Adipocyte-Derived KIF13B Aggravates Obesity-Associated Metabolic Dysfunction via LRP1/PPARγ Signaling

Obesity is driven by maladaptive adipose expansion, yet the intracellular machinery linking motor protein-associated intracellular regulation to adipogenic transcription remains incompletely understood. Here, we identify adipocyte-derived kinesin family member 13B (KIF13B) as a regulator of obesity-associated metabolic dysfunction through lipoprotein receptor-related protein 1 (LRP1)/peroxisome proliferator-activated receptor γ (PPARγ) signaling. KIF13B expression is markedly upregulated in adipose tissue from humans and mice with obesity. Adipocyte-specific Kif13b deletion protected mice from high-fat diet-induced weight gain, adipose expansion and inflammation, dyslipidemia, insulin resistance, and hepatic steatosis, while promoting thermogenic remodeling. In mice with established diet-induced obesity, adeno-associated virus serotype 9 (AAV9)-mediated adipocyte-targeted KIF13B knockdown improved adipose inflammation, lipid and glucose homeostasis, and liver injury; selected metabolic benefits were also observed in ob/ob mice. Mechanistically, KIF13B facilitates PPARγ-responsive transcriptional activity and adipogenic lipid accumulation via LRP1. This proadipogenic KIF13B/LRP1/PPARγ axis is further supported by human adipose transcriptomic analyses, which reveal positive correlations among its components in obesity and Type 2 diabetes. These findings define a previously unrecognized KIF13B-LRP1-PPARγ axis linking intracellular trafficking to pathological adipocyte remodeling and support adipocyte KIF13B as a potential therapeutic target for obesity-associated metabolic disease.