Through activation of the HPA axis, corticotropin-releasing hormone (CRH), the 41-amino acid hypothalamic peptide, plays a fundamental role in mammalian survival and response to stressful stimuli. CRH belongs to a family of stress-related peptides that includes urocortins (UCNs) that have been linked with many pathophysiological effects. Their actions are mediated via activation of two types of CRH receptors (CRH-R1 and R2) that exhibit distinct pharmacology and functional properties. Emerging evidence points towards important actions for CRH and UCNs in the regulation of energy balance and homeostasis. Central actions of these peptides control food uptake and exert potent anorectic and thermogenic effects. Moreover, new potential peripheral sites of CRH and UCNs actions have also been described; CRH and UCNs directly regulate skeletal muscle thermogenesis as well as insulin signalling whereas UCN-III modulates pancreatic insulin secretion. In vivo animal models and cellular studies have identified CRH and UCNs as important regulators of adipose tissue biology. CRH-Rs are expressed in both white and brown adipocytes. In white adipocytes, CRH peptides modulate 11β-HSD1 activity and cellular lipolysis, suggesting direct regulation of cortisol/cortisone levels. CRH also exerts in vivo effects on femoral adipose tissue metabolism, since i.v. administration leads to increased levels of interstitial and plasma glycerol suggesting stimulated lipolysis. Both CRH-R1 and R2 receptors are expressed in mouse interscapular brown adipocytes and in cellular models of brown adipocytes (T37i cell line). In the latter example, CRH and UCNs stimulate glycerol release and lipolysis through activation of the cAMP/PKA signalling pathway. This pathway also involves phosphorylation of hormone sensitive lipase (HSL) and redistribution of lipiddroplet-specific proteins such as perillipin. In brown adipocytes, UCN-II is also a potent activator of other signalling pathways such as ERK1/2 and p38MAPK, raising the possibility for diverse biological effects. Although the molecular and physiological characteristics of the adipocyte CRH-R system are still poorly characterised, these studies provide strong evidence for an important role for CRH /UCN-driven metabolic effects, important for maintenance of central stress pathways regulating energy homeostasis and adaptive responses to environmental perturbations. Important for maintenance of central stress pathways regulating energy homeostasis and adaptive responses to environmental perturbations.
03 - 07 May 2008
European Society of Endocrinology