Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity

Area of Science:

• Metabolic disease research
• Cellular and molecular biology
• Obesity research

Background:

• Adipose precursor cells (APCs) show varied responses to obesity, with underlying mechanisms unclear.
• White adipose tissue (WAT) remodeling and metabolic health are critical in obesity.
• Understanding depot-specific APC behavior is key to addressing obesity-related metabolic dysfunction.

Purpose of the Study:

• To elucidate the mechanism behind regional variations in APC response to obesity.
• To identify signaling pathways regulating adipogenesis in different adipose depots.
• To explore pharmacological targeting of APCs for improved metabolic health in obesity.

Main Methods:

• Investigated HIFα and PDGFRβ signaling in murine white adipose tissue (WAT) PDGFRβ+ cells.
• Analyzed serine 112 (S112) phosphorylation of PPARγ, a master regulator of adipogenesis.
• Utilized high-fat-diet feeding models and PDGFR antagonist (Imatinib) treatment in mice.

Main Results:

• HIFα-induced PDGFRβ signaling inhibits PPARγ phosphorylation at S112 in WAT PDGFRβ+ cells.
• PPARγ S112 phosphorylation levels are depot-dependent and inversely correlate with adipogenesis capacity.
• HIFα suppression in PDGFRβ+ progenitors enhanced adipogenesis, WAT remodeling, and metabolic health in obese mice.
• Imatinib treatment mimicked these benefits, promoting adipocyte hyperplasia and glucose tolerance.

Conclusions:

• A novel mechanism involving HIFα-driven PDGFRβ signaling and PPARγ phosphorylation explains depot-specific APC responses to high-fat feeding.
• Targeting PDGFRβ signaling in APCs represents a promising therapeutic strategy for improving metabolic health and combating obesity.