Serrano-Lope M, Tscherepentschuk K, Kasch LS, Paterson M, Täger P, Baidoe-Ansah D, Pandey S, Igual-Gil C, Braune A, Lippert RN. Developmental metformin exposure does not rescue physiological impairments derived from early exposure to altered maternal metabolic state in offspring mice. Mol Metab 2024; 79:101860. [PMID: 38142972 PMCID: PMC10792763 DOI: 10.1016/j.molmet.2023.101860] [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: 11/14/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 12/26/2023] Open
Abstract
OBJECTIVE The incidence of gestational diabetes mellitus (GDM) and metabolic disorders during pregnancy are increasing globally. This has resulted in increased use of therapeutic interventions such as metformin to aid in glycemic control during pregnancy. Even though metformin can cross the placental barrier, its impact on offspring brain development remains poorly understood. As metformin promotes AMPK signaling, which plays a key role in axonal growth during development, we hypothesized that it may have an impact on hypothalamic signaling and the formation of neuronal projections in the hypothalamus, the key regulator of energy homeostasis. We further hypothesized that this is dependent on the metabolic and nutritional status of the mother at the time of metformin intervention. Using mouse models of maternal overnutrition, we aimed to assess the effects of metformin exposure on offspring physiology and hypothalamic neuronal circuits during key periods of development. METHODS Female C57BL/6N mice received either a control diet or a high-fat diet (HFD) during pregnancy and lactation periods. A subset of dams was fed a HFD exclusively during the lactation. Anti-diabetic treatments were given during the first postnatal weeks. Body weights of male and female offspring were monitored daily until weaning. Circulating metabolic factors and molecular changes in the hypothalamus were assessed at postnatal day 16 using ELISA and Western Blot, respectively. Hypothalamic innervation was assessed by immunostaining at postnatal days 16 and 21. RESULTS We identified alterations in weight gain and circulating hormones in male and female offspring induced by anti-diabetic treatment during the early postnatal period, which were critically dependent on the maternal metabolic state. Furthermore, hypothalamic agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neuronal innervation outcomes in response to anti-diabetic treatment were also modulated by maternal metabolic state. We also identified sex-specific changes in hypothalamic AMPK signaling in response to metformin exposure. CONCLUSION We demonstrate a unique interaction between anti-diabetic treatment and maternal metabolic state, resulting in sex-specific effects on offspring brain development and physiological outcomes. Overall, based on our findings, no positive effect of metformin intervention was observed in the offspring, despite ameliorating effects on maternal metabolic outcomes. In fact, the metabolic state of the mother drives the most dramatic differences in offspring physiology and metformin had no rescuing effect. Our results therefore highlight the need for a deeper understanding of how maternal metabolic state (excessive weight gain versus stable weight during GDM treatment) affects the developing offspring. Further, these results emphasize that the interventions to treat alterations in maternal metabolism during pregnancy need to be reassessed from the perspective of the offspring physiology.
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Affiliation(s)
- Lídia Cantacorps
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Jiajie Zhu
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Selma Yagoub
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Bethany M Coull
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Joanne Falck
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Robert A Chesters
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Katrin Ritter
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Miguel Serrano-Lope
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Katharina Tscherepentschuk
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Lea-Sophie Kasch
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Maya Paterson
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Paula Täger
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - David Baidoe-Ansah
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Shuchita Pandey
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Carla Igual-Gil
- Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
| | - Annett Braune
- Research Group Intestinal Microbiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Rachel N Lippert
- Department of Neurocircuit Development and Function, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; NeuroCure Cluster of Excellence, Charité-Universitätsmedizin, Berlin, Germany.
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14
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Engin A. The Unrestrained Overeating Behavior and Clinical Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:167-198. [PMID: 39287852 DOI: 10.1007/978-3-031-63657-8_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Obesity-related co-morbidities decrease life quality, reduce working ability, and lead to early death. In the adult population, eating addiction manifests with excessive food consumption and the unrestrained overeating behavior, which is associated with increased risk of morbidity and mortality and defined as the binge eating disorder (BED). This hedonic intake is correlated with fat preference and the total amount of dietary fat consumption is the most potent risk factor for weight gain. Long-term BED leads to greater sensitivity to the rewarding effects of palatable foods and results in obesity fatefully. Increased plasma concentrations of non-esterified free fatty acids and lipid-overloaded hypertrophic adipocytes may cause insulin resistance. In addition to dietary intake of high-fat diet, sedentary lifestyle leads to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues. Lipid-induced apoptosis, ceramide accumulation, reactive oxygen species overproduction, endoplasmic reticulum stress, and mitochondrial dysfunction play role in the pathogenesis of lipotoxicity. Food addiction and BED originate from complex action of dopaminergic, opioid, and cannabinoid systems. BED may also be associated with both obesity and major depressive disorder. For preventing morbidity and mortality, as well as decreasing the impact of obesity-related comorbidities in appropriately selected patients, opiate receptor antagonists and antidepressant combination are recommended. Pharmacotherapy alongside behavioral management improves quality of life and reduces the obesity risk; however, the number of licensed drugs is very few. Thus, stereotactic treatment is recommended to break down the refractory obesity and binge eating in obese patient. As recent applications in the field of non-invasive neuromodulation, transcranial magnetic stimulation and transcranial direct current stimulation are thought to be important in image-guided deep brain stimulation in humans. Chronic overnutrition most likely provides repetitive and persistent signals that up-regulate inhibitor of nuclear factor kappa B (NF-κB) kinase beta subunit/NF-κB (IKKβ/NF-κB) in the hypothalamus before the onset of obesity. However, how the mechanisms of high-fat diet-induced peripheral signals affect the hypothalamic arcuate nucleus remain largely unknown.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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15
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Liu Z, Xiao T, Liu H. Leptin signaling and its central role in energy homeostasis. Front Neurosci 2023; 17:1238528. [PMID: 38027481 PMCID: PMC10644276 DOI: 10.3389/fnins.2023.1238528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
Leptin plays a critical role in regulating appetite, energy expenditure and body weight, making it a key factor in maintaining a healthy balance. Despite numerous efforts to develop therapeutic interventions targeting leptin signaling, their effectiveness has been limited, underscoring the importance of gaining a better understanding of the mechanisms through which leptin exerts its functions. While the hypothalamus is widely recognized as the primary site responsible for the appetite-suppressing and weight-reducing effects of leptin, other brain regions have also been increasingly investigated for their involvement in mediating leptin's action. In this review, we summarize leptin signaling pathways and the neural networks that mediate the effects of leptin, with a specific emphasis on energy homeostasis.
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Affiliation(s)
- Zhaoxun Liu
- Nursing Department, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tao Xiao
- Nursing Department, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hailan Liu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
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16
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Vivot K, Meszaros G, Pangou E, Zhang Z, Qu M, Erbs E, Yeghiazaryan G, Quiñones M, Grandgirard E, Schneider A, Clauss-Creusot E, Charlet A, Faour M, Martin C, Berditchevski F, Sumara I, Luquet S, Kloppenburg P, Nogueiras R, Ricci R. CaMK1D signalling in AgRP neurons promotes ghrelin-mediated food intake. Nat Metab 2023; 5:1045-1058. [PMID: 37277610 DOI: 10.1038/s42255-023-00814-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 04/25/2023] [Indexed: 06/07/2023]
Abstract
Hypothalamic AgRP/NPY neurons are key players in the control of feeding behaviour. Ghrelin, a major orexigenic hormone, activates AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signalling mechanisms in AgRP/NPY neurons remain poorly defined. Here we show that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated upon ghrelin stimulation and acts in AgRP/NPY neurons to mediate ghrelin-dependent food intake. Global Camk1d-knockout male mice are resistant to ghrelin, gain less body weight and are protected against high-fat-diet-induced obesity. Deletion of Camk1d in AgRP/NPY, but not in POMC, neurons is sufficient to recapitulate above phenotypes. In response to ghrelin, lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY in fibre projections to the paraventricular nucleus (PVN). Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons.
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Affiliation(s)
- Karl Vivot
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
- Centre National de la Recherche Scientifique, Illkirch, France.
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France.
- Université de Strasbourg, Strasbourg, France.
| | - Gergö Meszaros
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France
- Université de Strasbourg, Strasbourg, France
| | - Evanthia Pangou
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France
- Université de Strasbourg, Strasbourg, France
| | - Zhirong Zhang
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France
- Université de Strasbourg, Strasbourg, France
| | - Mengdi Qu
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France
- Université de Strasbourg, Strasbourg, France
| | - Eric Erbs
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France
- Université de Strasbourg, Strasbourg, France
| | - Gagik Yeghiazaryan
- Biocenter, Institute for Zoology, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, (CECAD), University of Cologne, Cologne, Germany
| | - Mar Quiñones
- Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Santiago de Compostela, Spain
| | - Erwan Grandgirard
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France
- Université de Strasbourg, Strasbourg, France
| | - Anna Schneider
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France
- Université de Strasbourg, Strasbourg, France
| | - Etienne Clauss-Creusot
- Université de Strasbourg, Strasbourg, France
- Centre National de la Recherche Scientifique, Institute of Cellular and Integrative Neurosciences, Strasbourg, France
| | - Alexandre Charlet
- Université de Strasbourg, Strasbourg, France
- Centre National de la Recherche Scientifique, Institute of Cellular and Integrative Neurosciences, Strasbourg, France
| | - Maya Faour
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | - Claire Martin
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | - Fedor Berditchevski
- Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, UK
| | - Izabela Sumara
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France
- Université de Strasbourg, Strasbourg, France
| | - Serge Luquet
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | - Peter Kloppenburg
- Biocenter, Institute for Zoology, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, (CECAD), University of Cologne, Cologne, Germany
| | - Ruben Nogueiras
- Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Romeo Ricci
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
- Centre National de la Recherche Scientifique, Illkirch, France.
- Institut National de la Santé et de la Recherche Médicale, Illkirch, France.
