77-OR: Targeting JunB Induces a Shift from Low- to High-Thermogenic Adipocytes and Ameliorates Diet-Induced Insulin Resistance

Abstract

The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue (BAT) heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. In the current study, we identified a population of JunB-enriched adipocytes (JunB+ adipocytes) within the brown fat depot that exhibits lower thermogenic capacity and fewer and smaller lipid droplets compared to high-thermogenic adipocytes. This population of JunB+ adipocytes exhibited marked expansion during obesity, in part through induction of pro-inflammatory cytokines TNFα and IL-6. Depletion of JunB in adipocytes or UCP1+ adipocytes increased the fraction of adipocytes exhibiting high mitochondrial content and thermogenic capacity, leading to enhanced basal and cold-induced energy expenditure and protection against diet-induced obesity and insulin resistance. Mechanistically, JunB directly binds to the promoter of estrogen-related receptor α (Errα), a downstream effector of PGC1α, and suppresses its transcriptional function. JunB antagonizes the stimulatory effects of PGC1α-ERRα on mitochondrial biogenesis and high-thermogenic adipocyte development. Taken together, our studies uncover a novel mechanism involving JunB that shapes thermogenic adipocyte heterogeneity and serves a critical role in maintaining systemic metabolic health. Disclosure X.Zhang: None. C.Wang: None. M.Liu: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK110439); American Heart Association (20POST35120020)