Gpc3 Selectively Suppresses Subcutaneous Adipogenesis in Diet-Induced Obesity

Subcutaneous and visceral adipose depots employ distinct expansion strategies in response to dietary cues, yet the molecular regulators underlying these depot-specific adaptations remain poorly understood. Through integrated proteomic profiling of human subcutaneous and visceral adipose tissues from paired obese/non-obese donors and temporal transcriptomic analysis of mouse adipose stem and progenitor cells (ASPCs) during diet switching, we identified Gpc3 as an obesity-responsive gene exhibiting reciprocal expression patterns between depots. ASPC-specific Gpc3 deletion in mice amplified high-fat diet (HFD)-induced weight and fat mass gain by selectively enhancing hyperplastic expansion in inguinal white adipose tissue (iWAT), without affecting epididymal WAT (eWAT). Mechanistically, Gpc3 loss biased ASPC fate toward proliferation over adipogenesis via depot-specific modulation of canonical Wnt signaling. These findings establish Gpc3 as a regulator for regional adipose plasticity, offering a molecular target for reprogramming pathological fat distribution in obesity and related metabolic disorders.