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 plays an active role in normal metabolic homeostasis as well as in the development of human disease. Beyond its obvious role as a depot for triglycerides, adipose tissue controls energy expenditure through secretion of several factors. Little attention has been given to the role of adipocytes in the pathogenesis of Chagas disease and the associated metabolic alterations. Our previous studies have indicated that hyperglycemia significantly increases parasitemia and mortality in mice infected with Trypanosoma cruzi. We determined the consequences of adipocyte infection in vitro and in vivo. Cultured 3T3-L1 adipocytes can be infected with high efficiency. Electron micrographs of infected cells revealed a large number of intracellular parasites that cluster around lipid droplets. Furthermore, infected adipocytes exhibited changes in expression levels of a number of different adipocyte-specific or adipocyte-enriched proteins. The adipocyte is therefore an important target cell during acute Chagas disease. Infection of adipocytes by T. cruzi profoundly influences the pattern of adipokines. During chronic infection, adipocytes may represent an important long-term reservoir for parasites from which relapse of infection can occur. We have demonstrated that acute infection has a unique metabolic profile with a high degree of local inflammation in adipose tissue, hypoadiponectinemia, hypoglycemia, and hypoinsulinemia but with relatively normal glucose disposal during an oral glucose tolerance test.

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The differentiation of preadipocyte fibroblasts to adipocytes is a crucial process to many disease states including obesity, cardiovascular, and autoimmune diseases. In Graves' disease, the orbit of the eye can become severely inflamed and infiltrated with T lymphocytes as part of the autoimmune process. The orbital fibroblasts convert to fat-like cells causing the eye to protrude, which is disfiguring and can lead to blindness. Recently, the transcription factor peroxisome proliferator activated receptor (PPAR)-gamma and its natural (15d-PGJ2) and synthetic (thiazolidinedione-type) PPAR-gamma agonists have been shown to be crucial to the in vitro differentiation of preadipocyte fibroblasts to adipocytes. We show herein several novel findings. First, that activated T lymphocytes from Graves' patients drive the differentiation of PPAR-gamma-expressing orbital fibroblasts to adipocytes. Second, this adipogenic differentiation is blocked by nonselective small molecule cyclooxygenase (Cox)-1/Cox-2 inhibitors and by Cox-2 selective inhibitors. Third, activated, but not naïve, human T cells highly express Cox-2 and synthesize prostaglandin D2 and related prostaglandins that are PPAR-gamma ligands. These provocative new findings provide evidence for how activated T lymphocytes, through production of PPAR-gamma ligands, profoundly influence human fibroblast differentiation to adipocytes. They also suggest the possibility that, in addition to the orbit, T lymphocytes influence the deposition of fat in other tissues.