Regulation of Beige Fat Development by mTORC1 and Autophagy

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Brown and Beige (or brite) adipose tissues burn lipid by converting chemical energy into heat, and have been considered as a new therapeutic target to counteract obesity. The regulation of thermogenic function in adipose tissue at the transcriptional level has been extensively studied in the past several years. However, the upstream signaling pathways that control the transcriptional machinery of thermogenic genes and effector mechanisms in brown or beige adipocytes remain largely unknown. Our recent study demonstrated that overactivation of mTOR Complex 1 (mTORC1) signaling is associated with impaired thermogenic function in vivo (Liu et al., 2014, Cell Metabolism). Consistent with this, our preliminary data showed that inactivation of mTORC1 by adipose-specific ablation of raptor, a key component of mTORC1, up-regulated the expression of thermogenic genes in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT or beige fat). In addition, we also found that the autophagy, a pathway downstream of mTORC1 is activated by cold stress and a β3-adrenoceptor agonist in vivo and in cells, and inhibition of autophagy diminishes β3-adrenoceptor agonist- induced UCP1 expression in primary adipocytes. In support of this, inhibition of autophagy by adipose-specific deletion of autophagy protein 7 (ATG7) suppresses basal and cold-induced energy expenditure, lipolysis and UCP1 expression in iWAT in vivo. Based on these findings, we hypothesize that autophagy plays a critical role in regulating the browning of white adipose tissue and mediates the beneficial effect of mTORC1 inhibition on thermogenesis in human brown adipocytes. We will first determine whether and how inhibiting mTORC1 and autophagy alters beige adipocyte differentiation and thermogenesis via cell-autonomous mechanisms. We will then investigate whether autophagy is an essential effector downstream of mTORC1 in regulating thermogenesis in WAT using adipose-specific autophagy-related protein 7 (ATG7)/raptor double KO mice. Lastly, we will delineate the role of mTORC1 and autophagy in regulating thermogenesis in primary human brown adipocytes. This study will lead to the identification of the mTORC1/autophagy pathway as a critical regulator of beige adipocyte differentiation and recruitment in response to various environmental factors. In addition, elucidation of the underlying signaling mechanisms involved in the browning of white fat may reveal promising new anti-obesity drug targets and lead to novel therapeutic approaches for obesity-associated metabolic diseases.