Adipose Tissue-specific Inhibition of Hypoxia-inducible Factor 1α Induces Obesity and Glucose Intolerance by Impeding Energy Expenditure in Mice*

Abstract

Hypoxia in adipose tissue has been postulated as a possible contributor to obesity-related chronic inflammation, insulin resistance, and metabolic dysfunction. HIF1␣ (hypoxia-inducible factor 1␣), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the role of HIF1␣ in obesity-related pathologies remains to be determined. Here we show that transgenic mice with adipose tissue-selective expression of a dominant negative version of HIF1␣ developed more severe obesity and were more susceptible to high fat diet-induced glucose intolerance and insulin resistance compared with their wild type littermates. Obesity in the transgenic mice was attributed to impaired energy expenditure and reduced thermogenesis. Histological examination of interscapular brown adipose tissue (BAT) in the transgenic mice demonstrated a markedly increased size of lipid droplets and decreased mitochondrial density in adipocytes, a phenotype similar to that in white adipose tissue. These changes in BAT of the transgenic mice were accompanied by decreased mitochondrial biogenesis and reduced expression of key thermogenic genes. In the transgenic mice, angiogenesis in BAT was decreased but was little affected in white adipose tissue. These findings support an indispensable role of HIF1␣ in maintaining the thermogenic functions of BAT, possibly through promoting angiogenesis and mitochondrial biogenesis in this tissue.

Control of Adipose Tissue Expandability in Response to High Fat Diet by the Insulin-like Growth Factor-binding Protein-4

“…Several studies have reported that adipose tissue expansion in response to HFD is accompanied by hypoxia, which could potentially elicit pro-angiogenic signaling and a subsequent expansion of the capillary network (35). However, hypoxia signaling in adipose tissue appears to result in fibrosis, rather than in angiogenesis (15,38). An alternative possibility is that expansion of the adipose tissue capillary network is triggered by factors that accompany excessive energy consumption.…”

Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance

“…In contrast, our observation is supported by several lines of evidence from genetically modified mice. 30,38,39 Overexpression of a dominant-negative form of HIF-1α in adipocytes accelerated HFD-induced glucose intolerance and insulin resistance and induced more severe obesity. 38 Another study showed that factor inhibiting HIF-1α-deficient mice that have elevated HIF activity are also resistant to HFD-induced body weight gain and glucose intolerance.…”

“…30,38,39 Overexpression of a dominant-negative form of HIF-1α in adipocytes accelerated HFD-induced glucose intolerance and insulin resistance and induced more severe obesity. 38 Another study showed that factor inhibiting HIF-1α-deficient mice that have elevated HIF activity are also resistant to HFD-induced body weight gain and glucose intolerance. 39 This evidence consistently suggests that HIF signaling is positively linked to resistance to obesity and associated metabolic abnormalities.…”

Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system

“…In this regard, there is evidence to suggest that HIF1a protein accumulates in adipocytes of obese humans and mouse models of obesity (Ye 2009). While mouse models wherein HIF1a has been either overexpressed (Halberg et al 2009), deleted in WAT (Jiang et al 2011), or expressed as a dominant-negative form (Zhang et al 2010) have been generated, they have not been suitable to interrogate a specific requirement of HIF1a function for maintaining the obese state (as opposed to the development of the obese state) and its associated pathologies. Hence, it remains unclear whether and how HIF1a function contributes to the maintenance of adiposity and its associated pathologies in the context of a pre-existing obese, diabetic, and cardiomyopathic state.…”