Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipose Tissue, White / drug effects
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Adipose Tissue, White / metabolism*
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Adipose Tissue, White / pathology*
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Animal Structures / metabolism
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Animals
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Antigens, CD / genetics
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Antigens, Differentiation, Myelomonocytic / genetics
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Blood Glucose / drug effects
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Blood Glucose / metabolism
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Cell Movement / drug effects
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Cell Movement / physiology
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Cytokines / genetics
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Dietary Fats / pharmacology
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Gene Expression / drug effects
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Gene Expression / genetics
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Glucose Clamp Technique
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Glucose Tolerance Test
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Humans
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Inflammation / metabolism*
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Inflammation / pathology
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Insulin / blood
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Insulin Receptor Substrate Proteins / metabolism
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Insulin Resistance*
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Isoenzymes / metabolism
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Lipid Metabolism / drug effects
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Lipid Metabolism / physiology
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Lipids / blood
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Lipolysis / drug effects
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Lipolysis / physiology
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Lipoprotein Lipase / genetics
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Lipoprotein Lipase / metabolism
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Macrophages / metabolism*
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Macrophages / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Protein Kinase C / metabolism
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Protein Kinase C-theta
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Resistin / blood
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Resistin / genetics
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Resistin / metabolism*
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Restless Legs Syndrome
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Signal Transduction / physiology
Substances
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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Blood Glucose
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CD68 antigen, human
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Cytokines
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Dietary Fats
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Insulin
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Insulin Receptor Substrate Proteins
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Irs1 protein, mouse
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Isoenzymes
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Lipids
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RETN protein, human
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Resistin
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Retn protein, mouse
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Prkcq protein, mouse
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Protein Kinase C
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Protein Kinase C-theta
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Lipoprotein Lipase