Junctophilin- 2 in brown Adipocyte Metabolic Regulation and Obesity

Obesity, a state of imbalance between caloric intake and energy expenditure, is a major global problem that increases the risk of developing a wide range of diseases including insulin resistance, type 2 diabetes, cardiovascular disease and COVID-19 among others. Brown adipocytes in brown adipose tissue (BAT) depots dissipate chemical energy in the form of heat through non-shivering thermogenesis, to increase systemic energy expenditure and maintain whole-body energy homeostasis in response to stresses, including cold exposure and overnutrition. Brown adipocytes share a common lineage with muscle cells, the source of shivering thermogenesis. We recently discovered that junctophilin-2 (JP2), a muscle specific protein, is also enriched in brown adipocytes. JP2 is a structural protein that spatially organizes endo/sarcoplasmic reticulum (ER/SR)-plasma membrane (PM) junctions in muscle cells. These EM/SR-PM junctions are essential for precise control of Ca2+ homeostasis and contractile function in cardiac and skeletal muscles. In addition to its structural role, we recently demonstrated that JP2 serves as a stress-adaptive transcriptional regulator, controlling the transcriptome that regulates metabolic pathways that are also relevant to adipose metabolism. However, it remains completely unknown whether JP2 also functions in regulating Ca2+ homeostasis, and thermogenic program in brown adipocytes. In pilot studies, JP2 expression in BAT was suppressed by diet-induced obesity. Furthermore, JP2 deficiency disrupts BAT calcium dynamics and blunts sympathetic nervous system activation of thermogenesis in BAT. Notably, adipose-specific JP2 deletion promotes cold intolerance, and worsens obesity-associated metabolic dysfunction. These pilot data indicate that JP2 is required for maintaining thermogenic and metabolic homeostasis in BAT. Based on these intriguing preliminary data, we hypothesize that JP2 is crucial in maintaining normal Ca2+ homeostasis and energy metabolism in brown adipocytes, and defects in JP2-mediated Ca2+ regulation lead to energy imbalance and metabolic dysfunction. To test this hypothesis, we will use a multidisciplinary approach, including multiple novel mouse models, high resolution confocal imaging, patch-clamp electrophysiology, cellular and molecular biology, biochemical analysis and a spectrum of in vitro and in vivo metabolic assays. Upon successful completion of this project, we will establish a mechanistic understanding of the physiological regulation of JP2 in brown adipocytes and the pathophysiological role of JP2 dysregulation in obesity and associated diseases, therefore revealing a novel molecular mechanism leading to metabolic disorders.