Bscl2, a unique player in lipolysis, adipose differentiation and metabolic disorders

Mutations in the BSCL2 gene (also called seipin) cause type 2, the most severe form of Congenital Generalized Lipodystrophy (CGL). CGL2 is an autosomal recessive disorder characterized by a near total absence of body fat from birth or infancy associated with earlier diabetes onset and debilitating metabolic disorders. I and others have demonstrated the important role of BSCL2 in lipid droplet biology and adipocyte differentiation in vitro. Recently, I was the first to generate and characterize global Bscl2 deficient (Bscl2-/-) mice. I found that Bscl2-/- mice recapitulate many lipodystrophic features of CGL2 in vivo. Importantly, Bscl2-/- mice exhibit unique metabolic disorders as compared to other lipodystrophic or lean mouse models. They are pre-diabetic as they have hyperinsulinemia and impaired postprandial glucose and lipid clearance. However, they develop no hypertriglyceridemia. Instead, their fasting triglycerides and free fatty acids are extremely low. Bscl2-/- mice have hepatic steatosis but reduced muscle lipid deposition. They are insulin resistant under insulin tolerance test; but are more insulin sensitive under hyperinsulinemic-euglycemic clamp. Moreover, their glucose metabolism is enhanced under either glucose tolerance test or clamp. Study in isolated Bscl2-/- Mouse Embryonic Fibroblasts (MEF) uncovered that Bscl2 is a novel cell autonomous regulator of cyclic AMP (cAMP)/protein kinase A (PKA) mediated stimulated lipolysis and essential for fat cell differentiation (manuscript in revision with PNAS). Here I hypothesize that 1) metabolic adaptations in the liver and muscle in response to reduced fatty acid contribute to the unique energy metabolism and insulin response in Bscl2-/- mice and 2) Bscl2 is a specific regulator of β-adrenergic receptor (-AR) signaling to mediate cAMP/PKA stimulated lipolysis and adipocyte differentiation. Therefore I propose: Aim 1: Identify the molecular mechanisms underlying the unique inter-relationships between insulin response and carbohydrate and lipid metabolism in the liver and muscle of Bscl2-/- mice. Aim 2: Elucidate the molecular role of Bscl2 in regulating cAMP/PKA mediated lipolysis. The above study aims to identify the unique pathways that link to the novel metabolic disorders in Bscl2-/- mice and the specific target of Bscl2 in regulating lipolysis and adipose differentiation. These studies will provide new therapeutic targets for treatment or prevention of lipodystrophy and obesity. (AHA Program: Scientist Development Grant)