Mouse adipocytes ex vivo from lean Rbm43 knockout mice

Obesity is associated with systemic inflammation that impairs mitochondrial function. These changes curtail oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1⍺, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1⍺-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1⍺ translation and oxidative metabolism. In obesity, Rbm43 loss confers body weight-independent protection from glucose intolerance, adipose inflammation, and activation of the innate immune sensor cGAS-STING. We further identify a role for PGC1⍺ in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory pathway by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.