Rora deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

摘要

The Rar-related orphan receptor-a (Rora) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Rora-deficient staggerer (sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucpl-dependent ther-mogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity. DEXA and MRI analysis demonstrated significantly decreased total fat mass and fat/lean mass tissue ratio in male chow-fed sg/sg mice relative to wt mice. In addition, we observed increased Ucpl expression in brown adipose and subcutaneous white adipose tissue but not in visceral adipose tissue from Rora-deficient mice. Moreover, this was associated with significant increases in the expression of the mRNAs encoding the thermogenic genes (i.e., markers of brown and beige adipose) Ppara, Erra, Dio2, Acotll/Bfit, Cptlp, and Cidea in the subcutaneous adipose in the sg/sg relative to WT mice. These changes in thermogenic gene expression involved the significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltrans-ferase 1 (Ehmtl), which stabilizes the Prdml6 transcriptional complex. Moreover, primary brown adipocytes from sg/sg mice displayed a higher metabolic rate, and further analysis was consistent with increased uncoupling. Finally, core body temperature analysis and infrared thermography demonstrated that the sg/sg mice maintained greater thermal control and cold tolerance relative to the WT litter-mates. We suggest that enhanced Ucpl and thermogenic gene expression/activity may be an important contributor to the lean, obesity-resistant phenotype in Rora-deficient mice.