- Université de Strasbourg, Strasbourg, France.
- Laboratoire de Biochimie et de Biologie Moléculaire, Nouvel Hôpital Civil, Strasbourg, France.
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17
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Kalra P, Khan H, Singh TG, Grewal AK. Mechanistic insights on impact of Adenosine monophosphate-activated protein kinase (AMPK) mediated signalling pathways on cerebral ischemic injury. Neurosci Res 2023; 190:17-28. [PMID: 36403790 DOI: 10.1016/j.neures.2022.11.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/23/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022]
Abstract
Cerebral ischemia is the primary cause of morbidity and mortality worldwide due to the perturbations in the blood supply to the brain. The brain triggers a cascade of complex metabolic and cellular defects in response to ischemic stress. However, due to the disease heterogeneity and complexity, ischemic injury's metabolic and cellular pathologies remain elusive, and the link between various pathological mechanisms is difficult to determine. Efforts to develop effective treatments for these disorders have yielded limited efficacy, with no proper cure available to date. Recent clinical and experimental research indicates that several neuronal diseases commonly coexist with metabolic dysfunction, which may aggravate neurological symptoms. As a result, it stands to a reason that metabolic hormones could be a potential therapeutic target for major NDDs. Moreover, fasting signals also influence the circadian clock, as AMPK phosphorylates and promotes the degradation of the photo-sensing receptor (cryptochrome). Here, the interplay of AMPK signaling between metabolic regulation and neuronal death and its role for pathogenesis and therapeutics has been studied. We have also highlighted a significant signaling pathway, i.e., the adenosine monophosphate-activated protein kinase (AMPK) involved in the relationship between the metabolism and ischemia, which could be used as a target for future studies therapeutics, and review some of the clinical progress in this area.
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Affiliation(s)
- Palak Kalra
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India.
| | - Amarjot Kaur Grewal
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
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18
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Balsevich G, Petrie GN, Heinz DE, Singh A, Aukema RJ, Hunker AC, Vecchiarelli HA, Yau H, Sticht M, Thompson RJ, Lee FS, Zweifel LS, Chelikani PK, Gassen NC, Hill MN. A genetic variant of fatty acid amide hydrolase (FAAH) exacerbates hormone-mediated orexigenic feeding in mice. eLife 2023; 12:e81919. [PMID: 37039453 PMCID: PMC10159625 DOI: 10.7554/elife.81919] [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: 07/15/2022] [Accepted: 04/06/2023] [Indexed: 04/12/2023] Open
Abstract
Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide. A polymorphism in FAAH (FAAH C385A) reduces FAAH expression, increases anandamide levels, and increases the risk of obesity. Nevertheless, some studies have found no association between FAAH C385A and obesity. We investigated whether the environmental context governs the impact of FAAH C385A on metabolic outcomes. Using a C385A knock-in mouse model, we found that FAAH A/A mice are more susceptible to glucocorticoid-induced hyperphagia, weight gain, and activation of hypothalamic AMP-activated protein kinase (AMPK). AMPK inhibition occluded the amplified hyperphagic response to glucocorticoids in FAAH A/A mice. FAAH knockdown exclusively in agouti-related protein (AgRP) neurons mimicked the exaggerated feeding response of FAAH A/A mice to glucocorticoids. FAAH A/A mice likewise presented exaggerated orexigenic responses to ghrelin, while FAAH knockdown in AgRP neurons blunted leptin anorectic responses. Together, the FAAH A/A genotype amplifies orexigenic responses and decreases anorexigenic responses, providing a putative mechanism explaining the diverging human findings.
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Affiliation(s)
| | - Gavin N Petrie
- Hotchkiss Brain Institute, University of CalgaryCalgaryCanada
| | - Daniel E Heinz
- Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, University Hospital BonnBonnGermany
| | - Arashdeep Singh
- Monell Chemical Senses Center and Department of Neuroscience, University of PennsylvaniaPhiladelphiaUnited States
| | - Robert J Aukema
- Hotchkiss Brain Institute, University of CalgaryCalgaryCanada
| | - Avery C Hunker
- Department of Psychiatry and Behavioral Sciences, University of WashingtonSeattleUnited States
| | | | - Hiulan Yau
- Hotchkiss Brain Institute, University of CalgaryCalgaryCanada
| | - Martin Sticht
- Hotchkiss Brain Institute, University of CalgaryCalgaryCanada
| | | | - Francis S Lee
- Weill Cornell Medical College, Cornell UniversityNew YorkUnited States
| | - Larry S Zweifel
- Department of Psychiatry and Behavioral Sciences, University of WashingtonSeattleUnited States
| | | | - Nils C Gassen
- Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, University Hospital BonnBonnGermany
| | - Matthew N Hill
- Hotchkiss Brain Institute, University of CalgaryCalgaryCanada
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19
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Jeon S, Park JE, Do YH, Santos R, Lee SM, Kim BN, Cheong JH, Kim Y. Atomoxetine and Fluoxetine Activate AMPK-ACC-CPT1 Pathway in Human SH-SY5Y and U-87 MG Cells. Psychiatry Investig 2023; 20:212-219. [PMID: 36990664 PMCID: PMC10064201 DOI: 10.30773/pi.2022.0255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/04/2022] [Indexed: 03/31/2023] Open
Abstract
OBJECTIVE Atomoxetine and fluoxetine are psychopharmacologic agents associated with loss of appetite and weight. Adenosine monophosphate-activated protein kinase (AMPK) is the cellular energy sensor that regulate metabolism and energy, being activated by fasting and inhibited by feeding in the hypothalamus. METHODS Human brain cell lines (SH-SY5Y and U-87 MG cells) were used to study the outcome of atomoxetine and fluoxetine treatment in the activity of AMPK-acetyl-CoA carboxylase (ACC)- carnitine palmitoyl transferase 1 (CPT1) pathway and upstream regulation by calcium/calmodulin-dependent kinase kinase β (CaMKKβ) using immunoblotting and CPT1 enzymatic activity measures. RESULTS Phosphorylation of AMPK and ACC increased significantly after atomoxetine and fluoxetine treatment in the first 30-60 minutes of treatment in the two cell lines. Activation of AMPK and inhibition of ACC was associated with an increase by 5-fold of mitochondrial CPT1 activity. Although the neuronal isoform CPT1C could be detected by immunoblotting, activity was not changed by the drug treatments. In addition, the increase in phospho-AMPK and phospho-ACC expression induced by atomoxetine was abolished by treatment with STO-609, a CaMKKβ inhibitor, indicating that AMPK-ACC-CPT1 pathway is activated through CaMKKβ phosphorylation. CONCLUSION These findings indicate that at the cellular level atomoxetine and fluoxetine treatments may activate AMPK-ACC-CPT1 pathways through CaMKKβ in human SH-SY5Y and U-87 MG cells.
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Affiliation(s)
- Songhee Jeon
- Center for Glocal Future Biomedical Scientists at Chonnam National University, Gwangju, Republic of Korea
| | - Jeong-Eun Park
- Department of Otorhinolaryngology Head and Neck Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Republic of Korea
| | - Young Ho Do
- Department of Child and Adolescent Psychiatry, National Center for Mental Health, Seoul, Republic of Korea
| | - Renata Santos
- INSERM U1266, Institute of Psychiatry and Neuroscience of Paris (IPNP), Laboratory of Dynamics of Neuronal Structure in Health and Disease, Université Paris Cité, Paris, France
| | - Seong Mi Lee
- Department of Child and Adolescent Psychiatry, National Center for Mental Health, Seoul, Republic of Korea
| | - Bung-Nyun Kim
- Division of Child & Adolescent Psychiatry, Department of Psychiatry and Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae Hoon Cheong
- Institute for New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju, Republic of Korea
| | - Yeni Kim
- Department of Child and Adolescent Psychiatry, National Center for Mental Health, Seoul, Republic of Korea
- Institute of Clinical Psychopharmacology, Dongguk University International Hospital, Goyang, Republic of Korea
- Department of Neuropsychiatry, Dongguk University School of Medicine, Goyang, Republic of Korea
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20
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Milbank E, Dragano N, Vidal-Gómez X, Rivas-Limeres V, Garrido-Gil P, Wertheimer M, Recoquillon S, Pata MP, Labandeira-Garcia JL, Diéguez C, Nogueiras R, Martínez MC, Andriantsitohaina R, López M. Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice. Metabolism 2023; 139:155350. [PMID: 36423694 DOI: 10.1016/j.metabol.2022.155350] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND AIMS Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorders. However, the current therapeutic options against this syndrome are scarce. METHODS db/db mice and their wildtypes were systemically treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) driven by steroidogenic factor 1 (SF1) promoter; this approach allowed to modulate AMPK activity, specifically in SF1 cells of the ventromedial nucleus of the hypothalamus (VMH). Animals were metabolically phenotyped. RESULTS db/db mice intravenously injected with SF1-AMPKα1-DN loaded sEVs showed a marked feeding-independent weight loss and decreased adiposity, associated with increased sympathetic tone, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). CONCLUSION Overall, this evidence indicates that specific modulation of hypothalamic AMPK using a sEV-based technology may be a suitable strategy against genetic forms of obesity, such as LEPR deficiency.
