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Resistin is an adipokine that contributes to insulin resistance in mice. In humans, however, studies investigating the link between resistin and metabolic disease are conflicting. Further complicating the matter, human resistin is produced mainly by macrophages rather than adipocytes. To address this important issue, we generated mice that lack adipocyte-derived mouse resistin but produce human resistin in a pattern similar to that found in humans, i.e., in macrophages (humanized resistin mice). When placed on a high-fat diet, the humanized resistin mice rapidly developed accelerated white adipose tissue (WAT) inflammation, leading to increased lipolysis and increased serum free fatty acids. Over time, these mice accumulated lipids, including diacylglycerols, in muscle. We found that this resulted in increased Pkcq pathway activity, leading to increased serine phosphorylation of Irs-1 and insulin resistance. Thus, although the site of resistin production differs between species, human resistin exacerbates WAT inflammation and contributes to insulin resistance.

Original publication

DOI

10.1172/JCI37273

Type

Journal article

Journal

J Clin Invest

Publication Date

03/2009

Volume

119

Pages

531 - 539

Keywords

Adipose Tissue, White, Animal Structures, Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Blood Glucose, Cell Movement, Cytokines, Dietary Fats, Gene Expression, Glucose Clamp Technique, Glucose Tolerance Test, Humans, Inflammation, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Isoenzymes, Lipid Metabolism, Lipids, Lipolysis, Lipoprotein Lipase, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Muscle, Skeletal, Protein Kinase C, Resistin, Restless Legs Syndrome, Signal Transduction