PDGFR + cell HIF2 is dispensable for white adipose tissue metabolic remodeling and hepatic lipid accumulation in obese mice

Background Obesity is associated with extensive white adipose tissue (WAT) expansion and remodeling. Healthy WAT expansion contributes to the maintenance of energy balance in the liver, thereby ameliorating obesity-related hepatic steatosis. Tissue-resident mesenchymal stromal cell populations, including PDGFR beta + perivascular cells, are increasingly recognized pivotal as determinants of the manner in which WAT expands. However, the full array of regulatory factors controlling WAT stromal cell functions remains to be fully elucidated. Hypoxia-inducible factors (HIFs) are critical regulators in WAT stromal cell populations such as adipocyte precursor cells (APCs). It is revealed that HIF1 alpha activation within PDGFR beta + stromal cells results in the suppression of de novo adipogenesis and the promotion of a pro-fibrogenic cellular program in obese animals. However, the role of HIF2 alpha in PDGFR beta + cells remains undetermined in vivo.Methods New genetic models were employed in which HIF1 alpha (encoded by the Hif1a gene) and HIF2 alpha (encoded by the Epas1 gene) are selectively inactivated in PDGFR beta + cells in an inducible manner using tamoxifen (TAM). With these models, both in vitro and in vivo functional analysis of PDGFR beta + cells lacking HIF proteins were performed. Additionally, comprehensive metabolic phenotyping in diet-induced mouse models were performed to investigate the roles of PDGFR beta + cell HIF proteins in WAT remodeling, liver energy balance and systemic metabolism.Results Unlike HIF1 alpha inactivation, the new findings in this study suggest that inducible ablation of HIF2 alpha in PDGFR beta + cells does not cause apparent effects on WAT expansion induced by obesogenic diet. The adipogenic ability of PDGFR beta + APCs is not significantly altered by genetic HIF2 alpha ablation. Moreover, no difference of key parameters associated with healthy WAT remodeling such as improvements of WAT insulin sensitivity, reduction in metabolic inflammation, as well as changes in liver fat accumulation or systemic glucose metabolism, is detected in PDGFR beta + cell Epas1-deficient mice.Conclusion The new findings in this study support that, in contrast to HIF1 alpha, PDGFR beta + cell HIF2 alpha appears dispensable for WAT metabolic remodeling and the resulting effects on liver metabolic homeostasis in diet-induced obesity, underscoring the isoform-specific roles of HIF alpha proteins in the regulation of adipose tissue biology.