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Affiliation(s)
- Edward Milbank
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Nathalia Dragano
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Xavi Vidal-Gómez
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France; SOPAM, U1063, INSERM, UNIV Angers, Angers, France
| | - Verónica Rivas-Limeres
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Pablo Garrido-Gil
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease (CiMUS), Department of Morphological Sciences, University of Santiago de Compostela, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | | | | | - María P Pata
- Biostatech Advice, Training and Innovation in Biostatistics, S.L., Santiago de Compostela 15782, Spain
| | - José Luis Labandeira-Garcia
- Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease (CiMUS), Department of Morphological Sciences, University of Santiago de Compostela, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Carlos Diéguez
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Rubén Nogueiras
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - M Carmen Martínez
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France; SOPAM, U1063, INSERM, UNIV Angers, Angers, France
| | - Ramaroson Andriantsitohaina
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France; SOPAM, U1063, INSERM, UNIV Angers, Angers, France.
| | - Miguel López
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
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21
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AMPK inhibits liver gluconeogenesis: fact or fiction? Biochem J 2023; 480:105-125. [PMID: 36637190 DOI: 10.1042/bcj20220582] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 01/04/2023] [Indexed: 01/14/2023]
Abstract
Is there a role for AMPK in the control of hepatic gluconeogenesis and could targeting AMPK in liver be a viable strategy for treating type 2 diabetes? These are frequently asked questions this review tries to answer. After describing properties of AMPK and different small-molecule AMPK activators, we briefly review the various mechanisms for controlling hepatic glucose production, mainly via gluconeogenesis. The different experimental and genetic models that have been used to draw conclusions about the role of AMPK in the control of liver gluconeogenesis are critically discussed. The effects of several anti-diabetic drugs, particularly metformin, on hepatic gluconeogenesis are also considered. We conclude that the main effect of AMPK activation pertinent to the control of hepatic gluconeogenesis is to antagonize glucagon signalling in the short-term and, in the long-term, to improve insulin sensitivity by reducing hepatic lipid content.
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22
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Roles of Ghrelin and Leptin in Body Mass Regulation under Food Restriction Based on the AMPK Pathway in the Red-Backed Vole, Eothenomys miletus, from Kunming and Dali Regions. Animals (Basel) 2022; 12:ani12233333. [PMID: 36496854 PMCID: PMC9739273 DOI: 10.3390/ani12233333] [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: 10/25/2022] [Revised: 11/24/2022] [Accepted: 11/24/2022] [Indexed: 11/30/2022] Open
Abstract
The phenotype plasticity of animals' physiological characteristics is an important survival strategy to cope with environmental changes, especially the change in climate factors. Small mammals that inhabit seasonally changing environments often face the stress of food shortage in winter. This study measured and compared the thermogenic characteristics and related physiological indicators in the adenosine-5'-monophosphate-activated protein kinase (AMPK) pathway in Eothenomys miletus between Kunming (KM, n = 18) and Dali (DL, n = 18) under food restriction and refeeding. The results showed that food restriction and the region have significant effects on body mass, the resting metabolic rate (RMR), hypothalamic neuropeptide gene expression, ghrelin levels in the stomach and serum, serum leptin level and the activity of AMPK, and malonyl CoA and carnitine palmitoyltransferase 1 (CPT-1) activity. Food restriction reduced the body mass, the gene expression of neuropeptide proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcription peptide (CART), and leptin level. However, the ghrelin concentration and AMPK activity increased. After refeeding, there was no difference in these physiological indexes between the food restriction and control groups. Moreover, the physiological indicators also showed regional differences, such as the body mass, POMC and CART gene expression, ghrelin concentration in the stomach and serum, and AMPK activity in DL changed more significantly. All these results showed that food restriction reduces energy metabolism in E. miletus. After refeeding, most of the relevant physiological indicators can return to the control level, indicating that E. miletus has strong phenotypic plasticity. Ghrelin, leptin, and the AMPK pathway play an important role in the energy metabolism of E. miletus under food restriction. Moreover, regional differences in physiological indicators under food restriction may be related to the different temperatures or food resources in different regions.
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23
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Ouchi Y, Komaki Y, Shimizu K, Fukano N, Sugino T, Shiraishi JI, Chowdhury VS, Bungo T. Comparison of oral administration of fructose and glucose on food intake and physiological parameters in broiler chicks. Poult Sci 2022; 102:102249. [PMID: 36335736 PMCID: PMC9640322 DOI: 10.1016/j.psj.2022.102249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/02/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
Like glucose, fructose is a monosaccharide, but the mechanisms of its absorption and metabolism in the body are very different between the 2 molecules. In this study, we investigated the effects of oral administration of glucose and fructose on food intake, diencephalic gene expression, and plasma metabolite concentrations in broiler chicks. The animals used in this study were 4-day-old male broiler chicks (Ross 308). They were given glucose, fructose (200 mg/ 0.5 mL/ bird), or a similar volume of distilled water orally after 6 h fasting. After treatment, measurements of food intake (at 0, 30, and 60 min), and blood glucose as well as insulin concentrations were measured over time; however, diencephalic (hypothalamus) gene expression and plasma metabolites were measured at 30 min. The results showed that glucose administration suppressed food intake, but fructose administration did not suppress food intake and it was at the same level as distilled water administration. In addition, fructose administration did not increase plasma glucose and insulin levels as did glucose administration. In the diencephalon, expression levels of genes related to the melanocortin system were unaffected by the treatment, while gene expression levels related to intracellular energy regulation, such as AMP-activated protein kinase were affected by the glucose treatment in the fasted chicks. These results suggest that fructose administration does not suppress feeding behavior as a result of possible reduction in the energy levels in the diencephalon and associated energy metabolism.
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Affiliation(s)
- Yoshimitsu Ouchi
- Faculty of Veterinary Medicine, Okayama University of Science, Imabari 794-8555, Japan
| | - Yoshinori Komaki
- Graduate School of Bioresource Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Kensuke Shimizu
- Graduate School of Bioresource Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Natsuki Fukano
- Graduate School of Bioresource Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Toshihisa Sugino
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Jun-ichi Shiraishi
- Department of Animal Science, Nippon Veterinary and Life Science University, Musashino 180-8602, Japan
| | - Vishwajit S. Chowdhury
- Faculty of Arts and Science, Graduate School of Bioresource and Bioenvironmental Science, Kyushu University, Fukuoka 819-0395, Japan
| | - Takashi Bungo
- Faculty of Veterinary Medicine, Okayama University of Science, Imabari 794-8555, Japan,Corresponding author:
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24
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Ngo FY, Li H, Zhang H, Lau CYG. Acute Fasting Modulates Food-Seeking Behavior and Neural Signaling in the Piriform Cortex. Nutrients 2022; 14:nu14194156. [PMID: 36235808 PMCID: PMC9572926 DOI: 10.3390/nu14194156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/01/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022] Open
Abstract
It is well known that the state of hunger can modulate hormones and hypothalamic neural circuits to drive food-seeking behavior and consumption. However, the role the sensory cortex plays in regulating foraging is much less explored. Here, we investigated whether acute fasting in mice can alter an odor-guided foraging behavior and how it can alter neurons and synapses in the (olfactory) piriform cortex (PC). Acute hunger enhances the motivation of a mouse to search for food pellets and increases food intake. The foraging behavior strongly activates the PC, as revealed by c-Fos immunostaining. The activation of PC is accompanied by an increase in excitation-inhibition ratio of synaptic density. Fasting also enhances the phosphorylation of AMP kinase, a biochemical energy regulator. Taken together, our results uncover a new regulatory brain region and implicate the PC in controlling foraging behavior.
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Affiliation(s)
- Fung-Yin Ngo
- Department of Neuroscience, City University of Hong Kong, Hong Kong, China
- Shenzhen Research Institute, City University of Hong Kong, Shenzhen 518057, China
| | - Huanhuan Li
- Department of Neuroscience, City University of Hong Kong, Hong Kong, China
- Shenzhen Research Institute, City University of Hong Kong, Shenzhen 518057, China
| | - Huiqi Zhang
- Department of Neuroscience, City University of Hong Kong, Hong Kong, China
- Shenzhen Research Institute, City University of Hong Kong, Shenzhen 518057, China
| | - Chun-Yue Geoffrey Lau
- Department of Neuroscience, City University of Hong Kong, Hong Kong, China
- Shenzhen Research Institute, City University of Hong Kong, Shenzhen 518057, China
- Correspondence: ; Tel.: +852-3442-4345
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25
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Abou Daher A, Alkhansa S, Azar WS, Rafeh R, Ghadieh HE, Eid AA. Translational Aspects of the Mammalian Target of Rapamycin Complexes in Diabetic Nephropathy. Antioxid Redox Signal 2022; 37:802-819. [PMID: 34544257 DOI: 10.1089/ars.2021.0217] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic regimens. The mammalian target of rapamycin (mTOR) pathway has emerged as an important candidate in the quest for drug discovery because of its role in regulating growth, proliferation, as well as protein and lipid metabolism. Recent Advances: Kidney cells have been found to rely on basal autophagy for survival and for conserving kidney integrity. Recent studies have shown that diabetes induces renal autophagy deregulation, leading to kidney injury. Hyper-activation of the mTOR pathway and oxidative stress have been suggested to play a role in diabetes-induced autophagy imbalance. Critical Issues: A detailed understanding of the role of mTOR signaling in diabetes-associated complications is of major importance in the search for a cure. In this review, we provide evidence that mTOR is heavily implicated in diabetes-induced kidney injury. We suggest possible mechanisms through which mTOR exerts its negative effects by increasing insulin resistance, upregulating oxidative stress, and inhibiting autophagy. Future Directions: Both increased oxidative stress and autophagy deregulation are deeply embedded in DN. However, the mechanisms controlling oxidative stress and autophagy are not well understood. Although Akt/mTOR signaling seems to play an important role in oxidative stress and autophagy, further investigation is required to uncover the details of this signaling pathway. Antioxid. Redox Signal. 37, 802-819.
