Endocrine Abstracts (2012) 28 P218

Unique roles of CRH-Rs controlling adipocyte biology and transdifferentiation

Buyu Lu1, D. Markovic1, Jeff Pessin2, Hendric Lehnert3 & Dimitris Grammatopoulos1

1Warwick Medical School, Coventry, United Kingdom; 2Albert Einstein College of Medicine, New York, NY 3University of Lübeck Medical School, Lübeck, Germany.

In addition to well established role in coordinating mammalian adaptive responses to stressful stimuli, the family of “stress” peptides that includes corticotropin releasing hormone (CRH) and urocortins (Ucns) are emerging as important regulators of the homeostatic mechanisms regulating energy balance and metabolism. CRH acting through specific G-protein coupled receptors, CRH-R1 and R2 can target multiple peripheral tissues such as skeletal muscle and adipose tissue to influence important metabolic pathways. Two types of adipose tissue exist in mammals: WAT and BAT. Since WAT is the largest energy reserve in mammals and BAT can utilize energy through adaptive thermogenesis, one of the goals in this study was to identify the presence of CRH system components in adipose tissue. Real time RT-PCR and immunofluorescence demonstrated that CRH-Rs as well as CRH, UCN-I, and UCN-II are expressed in both WAT and BAT, raising the possibility that CRH and UCNs are important regulators of energy storage and adaptive thermogenesis. Also the functional roles of CRH-Rs in adipose tissue were investigated. Using an experimental paradigm the T37i fibroblast that can differentiate into brown adipocyte, it was demonstrated that CRH at low (nanomolar) but not high (submicromolar) concentrations stimulated a signaling pathway involving the AC/cAMP/PKA/AMPK signaling cascade that regulates downstream phosphorylation of HSL. This was associated with a significant translocation of HSL toward lipid droplets and association with perilipin, as demonstrated with immunofluorescence. Further analysis using an experimental paradigm the 3T3L1 fibroblast that can differentiate into white adipocyte showed that activation of CRH-R2 or inhibition of CRH-R1 in 3T3L1 cells were able to induce morphological and biochemical characteristics suggesting adipocyte differentiation to a “beige” phenotype in white preadipocytes/adipocytes. Thus, CRH-R1 and R2 could be of potential importance in maintenance of energy homeostasis. This may suggest CRH family as a potential therapeutic target for obesity and associated type 2 diabetes.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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