Adipocyte-specific PIK3C3/VPS34 controls adipogenesis, metabolically-triggered inflammation, insulin resistance, and adaptive thermogenesis in mice

Abstract Interactions between cells of the immune and metabolic systems play critical roles in controlling immune responsiveness and metabolic health. When these interactions are dysregulated, metabolic diseases such as obesity or lipodystrophy may develop. We have focused on cellular processes related to autophagy, a cellular self-degradation process, in controlling interactions between the immune and metabolic systems. In this study, we analyzed mice with an adipocyte-selective deficiency in PIK3C3/VPS34, a key early player in autophagy. These animals showed reduced white and brown adipose tissue (WAT and BAT) with enhanced macrophage infiltration, systemic immune activation, and spontaneous insulin-resistance. The phenotype of these animals bears a striking resemblance with the disease manifestations seen in individuals with lipodystrophy. Mechanistically, we found that conditional Pik3c3-deficiency inhibits adipogenesis in both WAT and BAT by downregulating glucose uptake and fatty acid metabolism, and impairs the thermogenic function of BAT by downregulating the expression of key regulators (Prdm16, Ucp1, and Cidea). Upon acute cold exposure, Pik3c3-deficient mice became cold-sensitive under fasting conditions due to insufficient thermogenesis in BAT. In contrast, these animals exhibited blunted beige fat thermogenesis in subcutaneous WAT in response to administration of a b3-adrenergic receptor agonist. Collectively, our data demonstrate that PIK3C3 is a vital regulator of adipose tissue development, metabolically-triggered inflammation, insulin resistance, and adaptive thermogenesis. Hence, we identify PIK3C3 as a potential therapeutic target for metabolic diseases such as type 2 diabetes.