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Affiliation(s)
- Alaa Abou Daher
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Sahar Alkhansa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - William S Azar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,Department of Physiology and Biophysics, Georgetown University Medical School, Washington, District of Columbia, USA
| | - Rim Rafeh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Hilda E Ghadieh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
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26
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Dos Santos Neves L, Oliveira RKG, Dos Santos LS, Ribeiro IO, Medeiros JMB, de Matos RJB. Modulation of hypothalamic AMPK and hypothalamic neuropeptides in the control of eating behavior: A systematic review. Life Sci 2022; 309:120947. [PMID: 36096244 DOI: 10.1016/j.lfs.2022.120947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/03/2022] [Accepted: 09/07/2022] [Indexed: 12/09/2022]
Abstract
Eating behavior is regulated by central and peripheral signals, which interact to modulate the response to nutrient intake. Central control is mediated by the hypothalamus through neuropeptides that activate the orexigenic and anorexigenic pathways. Energy homeostasis depends on the efficiency of these regulatory mechanisms. This neuroendocrine regulation of hunger and appetite can be modulated by nutritional sensors such as adenosine monophosphate-activated protein kinase (AMPK). Thus, this systematic review discusses the literature on correlations between AMPK and hypothalamic neuropeptides regarding control of eating behavior. Lilacs, PubMed/Medline, ScienceDirect, and Web of Science were searched for articles published from 2009 to 2021 containing combinations of the following descriptors: "eating behavior," "hypothalamus," "neuropeptide," and "AMPK." Of the 1330 articles found initially, 27 were selected after application of the inclusion and exclusion criteria. Of the selected articles, 15 reported decreased AMPK activity, due to interventions using angiotensin II infusion, fructose, glucose, cholecystokinin, leptin, or lipopolysaccharide (LPS) injection; dietary control through a low-protein diet or a high-fat diet (60 % fat); induction of hyperthyroidism; or injection of AMPK inhibitors. Seven studies showed a decrease in neuropeptide Y (NPY) through CV4 AICAR administration; fructose, glucose, leptin, or angiotensin II injections; or infusion of LPS from Escherichia coli and liver kinase B1 (LKB1) overexpression. Eleven studies reported a decrease in food consumption due to a decrease in AMPK activity and/or hypothalamic neuropeptides such as NPY. The results indicate that there is a relationship between AMPK and the control of eating behavior: a decrease in AMPK activity due to a dietary or non-dietary stimulus is associated with a consequent decrease in food intake. Furthermore, AMPK activity can be modulated by glucose, thyroid hormones, estradiol, leptin, and ghrelin.
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Affiliation(s)
- Letycia Dos Santos Neves
- Vitoria Academic Center, Federal University of Pernambuco, Rua do Alto do Reservoir, S/N, Bela Vista, CEP 55608-680 Vitória de Santo Antão, PE, Brazil
| | - Renata Kelly Gomes Oliveira
- Vitoria Academic Center, Federal University of Pernambuco, Rua do Alto do Reservoir, S/N, Bela Vista, CEP 55608-680 Vitória de Santo Antão, PE, Brazil
| | - Lucimeire Santana Dos Santos
- Federal University of Bahia, School of Nutrition, Rua Basilio da Gama, s/n, Campus Canela, CEP: 40.110-907 Salvador, BA, Brazil
| | - Ingrid Oliveira Ribeiro
- Federal University of Bahia, School of Nutrition, Rua Basilio da Gama, s/n, Campus Canela, CEP: 40.110-907 Salvador, BA, Brazil
| | - Jairza Maria Barreto Medeiros
- Federal University of Bahia, School of Nutrition, Rua Basilio da Gama, s/n, Campus Canela, CEP: 40.110-907 Salvador, BA, Brazil
| | - Rhowena Jane Barbosa de Matos
- Health Sciences Center, Federal University of Recôncavo of Bahia, Avenida Carlos Amaral, 1015, Cajueiro, CEP 44574-490 Santo Antônio de Jesus, BA, Brazil.
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27
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Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther 2022; 7:298. [PMID: 36031641 PMCID: PMC9420733 DOI: 10.1038/s41392-022-01149-x] [Citation(s) in RCA: 170] [Impact Index Per Article: 56.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/26/2022] [Accepted: 08/08/2022] [Indexed: 12/19/2022] Open
Abstract
Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases the risk of several diseases, such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and is linked to lower life expectancy. Although lifestyle intervention (diet and exercise) has remarkable effects on weight management, achieving long-term success at weight loss is extremely challenging, and the prevalence of obesity continues to rise worldwide. Over the past decades, the pathophysiology of obesity has been extensively investigated, and an increasing number of signal transduction pathways have been implicated in obesity, making it possible to fight obesity in a more effective and precise way. In this review, we summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies, focusing on signaling pathways and their roles in the regulation of food intake, glucose homeostasis, adipogenesis, thermogenesis, and chronic inflammation. We also discuss the current anti-obesity drugs, as well as weight loss compounds in clinical trials, that target these signals. The evolving knowledge of signaling transduction may shed light on the future direction of obesity research, as we move into a new era of precision medicine.
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28
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Liu J, Lai F, Hou Y, Zheng R. Leptin signaling and leptin resistance. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:363-384. [PMID: 37724323 PMCID: PMC10388810 DOI: 10.1515/mr-2022-0017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/12/2022] [Indexed: 09/20/2023]
Abstract
With the prevalence of obesity and associated comorbidities, studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest. In 1994, the cloning of leptin was a milestone in metabolic research. As an adipocytokine, leptin governs food intake and energy homeostasis through leptin receptors (LepR) in the brain. The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance, which encompasses complex pathophysiological processes. Within the brain, LepR-expressing neurons are distributed in hypothalamus and other brain areas, and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects. In LepR-expressing neurons, the binding of leptin to LepR initiates multiple signaling cascades including janus kinase (JAK)-signal transducers and activators of transcription (STAT) phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), extracellular regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, etc., mediating leptin actions. These findings place leptin at the intersection of metabolic and neuroendocrine regulations, and render leptin a key target for treating obesity and associated comorbidities. This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis, and guides the development of safe and effective interventions to treat obesity and associated diseases.
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Affiliation(s)
- Jiarui Liu
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Futing Lai
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Yujia Hou
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Ruimao Zheng
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
- Neuroscience Research Institute, Peking University, Beijing, China
- Key Laboratory for Neuroscience of Ministry of Education, Peking University, Beijing, China
- Key Laboratory for Neuroscience of National Health Commission, Peking University, Beijing 100191, China
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López M. Hypothalamic AMPK as a possible target for energy balance-related diseases. Trends Pharmacol Sci 2022; 43:546-556. [DOI: 10.1016/j.tips.2022.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 10/18/2022]
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Strogulski NR, Kopczynski A, de Oliveira VG, Carteri RB, Hansel G, Venturin GT, Greggio S, DaCosta JC, De Bastiani MA, Rodolphi MS, Portela LV. Nandrolone Supplementation Promotes AMPK Activation and Divergent 18[FDG] PET Brain Connectivity in Adult and Aged Mice. Neurochem Res 2022; 47:2032-2042. [PMID: 35415802 DOI: 10.1007/s11064-022-03592-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/26/2022] [Accepted: 03/28/2022] [Indexed: 11/29/2022]
Abstract
Decreased anabolic androgen levels are followed by impaired brain energy support and sensing with loss of neural connectivity during physiological aging, providing a neurobiological basis for hormone supplementation. Here, we investigated whether nandrolone decanoate (ND) administration mediates hypothalamic AMPK activation and glucose metabolism, thus affecting metabolic connectivity in brain areas of adult and aged mice. Metabolic interconnected brain areas of rodents can be detected by positron emission tomography using 18FDG-mPET. Albino CF1 mice at 3 and 18 months of age were separated into 4 groups that received daily subcutaneous injections of either ND (15 mg/kg) or vehicle for 15 days. At the in vivo baseline and on the 14th day, brain 18FDG-microPET scans were performed. Hypothalamic pAMPKT172/AMPK protein levels were assessed, and basal mitochondrial respiratory states were evaluated in synaptosomes. A metabolic connectivity network between brain areas was estimated based on 18FDG uptake. We found that ND increased the pAMPKT172/AMPK ratio in both adult and aged mice but increased 18FDG uptake and mitochondrial basal respiration only in adult mice. Furthermore, ND triggered rearrangement in the metabolic connectivity of adult mice and aged mice compared to age-matched controls. Altogether, our findings suggest that ND promotes hypothalamic AMPK activation, and distinct glucose metabolism and metabolic connectivity rearrangements in the brains of adult and aged mice.
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Affiliation(s)
- N R Strogulski
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - A Kopczynski
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - V G de Oliveira
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - R B Carteri
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - G Hansel
- Neuroinflammation and Neuroimmunology Laboratory, Brain Institute of Rio Grande Do Sul, Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - G T Venturin
- Brain Institute of Rio Grande Do Sul (BraIns), Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - S Greggio
- Brain Institute of Rio Grande Do Sul (BraIns), Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - J C DaCosta
- Brain Institute of Rio Grande Do Sul (BraIns), Pontifical Catholic University of Rio Grande Do Sul (PUCRS), Porto Alegre, RS, Brazil
| | - M A De Bastiani
- Zimmer Neuroimaging Lab, Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - M S Rodolphi
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil
| | - L V Portela
- Laboratory of Neurotrauma and Biomarkers, Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil.
