Abstract
Disclosure: P.A. Dumesic: None. S.E. Wilensky: None. S. Bose: None. J.G. Van Vranken: None. S.P. Gygi: None. B. Spiegelman: None.
Obesity is associated with systemic inflammation that impairs mitochondrial function. In adipose tissue, pro-inflammatory cytokines impede oxidative metabolism and lipid handling by adipocytes, contributing to the pathogenesis of type 2 diabetes. We find that the transcriptional coactivator PGC1⍺—a central regulator of mitochondrial biogenesis and oxidative metabolism—is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. In isolated adipocytes and in mice, RBM43 suppresses mitochondrial biogenesis in a PGC1⍺-dependent manner. Rbm43 is itself induced by signals of inflammation and is responsible for a significant portion of TNF⍺’s repressive effects on mitochondrial gene expression and respiratory capacity. In obesity, mice lacking Rbm43 in adipocytes retain PGC1⍺ translation, mitochondrial content, and white fat respiratory capacity as compared to littermate controls. Rbm43 loss also protects against the development of obesity-associated glucose intolerance and adipose inflammation. These salutary changes are associated with reduced activity of the innate immune sensor cGAS-STING in adipocytes, leading us to identify a role for PGC1⍺ in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 thus defines a translational regulatory axis by which inflammatory signals can influence cellular energy metabolism and contribute to diabetes pathogenesis.
Presentation: Sunday, July 13, 2025