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 dietary transitions, we identified Glypican 3 (Gpc3) as an obesity-responsive gene exhibiting reciprocal expression patterns between depots. ASPC-specific Gpc3 deletion in mice amplified high-fat diet-induced weight and fat mass gain, with a selective enhancement of expansion in inguinal white adipose tissue (WAT) without affecting epididymal WAT. Mechanistically, Gpc3 loss biased ASPC fate toward adipogenesis over proliferation through 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.