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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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Serna A, Marhuenda J, Arcusa R, Pérez-Piñero S, Sánchez-Macarro M, García-Muñoz AM, Victoria-Montesinos D, Cánovas F, López-Román FJ. Effectiveness of a polyphenolic extract (Lippia citriodora and Hibiscus sabdariffa) on appetite regulation in overweight and obese grade I population: an 8-week randomized, double-blind, cross-over, placebo-controlled trial. Eur J Nutr 2022; 61:825-841. [PMID: 34591168 PMCID: PMC8854308 DOI: 10.1007/s00394-021-02678-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 09/11/2021] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Polyphenols have shown capacity to improve appetite sensation, leading to enhanced control of body weight. However, despite being related with hunger-related hormones, metabolic and mechanism are not well known. METHODS The effectiveness of a nutraceutical composed of extract to Lippia citriodora and Hibiscus sabdarrifa (Lc-Hs) for controlling satiety and hunger was analyzed in a cross-over, placebo-controlled (Pla) clinical intervention. The study was divided in two 60-day periods separated by 30-day length wash-out period. At the end of each period, overweight and obese subjects (n = 33; age = 33.76 ± 12.23; BMI = 28.20 kg/m2 ± 2.47; fat mass 30.65 ± 8.39%; both sexes were proposed to eat an ad-libitum meal. Meanwhile, appetite sensation was determined by visual analog scales at different times. Moreover, blood extraction was performed to determine biochemical parameters (lipid and glucidic profile and safety parameters) and to evaluate hunger-related hormones (insulin, leptin, ghrelin, adiponectin, GLP-1 and peptide YY). RESULTS A decrease in appetite sensation was observed in Lc-Hs treatment, showing higher satiety quotient (Pla = 3.36 ± 2.33%mm/kcal; Lc-Hs = 5.53 ± 2.91%mm/kcal; p < 0.0001). Area under the curve was higher in Pla compared to Lc-Hs during the test, from baseline to minute 240 (240 (Pla 9136.65 ± 2261.46% x min-1; Lc-Hs 8279.73 ± 2745.71% x min-1; p < 0.014). Energy consumption was lower for subjects treated with Lc-Hs (774.44 ± 247.77 kcal) compared to those treated with Pla (849.52 ± 246.54 kcal) (p < 0.004). Leptin values varied from baseline (Pla 12.36 ± 1.98 ng/mL; Lc-Hs 13.13 ± 1.99 ng/mL) to the end of the study (Pla 12.60 ± 2.02 ng/mL; Lc-Hs 12.06 ± 2.05 ng/mL; p < 0.047). GLP-1 values varied (p < 0.001) in Lc-Hs treatment from baseline (4.34 ± 0.49 ng/mL) to the end of the study (3.23 ± 0.52 ng/mL). CONCLUSION The supplementation with the Lc-Hs extract decreases appetite sensation in overweight and obese population, reducing calorie intake after an ad-libitum meal. Due to variation on hunger-related hormones and the relationship between satiety feeling, it would be interesting to develop future research focused on the variation of the hormones themselves.
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Affiliation(s)
- Ana Serna
- Faculty of Health Sciences, San Antonio Catholic University of Murcia (UCAM), 30107, Murcia, Spain
| | - Javier Marhuenda
- Faculty of Health Sciences, San Antonio Catholic University of Murcia (UCAM), 30107, Murcia, Spain.
| | - Raúl Arcusa
- Faculty of Health Sciences, San Antonio Catholic University of Murcia (UCAM), 30107, Murcia, Spain
| | - Silvia Pérez-Piñero
- Faculty of Health Sciences, San Antonio Catholic University of Murcia (UCAM), 30107, Murcia, Spain
| | | | - Ana María García-Muñoz
- Faculty of Health Sciences, San Antonio Catholic University of Murcia (UCAM), 30107, Murcia, Spain
| | | | - Fernando Cánovas
- Faculty of Health Sciences, San Antonio Catholic University of Murcia (UCAM), 30107, Murcia, Spain
| | - F Javier López-Román
- Faculty of Health Sciences, San Antonio Catholic University of Murcia (UCAM), 30107, Murcia, Spain
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), Murcia, Spain
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Mukherjee S, Skrede S, Milbank E, Andriantsitohaina R, López M, Fernø J. Understanding the Effects of Antipsychotics on Appetite Control. Front Nutr 2022; 8:815456. [PMID: 35047549 PMCID: PMC8762106 DOI: 10.3389/fnut.2021.815456] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/10/2021] [Indexed: 12/16/2022] Open
Abstract
Antipsychotic drugs (APDs) represent a cornerstone in the treatment of schizophrenia and other psychoses. The effectiveness of the first generation (typical) APDs are hampered by so-called extrapyramidal side effects, and they have gradually been replaced by second (atypical) and third-generation APDs, with less extrapyramidal side effects and, in some cases, improved efficacy. However, the use of many of the current APDs has been limited due to their propensity to stimulate appetite, weight gain, and increased risk for developing type 2 diabetes and cardiovascular disease in this patient group. The mechanisms behind the appetite-stimulating effects of the various APDs are not fully elucidated, partly because their diverse receptor binding profiles may affect different downstream pathways. It is critical to identify the molecular mechanisms underlying drug-induced hyperphagia, both because this may lead to the development of new APDs, with lower appetite-stimulating effects but also because such insight may provide new knowledge about appetite regulation in general. Hence, in this review, we discuss the receptor binding profile of various APDs in relation to the potential mechanisms by which they affect appetite.
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Affiliation(s)
- Sayani Mukherjee
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
| | - Silje Skrede
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Section of Clinical Pharmacology, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
| | - Edward Milbank
- NeurObesity Group, Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición, Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Madrid, Spain.,SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France
| | | | - Miguel López
- NeurObesity Group, Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición, Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición, Madrid, Spain
| | - Johan Fernø
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
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Han S, Zhang XL, Jiang X, Li X, Ding J, Zuo LJ, Duan SS, Chen R, Sun BB, Hu XY, Gao YN, Zhang XL. Long Non-Coding RNA and mRNA Expression Analysis in Liver of Mice With Clonorchis sinensis Infection. Front Cell Infect Microbiol 2022; 11:754224. [PMID: 35127549 PMCID: PMC8807509 DOI: 10.3389/fcimb.2021.754224] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022] Open
Abstract
Clonorchiasis is recognized as an important zoonotic parasitic disease worldwide. However, the roles of host long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in the response to Clonorchis sinensis (C. sinensis) infection remain unknown. Here we compared the expression of lncRNAs and mRNAs in the liver tissue of mice infected with C. sinensis, in order to further understand the molecular mechanisms of clonorchiasis. A total of 388 lncRNAs and 1,172 mRNAs were found to be differentially expressed with absolute value of fold change (FC) ≥ 2.0 and p < 0.05 by microarray. Compared with controls, Gm6135 and 4930581F22Rik were the most over- and under-expressed lncRNAs; flavin-containing monooxygenase 3 (Fmo3) and deleted in malignant brain tumors 1 (Dmbt1) were the most over- and under-expressed mRNAs. Moreover, functional annotation showed that the significantly different mRNAs were related with “FOXO signaling pathway”, “Wnt signaling pathway”, and “AMPK signaling pathway”. Remarkably, lncRNA Gm8801 were significantly correlated with mRNA glycerol-3-phosphate acyltransferase mitochondrial (Gpam), insulin receptor substrate 2 (Irs2), and tumor necrosis factor receptor superfamily member 19 (Tnfrsf19) in ceRNA networks. These results showed that the expression profiles of lncRNAs and mRNAs in the liver changed after C. sinensis infection. Our results provided valuable insights into the lncRNAs and mRNAs involved in clonorchiasis pathogenesis, which may be useful for future control strategies.
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Affiliation(s)
- Su Han
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Xue-Li Zhang
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Xu Jiang
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Xiang Li
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Jian Ding
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Li-Jiao Zuo
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Shan-Shan Duan
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Rui Chen
- Department of Orthopaedic Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei-Bei Sun
- Clinical Laboratory, Zhuhai Maternal and Child Health Hospital, Zhuhai, China
| | - Xin-Yi Hu
- Department of Stomatology, Laixi People’s Hospital, Qingdao, China
| | - Yan-Nan Gao
- Department of Parasitology, Harbin Medical University, Harbin, China
| | - Xiao-Li Zhang
- Department of Parasitology, Harbin Medical University, Harbin, China
- *Correspondence: Xiao-Li Zhang,
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Vohra MS, Benchoula K, Serpell CJ, Hwa WE. AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity. Eur J Pharmacol 2022; 915:174611. [PMID: 34798121 DOI: 10.1016/j.ejphar.2021.174611] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 10/27/2021] [Accepted: 10/27/2021] [Indexed: 02/08/2023]
Abstract
Obesity is a major health crisis affecting over a third of the global population. This multifactorial disease is regulated via interoceptive neural circuits in the brain, whose alteration results in excessive body weight. Certain central neuronal populations in the brain are recognised as crucial nodes in energy homeostasis; in particular, the hypothalamic arcuate nucleus (ARC) region contains two peptide microcircuits that control energy balance with antagonistic functions: agouti-related peptide/neuropeptide-Y (AgRP/NPY) signals hunger and stimulates food intake; and pro-opiomelanocortin (POMC) signals satiety and reduces food intake. These neuronal peptides levels react to energy status and integrate signals from peripheral ghrelin, leptin, and insulin to regulate feeding and energy expenditure. To manage obesity comprehensively, it is crucial to understand cellular and molecular mechanisms of information processing in ARC neurons, since these regulate energy homeostasis. Importantly, a specific strategy focusing on ARC circuits needs to be devised to assist in treating obese patients and maintaining weight loss with minimal or no side effects. The aim of this review is to elucidate the recent developments in the study of AgRP-, NPY- and POMC-producing neurons, specific to their role in controlling metabolism. The impact of ghrelin, leptin, and insulin signalling via action of these neurons is also surveyed, since they also impact energy balance through this route. Lastly, we present key proteins, targeted genes, compounds, drugs, and therapies that actively work via these neurons and could potentially be used as therapeutic targets for treating obesity conditions.
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Affiliation(s)
- Muhammad Sufyan Vohra
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Khaled Benchoula
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Christopher J Serpell
- School of Physical Sciences, Ingram Building, University of Kent, Canterbury, Kent, CT2 7NH, United Kingdom
| | - Wong Eng Hwa
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia.
