RBM43 links adipose inflammation and energy expenditure through translational regulation of PGC1alpha

Abstract

Adipose thermogenesis involves specialized mitochondrial function that counteracts metabolic disease through dissipation of chemical energy as heat. However, inflammation present in obese adipose tissue can impair oxidative metabolism. Here, we show that PGC1, a key governor of mitochondrial biogenesis and thermogenesis, is negatively regulated at the level of mRNA translation by the little-known RNA-binding protein RBM43. Rbm43 is expressed selectively in white adipose depots that have low thermogenic potential, and is induced by inflammatory cytokines. RBM43 suppresses mitochondrial and thermogenic gene expression in a PGC1-dependent manner and its loss protects cells from cytokine-induced mitochondrial impairment. In mice, adipocyte-selective Rbm43 disruption increases PGC1 translation, resulting in mitochondrial biogenesis and adipose thermogenesis. These changes are accompanied by improvements in glucose homeostasis during diet-induced obesity that are independent of body weight. The action of RBM43 suggests a translational mechanism by which inflammatory signals associated with metabolic disease dampen mitochondrial function and thermogenesis.