Novel role of BSCL2 in brown adipose tissue development and function

Brown adipose tissue (BAT) actively oxidizes nutrients and dissipates energy as heat which makes it an attractive therapeutic target for treatment of obesity, type 2 diabetes and its associated cardiovascular diseases. However, activating brown fat thermogenesis to efficiently and safely induce weight loss requires the discovery of novel adrenergic-independent brown fat activators. Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2 also called SEIPIN) is an endoplasmic reticulum membrane protein highly expressed in adipose tissue especially BAT. The specific function of BSCL2 in BAT development and activation has never been explored. We have intriguing preliminary data demonstrating that deletion of Bscl2 promotes brown adipocyte differentiation and activates brown adipocyte metabolism and uncoupling through increased cAMP/PKA signaling in the absence of norepinephrine stimulation; targeted deletion of BSCL2 in mature BAT increases cAMP/PKA signaling and ameliorates adiposity in vivo. Moreover, endogenous BSCL2 is localized in plasma-membrane associated ER membrane different from overexpressed BSCL2. Thus, we hypothesize that BSCL2 is a novel cell autonomous player of brown adipose tissue differentiation and activation independent of the sympathetic nervous system to modulate substrate metabolism, adaptive thermogenesis and whole body energy balance. The specific aims are to identify (1) BSCL2 is essential for brown adipose tissue differentiation and activation through its inhibition of G protein mediated cAMP/PKA signaling; (2) BSCL2 deficiency activates mature brown adipose tissue to regulate adaptive thermogenesis and energy expenditure independent of sympathetic nervous system (SNS). This proposal will uncover BSCL2 as a novel 'bottleneck' for brown adipocyte cAMP/PKA signaling and a key upstream 'metabolic inhibitor' of both glucose and lipid metabolism that determines BAT differentiation and mature BAT activation independent of the SNS. It will provide novel insights into the molecular function of BSCL2 in brown adipose tissue biology. More importantly, it could reveal potential therapeutic approaches to activate the thermogenic function of BAT without side effects derived from global SNS activation. (AHA Program: Grant-in-Aid)