Transcriptomic analysis of primary mouse adipocytes after Rbm43 knockdown

Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1a, 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 PGC1a-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1a translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1a in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis. Overall design: Primary Ppargc1a(fl/fl) adipocytes were transduced with adenovirus encoding Gfp (control) or Cre (to excise the Ppargc1a gene). Cells were subsequently treated with control siRNA or an siRNA targeting Rbm43. Cells were differentiated completely, then RNA was harvested in biological duplicates using trizol.