Hypoxia-Inducible Factor 1α Induces Fibrosis and Insulin Resistance in White Adipose Tissue

Abstract

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␤ ...

Adipose tissue remodeling and obesity

“…This has been verified by recent clinical observations in humans, which suggest that AT is poorly oxygenated in the obese state (20,21). The effects of the local AT hypoxia have been investigated both in isolated murine adipocytes and in animal models (4,(22)(23)(24)(25). These papers suggest that many adipokines that are related to inflammation, such as macrophage migration inhibitory factor (MIF), the matrix metalloproteinases MMP2 and MMP9, IL-6, Angplt4, PAI-1, VEGF, and leptin are all upregulated by hypoxia (22)(23)(24)(25).…”

“…We have discussed hypoxia as a key player in expanding AT that serves as a driving force for macrophage infiltration. Compared to brown AT, white AT is not particularly well vascularized (4,20). The O 2 tension in obese white AT can reach levels as low as 15 mmHg, much lower than that in normal lean AT, in which values would typically reach 45-50 mmHg (23).…”

“…To investigate the effects of HIF-1α in white AT, we analyzed a transgenic mouse model in which we overexpressed a dominant active (degradation-resistant) deletion mutant of HIF-1α (HIF-1α-ΔODD) specifically in adipocytes (4). Unexpectedly, our model failed to induce any classical HIF-1α targets, such as VEGF-A.…”

“…Many physiologically relevant processes important for human AT remodeling can be studied in rodent models, with the added advantage that processes related to AT expansion and reduction can occur at an extremely rapid rate. A 24-hour fast in a mouse is associated with a dramatic loss of AT mass and an acute remodeling process that involves rapid infiltration of macrophages; moreover, merely 24 to 48 hours of exposure to a high-fat diet (HFD) can cause a prompt increase in adipocyte size (4). AT is therefore an ideal model system to study rapid alterations in tissue expansion and reduction, as it adapts to a differential nutrient supply.…”

Adiponectin Regulation of Stellate Cell Activation via PPARγ-Dependent and -Independent Mechanisms

“…36 -38 Although stellate cells in the liver and pancreas and in related cells in other tissues clearly regulate fibrosis in these organs, the cellular drivers of fibrosis in adipose tissue are unknown, even though adipocytes may contribute to the phenomenon. 39 A particularly intriguing possibility is that a stellate cell-like cell type may exist in adipose tissue. A final important question related to adipose tissue and adiponectin is whether healthy adipose tissue that expresses and releases high levels of adiponectin may have antifibrotic therapeutic potential.…”