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The activation of hypothalamic AMP-activated protein kinase by oxidative stress is related to hyperphagia in diabetic rats. Neuroreport 2021; 33:72-80. [PMID: 34954771 DOI: 10.1097/wnr.0000000000001759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE During diabetes, there are increased blood glucose levels and oxidative stress. The relationship between oxidative stress and the phosphorylation of AMP-activated protein kinase at the hypothalamic level has been little studied. The objective of this study was to analyze the relationship between oxidative stress and AMP-activated protein kinase activation in Wistar rats with hyperphagia and hyperglycemia. METHODS Rats at 7, 14, and 28 days with diabetes were used. Control rats were included. Food intake was calculated to determine hyperphagia. The hypothalamus was extracted to evaluate oxidative stress markers by spectrophotometry; phosphorylation of AMP-activated protein kinase, growth hormone receptor 1a, and neuropeptide Y expression were determined by Western blot. RESULTS There was a significant increase in the consumption of food in the experimental groups. The level of malondialdehyde decreased in the 7-day group (33%) and increased significantly in the 28-day group (90%), glutathione peroxidase activity increased in the 7-day group (70%) and decreased in the 28-day group (34%), and the phosphorylation of AMP-activated protein kinase increased significantly in the 28-day group (86%). Under ex-vivo conditions in animals with 28 days of hyperglycemia, glutathione peroxidase activity increased 195%, the malondialdehyde level decreased 87%, phosphorylation of AMP-activated protein kinase decreased 53%, and growth hormone receptor 1a expression decreased 66%, when treating hyperglycemic hypothalamic tissue with an antioxidant. NPY expression increased in hyperglycemia, and antioxidant treatment did not regulate its expression. CONCLUSIONS The activation of AMP-activated protein kinase is related with an increase in oxidative stress markers in hyperglycemic and hyperphagic rats.
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Cai J, Hu Q, Lin H, Zhao J, Jiao H, Wang X. Adiponectin/adiponectin receptors mRNA expression profiles in chickens and their response to feed restriction. Poult Sci 2021; 100:101480. [PMID: 34700095 PMCID: PMC8554277 DOI: 10.1016/j.psj.2021.101480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/06/2021] [Accepted: 09/13/2021] [Indexed: 11/08/2022] Open
Abstract
Adiponectin (ADPN) is related to fatty acid synthesis and oxidation in mammals. In chickens, the lipid metabolism, structure and sequence of ADPN are different from that in mammals. The aim of this study was to determine the role of ADPN in broilers lipid metabolism by investigating the temporal and spatial expression profiles of ADPN and its receptors, as well as their response to feed restriction. The results showed that the abdominal fat has the highest expression level, followed by the duodenum, glandular stomach, heart, hypothalamus, liver, and skeletal muscle. Broilers have high energy mobilization during their early stage of growth, in which the fat demand in the liver and muscles is high, thus the expression of ADPN and its receptor are also increased. To study the effects of feed restriction on ADPN and lipid metabolism, broilers were fasted for 12 h and refeed for 2 h. The results showed that fasting decreased the concentration of triglyceride (TG) (P < 0.05) and total cholesterol (TCHO) (P < 0.05) in plasma. The mRNA expression of ADPN in the liver (P < 0.05), breast (P < 0.05) and thigh (P < 0.05), and the mRNA expression of ADPNR1 in the liver (P < 0.05) and duodenum (P < 0.05) were significantly increased in the Fasted group. All above phenomena were recovered after refeeding, suggesting that feed restriction may promote the utilization of fatty acids in active metabolism tissues through ADPN, to guarantee the energy homeostasis of the body. However, the AMP-activated protein kinase (AMPK) signaling pathway and hepatic lipid metabolism were not necessary to cause the above changes under this experimental condition.
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Affiliation(s)
- Jiangxue Cai
- Department of Animal Science & Technology, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, 271018, P. R. China
| | - Qingmei Hu
- Department of Animal Science & Technology, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, 271018, P. R. China
| | - Hai Lin
- Department of Animal Science & Technology, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, 271018, P. R. China
| | - Jingpeng Zhao
- Department of Animal Science & Technology, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, 271018, P. R. China
| | - Hongchao Jiao
- Department of Animal Science & Technology, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, 271018, P. R. China
| | - Xiaojuan Wang
- Department of Animal Science & Technology, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, 271018, P. R. China.
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Wang X, Huang H, Zhu Y, Li S, Zhang P, Jiang J, Xi C, Wu L, Gao X, Fu Y, Zhang D, Chen Y, Hu S, Lai J. Metformin acts on the gut-brain axis to ameliorate antipsychotic-induced metabolic dysfunction. Biosci Trends 2021; 15:321-329. [PMID: 34588398 DOI: 10.5582/bst.2021.01317] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Antipsychotic-induced metabolic dysfunction (AIMD) is an intractable clinical challenge worldwide. The situation is becoming more critical as second-generation antipsychotics (SGAs), to a great extent, have replaced the role of first-generation antipsychotics in managing major psychiatric disorders. Although the exact mechanisms for developing AIMD is intricate, emerging evidence has indicated the involvement of the microbiota-gut-brain axis in AIMD. SGAs treatment may change the diversity and compositions of intestinal flora (e.g., decreased abundance of Bacteroidetes and Akkermansia muciniphila, and increased Firmicutes). Short-chain fatty acids and other metabolites derived from gut microbiota, on the one hand, can regulate the activity of intestinal endocrine cells and their secretion of satiety hormones (e.g., glucagon-like peptide 1, peptide YY, cholecystokinin and ghrelin); on the other hand, can activate the vagus nerve or transport into the brain to exert a central modulation of foraging behaviors via binding to neuropeptide receptors. Interestingly, metformin, a classical antidiabetic agent, is capable of alleviating AIMD possibly by regulating the microbiota-gut-brain axis. That is, metformin can not only partially reverse the alterations of gut microbial communities due to SGAs treatment, but also play a positive role in rectifying the disturbances of peripheral and central satiety-related neuropeptides. Current evidence has indicated a promising role for metformin on ameliorating AMID, but further verifications in well-designed clinical trials are still warranted.
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Affiliation(s)
- Xiaorong Wang
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,The Key Laboratory of Mental Disorder's Management in Zhejiang Province, Hangzhou, Zhejiang, China.,Brain Research Institute of Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou, Zhejiang, China
| | - Huimin Huang
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yiyi Zhu
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shaoli Li
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Peifen Zhang
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jiajun Jiang
- The Key Laboratory of Mental Disorder's Management in Zhejiang Province, Hangzhou, Zhejiang, China
| | - Caixi Xi
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lingling Wu
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xingle Gao
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yaoyang Fu
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Danhua Zhang
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yiqing Chen
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shaohua Hu
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,The Key Laboratory of Mental Disorder's Management in Zhejiang Province, Hangzhou, Zhejiang, China.,Brain Research Institute of Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou, Zhejiang, China
| | - Jianbo Lai
- Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,The Key Laboratory of Mental Disorder's Management in Zhejiang Province, Hangzhou, Zhejiang, China.,Brain Research Institute of Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou, Zhejiang, China
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Chatterjee O, Gopalakrishnan L, Mol P, Advani J, Nair B, Shankar SK, Mahadevan A, Prasad TSK. The Normal Human Adult Hypothalamus Proteomic Landscape: Rise of Neuroproteomics in Biological Psychiatry and Systems Biology. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:693-710. [PMID: 34714154 DOI: 10.1089/omi.2021.0158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The human hypothalamus is central to the regulation of neuroendocrine and neurovegetative systems, as well as modulation of chronobiology and behavioral aspects in human health and disease. Surprisingly, a deep proteomic analysis of the normal human hypothalamic proteome has been missing for such an important organ so far. In this study, we delineated the human hypothalamus proteome using a high-resolution mass spectrometry approach which resulted in the identification of 5349 proteins, while a multiple post-translational modification (PTM) search identified 191 additional proteins, which were missed in the first search. A proteogenomic analysis resulted in the discovery of multiple novel protein-coding regions as we identified proteins from noncoding regions (pseudogenes) and proteins translated from short open reading frames that can be missed using the traditional pipeline of prediction of protein-coding genes as a part of genome annotation. We also identified several PTMs of hypothalamic proteins that may be required for normal hypothalamic functions. Moreover, we observed an enrichment of proteins pertaining to autophagy and adult neurogenesis in the proteome data. We believe that the hypothalamic proteome reported herein would help to decipher the molecular basis for the diverse range of physiological functions attributed to it, as well as its role in neurological and psychiatric diseases. Extensive proteomic profiling of the hypothalamic nuclei would further elaborate on the role and functional characterization of several hypothalamus-specific proteins and pathways to inform future research and clinical discoveries in biological psychiatry, neurology, and system biology.
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Affiliation(s)
- Oishi Chatterjee
- Institute of Bioinformatics, Bangalore India.,Amrita School of Biotechnology, Amrita University, Kollam, India.,Center for Systems Biology and Molecular Medicine, Yenepoya Research Center, Yenepoya (Deemed to be University), Mangalore, India
| | - Lathika Gopalakrishnan
- Institute of Bioinformatics, Bangalore India.,Center for Systems Biology and Molecular Medicine, Yenepoya Research Center, Yenepoya (Deemed to be University), Mangalore, India.,Manipal Academy of Higher Education, Manipal, India
| | - Praseeda Mol
- Institute of Bioinformatics, Bangalore India.,Amrita School of Biotechnology, Amrita University, Kollam, India
| | | | - Bipin Nair
- Amrita School of Biotechnology, Amrita University, Kollam, India
| | - Susarla Krishna Shankar
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.,Human Brain Tissue Repository, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Anita Mahadevan
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.,Human Brain Tissue Repository, National Institute of Mental Health and Neurosciences, Bangalore, India
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40
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Saikia R, Joseph J. AMPK: a key regulator of energy stress and calcium-induced autophagy. J Mol Med (Berl) 2021; 99:1539-1551. [PMID: 34398293 DOI: 10.1007/s00109-021-02125-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023]
Abstract
Autophagy is a well-known cell-survival strategy orchestrated by a conserved set of proteins. It equips the cells with mechanisms to attain homeostasis during unfavorable conditions such as stress by breaking down the cellular components and reusing them for energy as well as for building new components required for survival. A basal level of autophagy is required for achieving homeostasis under normal conditions through regular turnover of macromolecules and organelles. Initiation of autophagy is regulated by two key components of the nutrient/energy sensor pathways; mammalian target of rapamycin 1 (mTORC1) and AMP-activated kinase (AMPK). Under energy-deprived conditions, AMPK is activated triggering autophagy, whereas, in nutrient-rich conditions, the growth-promoting kinase mTORC1 is activated inhibiting autophagy. Thus, the reciprocal regulation of autophagy by AMPK and mTORC1 defines a fundamental mechanism by which cells respond to nutrient availability. Interestingly, cytoplasmic calcium is also found to be an activator of AMPK and autophagy through a calmodulin/CaMKKβ pathway. However, the physiological significance of the regulation of autophagy by cytoplasmic calcium is currently unclear. This review focuses on the current understanding of the mechanism of autophagy and its regulation by AMPK.
