Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis

Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here, we report that adipose-specific knockout of the peroxisomal lipid synthetic protein PexRAP promotes diet-induced obesity and insulin resistance through activation of de novo lipogenesis. PexRAP inactivation inhibits the flux of carbons to ethanolamine plasmalogens. This increases nuclear PC/PE ratio and promotes cholesterol mislocalization, resulting in the activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation leads to increased expression of the phospholipid remodeling enzyme LPCAT3 and induces fatty acid synthase-mediated lipogenesis, which promotes diet-induced obesity and insulin resistance. Treatment of PexRAP-deficient adipocytes with alkylglycerol, a plasmalogen precursor that enters the synthetic pathway downstream of PexRAP, rescues nuclear cholesterol mislocalization and LXR activation. These studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation.