Gpc3 selectively suppresses subcutaneous adipogenesis in diet-induced obesity

TL;DR

This study identifies a gene, Gpc3, that controls how fat expands in different body regions during obesity.

Contribution

The study discovers Gpc3 as a novel obesity-responsive gene that regulates depot-specific adipose expansion.

Findings

ASPC-specific Gpc3 deletion in mice increases high-fat diet-induced weight and fat mass gain.

Gpc3 loss biases adipose stem cell fate toward adipogenesis in inguinal white adipose tissue.

Gpc3 modulates adipose expansion through depot-specific effects on Wnt signaling.

Abstract

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.

Why does fat expand differently in distinct body regions? This study identifies Gpc3 as regional depot-specific obesity responsive gene that selectively promotes the expansion of inguinal, but not epididymal, white adipose tissue in mice fed a high fat diet.

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