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Affiliation(s)
- Rimpi Saikia
- National Centre for Cell Science, S. P. Pune University Campus, Pune, 411007, Maharashtra State, India
| | - Jomon Joseph
- National Centre for Cell Science, S. P. Pune University Campus, Pune, 411007, Maharashtra State, India.
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41
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Ullah R, Rauf N, Nabi G, Yi S, Yu-Dong Z, Fu J. Mechanistic insight into high-fat diet-induced metabolic inflammation in the arcuate nucleus of the hypothalamus. Biomed Pharmacother 2021; 142:112012. [PMID: 34388531 DOI: 10.1016/j.biopha.2021.112012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/31/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022] Open
Abstract
A high-fat diet (HFD) is linked with cytokines production by non-neuronal cells within the hypothalamus, which mediates metabolic inflammation. These cytokines then activate different inflammatory mediators in the arcuate nucleus of the hypothalamus (ARC), a primary hypothalamic area accommodating proopiomelanocortin (POMC) and agouti-related peptide (AGRP) neurons, first-order neurons that sense and integrate peripheral metabolic signals and then respond accordingly. These mediators, such as inhibitor of κB kinase-β (IKKβ), suppression of cytokine signaling 3 (SOCS3), c-Jun N-terminal kinases (JNKs), protein kinase C (PKC), etc., cause insulin and leptin resistance in POMC and AGRP neurons and support obesity and related metabolic complications. On the other hand, inhibition of these mediators has been shown to counteract the impaired metabolism. Therefore, it is important to discuss the contribution of neuronal and non-neuronal cells in HFD-induced hypothalamic inflammation. Furthermore, understanding few other questions, such as the diets causing hypothalamic inflammation, the gender disparity in response to HFD feeding, and how hypothalamic inflammation affects ARC neurons to cause impaired metabolism, will be helpful for the development of therapeutic approaches to prevent or treat HFD-induced obesity.
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Affiliation(s)
- Rahim Ullah
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China
| | - Naveed Rauf
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Ghulam Nabi
- Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China; Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
| | - Shen Yi
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Zhou Yu-Dong
- Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
| | - Junfen Fu
- Department of Endocrinology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; National Children's Regional Medical Center, Hangzhou 310052, China.
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42
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Muraleedharan R, Dasgupta B. AMPK in the brain: its roles in glucose and neural metabolism. FEBS J 2021; 289:2247-2262. [PMID: 34355526 DOI: 10.1111/febs.16151] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/22/2021] [Accepted: 08/04/2021] [Indexed: 11/28/2022]
Abstract
The adenosine monophosphate-activated protein kinase (AMPK) is an integrative metabolic sensor that maintains energy balance at the cellular level and plays an important role in orchestrating intertissue metabolic signaling. AMPK regulates cell survival, metabolism, and cellular homeostasis basally as well as in response to various metabolic stresses. Studies so far show that the AMPK pathway is associated with neurodegeneration and CNS pathology, but the mechanisms involved remain unclear. AMPK dysregulation has been reported in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neuropathies. AMPK activation appears to be both neuroprotective and pro-apoptotic, possibly dependent upon neural cell types, the nature of insults, and the intensity and duration of AMPK activation. While embryonic brain development in AMPK null mice appears to proceed normally without any overt structural abnormalities, our recent study confirmed the full impact of AMPK loss in the postnatal and aging brain. Our studies revealed that Ampk deletion in neurons increased basal neuronal excitability and reduced latency to seizure upon stimulation. Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in the brain. AMPK's regulation of aerobic glycolysis in astrocytic metabolism warrants further deliberation, particularly glycogen turnover and shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation. In this minireview, we focus on recent advances in AMPK and energy-sensing in the brain.
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Affiliation(s)
| | - Biplab Dasgupta
- Division of Oncology, Cincinnati Children's Hospital Medical Center, OH, USA
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Medina-Vera D, Navarro JA, Tovar R, Rosell-Valle C, Gutiérrez-Adan A, Ledesma JC, Sanjuan C, Pavón FJ, Baixeras E, Rodríguez de Fonseca F, Decara J. Activation of PI3K/Akt Signaling Pathway in Rat Hypothalamus Induced by an Acute Oral Administration of D-Pinitol. Nutrients 2021; 13:2268. [PMID: 34209137 PMCID: PMC8308282 DOI: 10.3390/nu13072268] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/23/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.
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Affiliation(s)
- Dina Medina-Vera
- Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain; (D.M.-V.); (J.A.N.); (R.T.); (C.R.-V.); (J.C.L.); (F.J.P.)
- Facultad de Ciencias, Universidad de Málaga, 29010 Málaga, Spain
- Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), UGC del Corazón, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Málaga, Spain
| | - Juan Antonio Navarro
- Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain; (D.M.-V.); (J.A.N.); (R.T.); (C.R.-V.); (J.C.L.); (F.J.P.)
- Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
| | - Rubén Tovar
- Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain; (D.M.-V.); (J.A.N.); (R.T.); (C.R.-V.); (J.C.L.); (F.J.P.)
- Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
| | - Cristina Rosell-Valle
- Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain; (D.M.-V.); (J.A.N.); (R.T.); (C.R.-V.); (J.C.L.); (F.J.P.)
| | - Alfonso Gutiérrez-Adan
- Departamento de Reproducción Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, 28040 Madrid, Spain;
| | - Juan Carlos Ledesma
- Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain; (D.M.-V.); (J.A.N.); (R.T.); (C.R.-V.); (J.C.L.); (F.J.P.)
| | - Carlos Sanjuan
- Euronutra S.L. Calle Johannes Kepler, 3, 29590 Málaga, Spain;
| | - Francisco Javier Pavón
- Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain; (D.M.-V.); (J.A.N.); (R.T.); (C.R.-V.); (J.C.L.); (F.J.P.)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), UGC del Corazón, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Málaga, Spain
| | - Elena Baixeras
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain;
| | - Fernando Rodríguez de Fonseca
- Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain; (D.M.-V.); (J.A.N.); (R.T.); (C.R.-V.); (J.C.L.); (F.J.P.)
| | - Juan Decara
- Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain; (D.M.-V.); (J.A.N.); (R.T.); (C.R.-V.); (J.C.L.); (F.J.P.)
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Park YJ, Cominguez DC, Kim HJ, Jin JS, Koh DJ, Kim SY, Lim YW, Park YB, An HJ. Therapeutic effects of Gambi-jung for the treatment of obesity. Biomed Pharmacother 2021; 141:111838. [PMID: 34182414 DOI: 10.1016/j.biopha.2021.111838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/14/2021] [Accepted: 06/14/2021] [Indexed: 01/09/2023] Open
Abstract
Obesity is known as metabolic syndrome and it affects many tissues including adipose tissue, liver, and central nervous system (CVS). Gambi-jung (GBJ) is a modified prescription of Taeumjowi-tang (TJT), which has been used to treat obesity in Korea. GBJ is composed of 90% Ephedra sinica Stapf (ES). Therefore, the present study was designed to assess the antiobesity effects of GBJ and to compare the effects of GBJ and ES on obesity. GBJ administration remarkably reduced the body weight, Body mass index (BMI), and body fat percentage compared to the ES administration in human subjects. GBJ-treated mice had lower white adipose tissue (WAT) amounts than ES-treated mice. GBJ and ES administration enhanced adenosine monophosphate-activated protein kinase (AMPK) expression in 3T3-L1 adipocytes, epididymal WAT and liver of HFD-induced obese mice. Moreover, GBJ and ES reduced food intake by suppressing the mRNA levels of orexigenic peptides, agouti-related protein (AgRP) and neuropeptide-Y (NPY), as well as AMPK in the brain of HFD-induced obese mice. Furthermore, GBJ-treated mice had dramatically lower expression of macrophage marker F4/80 in epididymal WAT than those of ES-treated mice. Based on these results, we suggest the use of GBJ as a natural drug to control weight gain.
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Affiliation(s)
- Yea-Jin Park
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju, Gangwon-do 26339, Republic of Korea.
| | - Divina C Cominguez
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju, Gangwon-do 26339, Republic of Korea.
| | - Hyo-Jung Kim
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju, Gangwon-do 26339, Republic of Korea.
| | - Jong-Sik Jin
- Department of Oriental Medicine Resources, Chonbuk National University, Iksan, Republic of Korea.
| | - Duck-Jae Koh
- Nubebe Korean Medical Clinic, Republic of Korea.
| | | | - Young-Woo Lim
- Nubebe Mibyeong Research Institute, Republic of Korea.
| | | | - Hyo-Jin An
- Department of Pharmacology, College of Korean Medicine, Sangji University, Wonju, Gangwon-do 26339, Republic of Korea.
