HO-1 inhibits preadipocyte proliferation and differentiation at the onset of obesity via ROS dependent activation of Akt2

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.

Insight into the development of obesity: functional alterations of adipose‐derived mesenchymal stem cells

“…In further support of these observations, mouse obese ASCs exhibited a reduced capability for adipogenic differentiation associated with a decreased expression of related genes insulin receptor substrate 1 (IRS1), IRS2 and FABP4 compared with mouse control ASCs . In addition, it was demonstrated that the heme oxygenase‐1 inhibited proliferation and differentiation of preadipocytes at the onset of obesity via reactive oxygen species dependent activation of Akt/PKB (protein kinase B) in obese mouse models . By contrast, the data from a transcriptomic profile analysis displayed an increased commitment to an adipocyte‐like phenotype , supported by another report showing that obese ASCs conferred an enhanced potential of adipogenic differentiation associated with increased mRNA expression of the adipogenic markers PPARγ and FABP4 .…”

Mechanistic Insight of Na/K-ATPase Signaling and HO-1 into Models of Obesity and Nonalcoholic Steatohepatitis

“…Heme increases lipid accumulation, promotes cell enlargement, induces over-expression of adipogenic genes, such as PPARG, C/EBP-α and adipocyte protein 2 (aP2), and downregulates adiponectin [32,34,54]. The increase in heme combined with increased ROS leads to adipocyte dysfunction by promoting inflammatory infiltration of macrophages and other inflammatory molecules, increases in circulating levels of glucose and a decrease in cytoprotective molecules, such as adiponectin and HO-1 [33,34,55]. Chronic oxidative stress leads to further adipocyte dysfunction, and can increase lipid accumulation [33,34].…”

“…Chronic oxidative stress leads to further adipocyte dysfunction, and can increase lipid accumulation [33,34]. The induction of HO-1 in disease models of obesity provide an antioxidant setting, which increases mitochondrial fusion and improves the secretory profile of adipocytes (i.e., increased adiponectin expression and decreased inflammatory cytokine release) [33,55]. HO-1 upregulation has also been linked to increased insulin sensitivity, improvement in phosphorylation of insulin receptors, and improved adipocyte function [35].…”

“…Current literature hypothesizes that FoxO1 negatively regulates adipogenesis by preventing transcription of PPARγ; decreased adipogenesis leads to a decrease in systemic oxidative stress and inflammatory cytokines [36,56]. Previous studies have shown that HO-1 induction by CoPP reduces visceral adiposity and attenuates metabolic imbalance, increases levels of phosphorylated AKT, AMPK, mTOR in adipocytes, improved oxidative stress, decreased release of inflammatory cytokines, decreased lipid accumulation and increased adiponectin levels [36,55,70]. Pharmacological inductions of HO-1 are not only limited to CoPP; hemin and epoxyeicosatrienoic acid (EET) have been implicated as pharmacological inducers of HO-1 [54,71].…”

Mitochondrial oxidative stress in obesity: role of the mineralocorticoid receptor

“…ROS are highly reactive molecules, which makes them essential second messengers, participating in many cell signaling pathways including proliferation, differentiation, immune response and apoptosis (Simon et al 1998, Griendling et al 2000. At physiological levels in adipose tissue, ROS participate in metabolic homeostasis as well as preadipocyte proliferation through an insulin-dependent pathway (Castro et al 2016, Wagner et al 2017 and in adipocyte differentiation through H 2 O 2 -induced cAMP response element-binding protein beta (C/EBP-beta) DNA-binding activity, along with C/EBP-beta phosphorylation (Lee et al 2009, Tormos et al 2011.…”