Opposing Actions of Adrenocorticotropic Hormone and Glucocorticoids on UCP1-Mediated Respiration in Brown Adipocytes

• Main Authors: Katharina Schnabl, Julia Westermeier, Yongguo Li, Martin Klingenspor
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-01-01
• Series: Frontiers in Physiology
• Subjects: glucocorticoids (GC); brown adipose tissue; non-adrenergic activation; non-shivering thermogenesis; uncoupling protein 1; adrenocorticotropic hormone
• Online Access: https://www.frontiersin.org/article/10.3389/fphys.2018.01931/full

Brown fat is a potential target in the treatment of metabolic disorders as recruitment and activation of this thermogenic organ increases energy expenditure and promotes satiation. A large variety of G-protein coupled receptors, known as classical drug targets in pharmacotherapy, is expressed in brown adipocytes. In the present study, we analyzed transcriptome data for the expression of these receptors to identify potential pathways for the recruitment and activation of thermogenic capacity in brown fat. Our analysis revealed 12 Gs-coupled receptors abundantly expressed in murine brown fat. We screened ligands for these receptors in brown adipocytes for their ability to stimulate UCP1-mediated respiration and Ucp1 gene expression. Adrenocorticotropic hormone (ACTH), a ligand for the melanocortin 2 receptor (MC2R), turned out to be the most potent activator of UCP1 whereas its capability to stimulate Ucp1 gene expression was comparably low. Adrenocorticotropic hormone is the glandotropic hormone of the endocrine hypothalamus–pituitary–adrenal-axis stimulating the release of glucocorticoids in response to stress. In primary brown adipocytes ACTH acutely increased the cellular respiration rate similar to isoproterenol, a β-adrenergic receptor agonist. The effect of ACTH on brown adipocyte respiration was mediated via the MC2R as confirmed by using an antagonist. Inhibitor-based studies revealed that ACTH-induced respiration was dependent on protein kinase A and lipolysis, compatible with a rise of intracellular cAMP in response to ACTH. Furthermore, it is dependent on UCP1, as cells from UCP1-knockout mice did not respond. Taken together, ACTH is a non-adrenergic activator of murine brown adipocytes, initiating the canonical adenylyl cyclase–cAMP–protein kinase A-lipolysis-UCP1 pathway, and thus a potential target for the recruitment and activation of thermogenic capacity. Based on these findings in primary cell culture, the physiological significance might be that cold-induced ACTH in concert with norepinephrine released from sympathetic nerves contributes to BAT thermogenesis. Notably, dexamethasone attenuated isoproterenol-induced respiration. This effect increased gradually with the duration of pretreatment. In vivo, glucocorticoid release triggered by ACTH might oppose beta-adrenergic stimulation of metabolic fuel combustion in BAT and limit stress-induced hyperthermia.