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Hypothalamic regulation of energy homoeostasis when consuming diets of different energy concentrations: comparison between Tibetan and Small-tailed Han sheep. Br J Nutr 2021; 127:1132-1142. [PMID: 34085612 DOI: 10.1017/s0007114521001902] [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: 11/06/2022]
Abstract
Seasonal energy intake of Tibetan sheep on the harsh Qinghai-Tibetan Plateau (QTP) fluctuates greatly and is often well below maintenance requirements. The aim of this study was to gain insight into how the hypothalamus regulates energy homoeostasis in Tibetan sheep. We compared Tibetan and Small-tailed Han sheep (n 24 of each breed), which were each allocated randomly into four groups and offered one of four diets that differed in digestible energy densities: 8·21, 9·33, 10·45 and 11·57 MJ/kg DM. Sheep were weighed every 2 weeks, and it was assumed that the change in body weight (BW) reflected the change in energy balance. The arcuate nucleus of the hypothalamus in Tibetan sheep had greater protein expressions of neuropeptide Y (NPY) and agouti-related peptide (AgRP) when in negative energy balance, but lesser protein expressions of proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) when in positive energy balance than Small-tailed Han sheep. As a result, Tibetan sheep had a lesser BW loss when in negative energy balance and stored more energy and gained more BW when in positive energy balance than Small-tailed Han sheep with the same dietary intake. Moreover, in the hypothalamic adenosine monophosphate-activated protein kinase (AMPK) regulation pathway, Tibetan sheep had greater adenosine monophosphate-activated protein kinase-α 2 protein expression than Small-tailed Han sheep, which supported the premise of a better ability to regulate energy homoeostasis and better growth performance. These differences in the hypothalamic NPY/AgRP, POMC/CART and AMPK pathways between breeds conferred an advantage to the Tibetan over Small-tailed Han sheep to cope with low energy intake on the harsh QTP.
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Role of the Endocannabinoid System in the Adipose Tissue with Focus on Energy Metabolism. Cells 2021; 10:cells10061279. [PMID: 34064024 PMCID: PMC8224009 DOI: 10.3390/cells10061279] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/12/2021] [Accepted: 05/15/2021] [Indexed: 12/15/2022] Open
Abstract
The endocannabinoid system is involved in a wide range of processes including the control of energy acquisition and expenditure. Endocannabinoids and their receptors are present in the central nervous system but also in peripheral tissues, notably the adipose tissues. The endocannabinoid system interacts with two main hormones regulating appetite, namely leptin and ghrelin. The inhibitory effect of the cannabinoid receptor 1 (CB1) antagonist rimonabant on fat mass suggested that the endocannabinoid system can also have a peripheral action in addition to its effect on appetite reduction. Thus, several investigations have focused on the peripheral role of the endocannabinoid system in the regulation of metabolism. The white adipose tissue stores energy as triglycerides while the brown adipose tissue helps to dissipate energy as heat. The endocannabinoid system regulates several functions of the adipose tissues to favor energy accumulation. In this review we will describe the presence of the endocannabinoid system in the adipose tissue. We will survey the role of the endocannabinoid system in the regulation of white and brown adipose tissue metabolism and how the eCB system participates in obesity and metabolic diseases.
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Hu X, Kong L, Xiao C, Zhu Q, Song Z. The AMPK-mTOR signaling pathway is involved in regulation of food intake in the hypothalamus of stressed chickens. Comp Biochem Physiol A Mol Integr Physiol 2021; 258:110979. [PMID: 33991669 DOI: 10.1016/j.cbpa.2021.110979] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 05/09/2021] [Accepted: 05/10/2021] [Indexed: 11/26/2022]
Abstract
Glucocorticoids (GCs) can stimulate the appetite and AMPK in broilers. The activation of hypothalamic mTOR has been proposed as an important anorexigenic signal. However, inhibitory effect of AMPK activity on appetite and AMPK downstream signaling pathway under stress has not been reported. In this study, we performed an intracerebroventricular (icv) injection of compound C, an AMPK inhibitor, in GC-treated birds to explore the regulatory mechanism on appetite and AMPK downstream signaling pathway. A total of 48 7-day-old broilers, which had received an icv cannula, were randomly subjected to one of two treatments: subcutaneous injection of dexamethasone (DEX) or saline. After 3 days of continuous DEX injection, chicks of each group received an icv injection with either compound C (6 μg/2 μL) or vehicle (dimethyl sulfoxide, 2 μL). The results showed that body weight gain was reduced by the DEX treatment. Compared with the control, icv injection of compound C reduced feed intake at 0.5-1.5 h. In the DEX-treated group, the inhibitory effect of compound C on appetite remained apparent at 0.5-1 h. The DEX treatment increased the gene expression of liver kinase B1 (LKB1), neuropeptide Y (NPY), and decreased p-mTOR protein level. In stressed broilers, inhibition of AMPK relieved the decreased mTOR activity. A significant interaction was noted in DEX and compound C on protein expression of phospho-AMPK. Taken together, in stressed broilers, the central injection of compound C could inhibit central AMPK activity and reduce appetite, in which the AMPK/mTOR signaling pathway might be involved.
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Affiliation(s)
- Xiyi Hu
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China
| | - Linglian Kong
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China
| | - Chuanpi Xiao
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China; Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, University of Liège, Gembloux 5030, Belgium
| | - Qidong Zhu
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China
| | - Zhigang Song
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China.
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Individuals Diagnosed with Binge-Eating Disorder Have DNA Hypomethylated Sites in Genes of the Metabolic System: A Pilot Study. Nutrients 2021; 13:nu13051413. [PMID: 33922358 PMCID: PMC8145109 DOI: 10.3390/nu13051413] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/06/2021] [Accepted: 04/16/2021] [Indexed: 02/07/2023] Open
Abstract
Binge-eating disorder, recently accepted as a diagnostic category, is differentiated from bulimia nervosa in that the former shows the presence of binge-eating episodes and the absence of compensatory behavior. Epigenetics is a conjunct of mechanisms (like DNA methylation) that regulate gene expression, which are dependent on environmental changes. Analysis of DNA methylation in eating disorders shows that it is reduced. The present study aimed to analyze the genome-wide DNA methylation differences between individuals diagnosed with BED and BN. A total of 46 individuals were analyzed using the Infinium Methylation EPIC array. We found 11 differentially methylated sites between BED- and BN-diagnosed individuals, with genome-wide significance. Most of the associations were found in genes related to metabolic processes (ST3GAL4, PRKAG2, and FRK), which are hypomethylated genes in BED. Cg04781532, located in the body of the PRKAG2 gene (protein kinase AMP-activated non-catalytic subunit gamma 2), was hypomethylated in individuals with BED. Agonists of PRKAG2, which is the subunit of AMPK (AMP-activated protein kinase), are proposed to treat obesity, BED, and BN. The present study contributes important insights into the effect that BED could have on PRKAG2 activation.
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Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan. Antioxidants (Basel) 2021; 10:antiox10040572. [PMID: 33917812 PMCID: PMC8068152 DOI: 10.3390/antiox10040572] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/16/2022] Open
Abstract
Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.
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Estienne A, Ramé C, Ganier P, Chahnamian M, Barbe A, Grandhaye J, Dubois JP, Batailler M, Migaud M, Lecompte F, Adriaensen H, Froment P, Dupont J. Chemerin impairs food intake and body weight in chicken: Focus on hypothalamic neuropeptides gene expression and AMPK signaling pathway. Gen Comp Endocrinol 2021; 304:113721. [PMID: 33493505 DOI: 10.1016/j.ygcen.2021.113721] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/31/2020] [Accepted: 01/15/2021] [Indexed: 12/11/2022]
Abstract
Unlike mammals, the role of adipokines and more particularly of chemerin in the regulation of food intake is totally unknown in avian species. Here we investigated the effect of chemerin on the food and water consumption and on the body weight in chicken. We studied the effects on the plasma glucose and insulin concentrations and the hypothalamic neuropeptides and AMPK signaling pathway. Female broiler chickens were intraperitoneally injected, daily for 13 days with either vehicle (saline; n = 25) or chemerin (8 μg/kg; n = 25 and 16 μg/kg; n = 25). Food and water intakes were recorded 24 h after each administration. Overnight fasted animals were sacrificed at day 13 (D13), 24 h after the last injection and hypothalamus and left cerebral hemispheres were collected. Chemerin and its receptors protein levels were determined by western-blot. Gene expression of neuropeptide Y (Npy), agouti-related peptide (Agrp), corticotrophin releasing hormone (Crh), pro-opiomelanocortin (Pomc), cocaine and amphetamine-regulated transcript (Cart) and Taste 1 Receptor Member 1 (Tas1r1) were evaluated by RT-qPCR. In chicken, we found that the protein amount of chemerin, CCRL2 and GPR1 was similar in left cerebral hemisphere and hypothalamus whereas CMKLR1 was higher in hypothalamus. Chemerin administration (8 and 16 μg/kg) decreased both food intake and body weight compared to vehicle without affecting water intake and the size or volume of different brain subdivisions as determined by magnetic resonance imaging. It also increased plasma insulin levels whereas glucose levels were decreased. These data were associated with an increase in Npy and Agrp expressions and a decrease in Crh, Tas1r1 mRNA expression within the hypothalamus. Furthermore, chemerin decreased hypothalamic CMKLR1 protein expression and AMPK activation. Taken together, these results support that chemerin could be a peripheral appetite-regulating signal through modulation of hypothalamic peptides expression in chicken.
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Affiliation(s)
- Anthony Estienne
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Christelle Ramé
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Patrice Ganier
- INRAE - Unité Expérimentale du Pôle d'Expérimentation Avicole de Tours UEPEAT, 1295, Nouzilly, France
| | - Marine Chahnamian
- INRAE - Unité Expérimentale du Pôle d'Expérimentation Avicole de Tours UEPEAT, 1295, Nouzilly, France
| | - Alix Barbe
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Jérémy Grandhaye
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Jean-Philippe Dubois
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Martine Batailler
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Martine Migaud
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - François Lecompte
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Hans Adriaensen
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Pascal Froment
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France
| | - Joëlle Dupont
- INRAE UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France CNRS UMR7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France Université François Rabelais de Tours F-37041 Tours, France IFCE F-37380 Nouzilly, France.
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