title: Melanocortin crosstalk with adipose functions: ACTH directly induces insulin resistance, promotes a pro-inflammatory adipokine profile and stimulates UCP-1 in adipocytes.
abstract: The melanocortin (MC) system is a pivotal component of the hypothalamo-pituitary-adrenal (HPA) stress axis and plays an important role in the pathogenesis of obesity and the metabolic syndrome. Adipose dysfunction is implicated in the pathogenesis of these disorders. We investigated direct ACTH effects on adipose functions in immortalised murine white and brown adipocytes. MC receptor types 2 and 5 were expressed at the mRNA and protein levels and were strongly up-regulated during differentiation. Chronic ACTH stimulation did not affect adipogenesis. Insulin-induced glucose uptake in white adipocytes was acutely and transiently reduced by 45% upon ACTH treatment. Visfatin and adiponectin gene expression was reduced by about 50% in response to ACTH, while interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were acutely up-regulated by 2100 and 60% respectively. Moreover, IL-6 secretion was increased by 1450% within 4 h of ACTH treatment. In brown adipocytes, stimulation with ACTH caused a 690% increase in uncoupling protein (UCP)-1 mRNA levels within 8 h, followed by a 470% increase in UCP-1 protein concentrations after 24 h. Consistently, p38 mitogen-activated protein kinase (MAPK) phosphorylation was acutely increased by 1800% in response to ACTH stimulation, and selective inhibition of p38 MAPK abolished the ACTH-mediated UCP-1 protein increase. Taken together, ACTH acutely promotes an insulin-resistant, pro-inflammatory state and transiently enhances energy combustion. In conditions characterised by a dysregulation of the HPA stress axis such as the metabolic syndrome, direct MC interaction with adipocytes may contribute to dysregulated energy balance, insulin resistance and cardiometabolic complications.
authors.affiliation: Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
authors.forename: K Alexander H
authors.initials: KA
authors.lastname: Iwen
authors.forename: Oezge
authors.initials: O
authors.lastname: Senyaman
authors.forename: Arne
authors.initials: A
authors.lastname: Schwartz
authors.forename: Maren
authors.initials: M
authors.lastname: Drenckhan
authors.forename: Britta
authors.initials: B
authors.lastname: Meier
authors.forename: Dirk
authors.initials: D
authors.lastname: Hadaschik
authors.forename: Johannes
authors.initials: J
authors.lastname: Klein
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D054392:Adipokines / Q000276:immunology / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002461:Cell Line, Transformed; D004734:Energy Metabolism / Q000502:physiology; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000276:immunology*; D015850:Interleukin-6 / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000235:genetics / Q000378:metabolism*; D000071256:Uncoupling Protein 1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D054392:Adipokines; D015850:Interleukin-6; D007473:Ion Channels; C470053:Mc3r protein, mouse; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D044102:Receptor, Melanocortin, Type 1; D044103:Receptor, Melanocortin, Type 2; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C086971:melanocortin 5 receptor; D000324:Adrenocorticotropic Hormone; D048051:p38 Mitogen-Activated Protein Kinases