Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes

Abstract

Thermogenic adipocytes generate heat to maintain body temperature against hypothermia in response to cold. Although tight regulation of thermogenesis is required to prevent energy sources depletion, the molecular details that tune thermogenesis are not thoroughly understood. Here, we demonstrate that adipocyte hypoxia-inducible factor alpha (HIF alpha) plays a key role in calibrating thermogenic function upon cold and re-warming. In beige adipocytes, HIF alpha attenuates protein kinase A (PKA) activity, leading to suppression of thermogenic activity. Mechanistically, HIF2 alpha suppresses PKA activity by inducing miR-3085-3p expression to downregulate PKA catalytic subunit alpha (PKA C alpha). Ablation of adipocyte HIF2 alpha stimulates retention of beige adipocytes, accompanied by increased PKA C alpha during re-warming after cold stimuli. Moreover, administration of miR-3085-3p promotes beige-to-white transition via downregulation of PKA C alpha and mitochondrial abundance in adipocyte HIF2 alpha deficient mice. Collectively, these findings suggest that HIF2 alpha-dependent PKA regulation plays an important role as a thermostat through dynamic remodeling of beige adipocytes. Thermogenic adipocytes maintain body temperature in response to cold, but how this is tuned during cold and re-warming is unclear. Here, the authors show HIF2 alpha inhibits beige adipocyte retention, regulating PKA catalysis to control dynamic adipocyte remodelling.