Emerging role of adipose tissue hypoxia in obesity and insulin resistance

Abstract

Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.

Fig. 1. Mechanisms of inflammation-mediated alteration of insulin signaling

Hypoxia and FFAs in obesity lead to activation of NF-kB pathway, which induces expression of inflammatory cytokines (TNF-a, IL-1, IL-6, et al) in adipose tissue. Through receptor-mediated signal transduction, these cytokines activates serine kinases including IKK, JNK, PKC and p70S6K to inhibit IRS-1 function. NF-kB inhibits PPARγ function through nuclear corepressor and results in suppression of the gene transcription of CAP and IRS-2, which are signaling molecules in PI(3)K-independent and -dependent signaling pathways for insulin-induced GLUT4 translocation. Hypoxia also induces FFA level through lipolysis.

Fig. 2. Up- and down-stream of ATH

Rapid growth of adipose tissue leads to quick expansion of adipose tissue. When angiogenesis or vessel dilation can not meet the demand for blood supply, reduction in adipose tissue blood flow (ATBF) will happen leading to adipose tissue hypoxia (ATH). ATH will induce angiogenesis and trigger inflammation. Inflammation will promote angiogenesis and vasodilation. When inflammation is out of control, it will promote insulin resistance locally and systemically. ATH is a signal for remodeling of extra-cellular matrix in the adipose tissue. Please refer to Fig. 1 for mechanism of inflammation in insulin resistance.

Fig. 3. Cytokines/hormones in angiogenesis

Cytokines or hormones from adipocytes and macrophages are able to regulate angiogenesis. These include leptin, adiponectin, VEGF (vascular endothelial growth factor), TNF-α (tumor necrosis factor-alpha), MIF (macrophage migration inhibitory factor), IL-6 (interleukin-6), IL-8, PDGF (platelet-derived growth factor), TGF-β (transforming growth factor beta), and angiopoietin.