Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice.
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.
Qatanani
Mohammed
M
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149, USA.
Szwergold
Nava R
NR
Greaves
David R
DR
Ahima
Rexford S
RS
Lazar
Mitchell A
MA
D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008055:Lipids / Q000097:blood; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D052243:Resistin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012148:Restless Legs Syndrome; D015398:Signal Transduction / Q000502:physiology; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001786:Blood Glucose; D016207:Cytokines; D004041:Dietary Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes; D008055:Lipids; D008071:Lipoprotein Lipase; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D052243:Resistin; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C526295:Irs1 protein, mouse; C499624:RETN protein, human; C499623:Retn protein, mouse; C489593:Prkcq protein, mouse