Adipose Precursor HO-1 prevents healthy visceral adipose tissue expansion during obesity [I]

Excessive accumulation of white adipose tissue (WAT) is a hallmark of obesity. The expansion of WAT in obesity involves proliferation and differentiation of adipose precursors (APs), however, the underlying molecular mechanisms remain unclear. Here, we identify Heme Oxygenase-1 (HO-1) as selectively being upregulated in the AP fraction of WAT, upon high-fat diet (HFD) feeding. Specific conditional deletion of HO-1 in APs of Hmox1fl/fl-Pdgfra Cre mice enhanced HFD-dependent visceral AP proliferation and differentiation, upstream of Cebp and PPAR. Opposite effects on human preadipocyte proliferation and differentiation in vitro were observed following HO-1 overexpression. Mechanistically, HO-1 acts upstream of AKT2 via ROS thresholding in mitochondria. Deletion of HO-1 in APs is sufficient to lower blood glucose, insulin and free fatty acid levels as well as liver steatosis during obesity, an effect not seen when HO-1 was conditionally deleted at later stages of adipogenesis using AdipoQ-Cre. Together, our data identify HO-1 as a diet-induced regulator limiting visceral adipose tissue hyperplasia during obesity.

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Wagner G, Lindroos-Christensen J, Einwallner E, Husa J, Zapf TC, Lipp K, Rauscher S, Gröger M, Spittler A, Loewe R, Gruber F, Duvigneau JC, Mohr T, Sutterlüty-Fall H, Klinglmüller F, Prager G, Huppertz B, Yun J, Wagner O, Esterbauer H, Bilban M