Abstract
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, however, the underlying molecular mechanisms remain unclear. Here, we used an unbiased transcriptomics approach to identify the earliest molecular underpinnings occuring in adipose precursors following a brief HFD in mice. Our analysis identifies Heme Oxygenase-1 (HO-1) as strongly and selectively being upregulated in the adipose precursor fraction of WAT, upon high-fat diet (HFD) feeding. Specific deletion of HO-1 in adipose precursors of Hmox1fl/flPdgfraCre mice enhanced HFD-dependent visceral adipose precursor proliferation and differentiation. Mechanistically, HO-1 reduces HFD-induced AKT2 phosphorylation via ROS thresholding in mitochondria to reduce visceral adipose precursor proliferation. HO-1 influences adipogenesis in a cell-autonomous way by regulating events early in adipogenesis, during the process of mitotic clonal expansion, upstream of Cebpα and PPARγ. Similar effects on human preadipocyte proliferation and differentiation in vitro were observed upon modulation of HO-1 expression. This collectively renders HO-1 as an essential factor linking extrinsic factors (HFD) with inhibition of specific downstream molecular mediators (ROS & AKT2), resulting in diminished adipogenesis that may contribute to hyperplastic adipose tissue expansion.
Highlights
White adipose tissue (WAT) has a remarkable capacity to expand or remodel in order to meet the energy demands of the organism
Microarray analysis was performed on adipose precursors (APs) cells lysed directly after isolation to avoid cellular phenotype alterations occuring in culture[28]
We aimed to identify novel HFD target genes involved in the activation of adipose precursor cells, on the basis of (1) a hitherto unknown function in adipocyte biology, (2) a robust induction upon HFD feeding in APs in vivo, and (3) the potential to act upstream of the adipogenic master regulators Cebpαand PPARγ
Summary
White adipose tissue (WAT) has a remarkable capacity to expand or remodel in order to meet the energy demands of the organism. Lineage tracing studies have demonstrated that most adipose precursors within WAT are of non-endothelial and non-hematopoietic origin (CD31− and CD45−, respectively) and express surface cell markers including CD34, CD29, as well as Platelet-derived growth factor receptor alpha (Pdgfra)[17,18,19,20]. These studies have shown that HFD-induced adipose tissue hyperplasia is restricted to visceral fat[19,21,22,23]. We demonstrate that deficiency of HO-1 in viAPs raised reactive oxygen species (ROS) levels and promoted proliferation and differentiation via increasing Akt[2] signaling
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