Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1␣ (HIF1␣) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1␣, we determined that HIF1␣ fails to induce the expected proangiogenic response. In contrast, we observed that HIF1␣ initiates adipose tissue fibrosis, with an associated increase in local inflammation. The dramatic rise in the prevalence of obesity has lead to increased efforts aimed at gaining a better understanding of the physiology and pathophysiology of adipose tissue and adipocytes. One of the more-surprising features of adipose tissue described over the past 10 years is the realization that adipose tissue in general and adipocytes in particular have the potential to be a rich source of a vast array of secretory proteins. Since infiltrating immune cells, most notably monocytes, are known to have a profound effect on adipocytes, interest in the stromal fraction of adipose tissue has increased considerably. These stromal components consist of fibroblastlike preadipocytes, endothelial cells, vascular smooth muscle cells, neurons, and immune cells. It is currently not established how these stromal components interact with adipocytes during adipose tissue expansion. The nature of the local endothelium, a key constituent of the vasculature, has received limited attention to date.Destruction of local endothelial cells results in a reduction in fat mass during times of excess caloric intake independent of food intake (2,30,38). Functioning through an as yet unidentified mechanism, such a reduction in fat mass results in decreased levels of steatosis in the liver and enhanced glucose tolerance. These metabolic improvements are somewhat surprising, considering that the forced reduction of fat mass in the context of lipodystrophies leads to a decrease rather than an increase in systemic insulin sensitivity (30,36). These observations highlight the need for a better understanding of the adipose tissue vasculature.During times of positive energy balance, adipose tissue absorbs the energy surplus by increasing both cell size and number. The ability of adipose tissue to expand critically depends on vascular outgrowth (4). At the same time, the increased adipocyte size requires oxygen to diffuse over longer distances prior to reaching adipocyte mitochondria; this is evident by a decreased partial oxygen pressure (20 mmHg versus 40 mmHg) in obese versus lean mice, respectively (20,37,53). Hypoxia in obese adipose tissue has been observed by several groups and results in the induction of the key hypoxia regulator, hypoxia-inducible factor 1 (HIF1) (20,37,49,53). HIF1 is a heterodimer consisting of the oxygen-regulated HIF1␣ subunit and the constitutively expressed HIF1␤ ...

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Hypoxia-inducible factor 1␣ (HIF1␣) induction in adipocytes is a critical component of the "fibrotic response," directly linked to metabolic dysfunction in adipose tissues under hypoxic conditions. We reasoned that inhibition of HIF1␣ may ameliorate the negative aspects of the obesity-associated fat pad expansion. We used the selective HIF1␣ inhibitor PX-478, whose effectiveness has previously been established in tumor models. We demonstrate that PX-478 treatment effectively suppresses the high-fat-diet (HFD)-induced HIF1␣ activation in adipose tissue. HIF1␣ inhibition causes a reduction of weight gain in mice on an HFD but not on a chow diet. Treatment increases energy expenditure and prompts resistance to HFD-mediated deterioration of metabolic parameters. Moreover, PX-478-treated mice have reduced fibrosis and fewer inflammatory infiltrates in their adipose tissues. We confirm the metabolic effects obtained with PX-478 treatment using an adipose tissue-specific, doxycycline-inducible dominant negative HIF1␣ mutant (dn-HIF1␣). Consistent with the pharmacological results, genetic inhibition of endogenous HIF1␣ activity prompts similar metabolic improvements in HFD-fed mice. Collectively, our results demonstrate that HIF1␣ inhibition in the adipocyte leads to significant metabolic improvements, suggesting that selective HIF1␣ inhibition in adipose tissue may be an effective therapeutic avenue in the context of metabolic dysfunction.

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