Cytokine Activity Links Resistin to Obesity and Diabetes

Researchers seeking to establish a link between obesity and diabetes have found that levels of resistin, a hormone produced by fat cells in mice and by immune macrophages in humans, are chronically elevated in obese individuals.

Resistin, a small protein (114 amino acids) secreted by fat cells in mice, causes tissues-- especially the liver--to be less sensitive to the action of insulin, which is the hallmark of noninsulin-dependent diabetes mellitus (NIDDM), known as type 2 diabetes. Blood glucose levels rise because of increased glycogenolysis and gluconeogenesis in the liver. In humans, resistin is primarily a product of macrophages, not fat cells. Nevertheless, there is a strong association in humans between elevated levels of resistin, obesity, and type 2 diabetes. More than 80% of individuals with NIDDM are obese.

Investigators at the University of Pennsylvania School of Medicine (Philadelphia, USA), who had been the first to identify resistin in mice, worked with obese humans and human macrophage cultures to establish the role of the hormone in humans. They reported in the November 30, 2004, issue of PloS Biology that inflammatory stimulators such as bacterial endotoxin significantly increase resistin production in macrophages and serum levels in patients. This response could be blocked by the rosiglitazone and by aspirin, two drugs that have dual anti-inflammatory and insulin-sensitizing actions. Cytokines were required for the increase in resistin in the presence of endotoxin.

"That told us that cytokines like TNF-alpha and IL-6 are responsible for the increase in resistin in macrophages,” explained senior author Dr. Mitch Lazar, chief of the division of endocrinology, diabetes, and metabolism at the University of Pennsylvania School of Medicine. "Our work suggests that the increases in resistin seen in people is related to the increase in cytokines. The hypothesis is that there is cross-talk between fat cells and macrophages via cytokines, both in mice and humans.”





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