Reversal of inflammation-induced impairment of glucose uptake in adipocytes by direct effect of CB1 antagonism on adipose tissue macrophages.
Macrophage infiltration into adipose tissue (AT-MP) is thought to induce insulin resistance and diabetes in obesity. Here, we investigated the effect of the antiobesity drug SR141716 (a CB1 antagonist) on macrophage-mediated inhibition of insulin signaling in adipocytes. THP1 macrophages (THP1) were stimulated in vitro with lipopolysaccharide (LPS) and SR141716 or vehicle. The resulting conditioned medium (CM) was analyzed and incubated on human adipocytes. CM from LPS-stimulated THP1 inhibited insulin-induced AKT phosphorylation in adipocytes, in contrast to CM from nonactivated THP1. Moreover, it contained higher concentrations of tumor necrosis factor-α (TNFα) and lower levels of the anti-inflammatory cytokine IL-10. SR141716 reduced TNFα production and increased IL-10 secretion, resulting in a rescue of insulin signaling in adipocytes. To confirm these findings in vivo, AT-MP CM from cafeteria diet-fed or Zucker diabetic fatty (ZDF) rats that had received SR141716 for 3 weeks were isolated, analyzed, and incubated with adipocytes. Cafeteria diet induced macrophage-mediated inhibition of insulin signaling in adipocytes. Interestingly, SR141716 rescued insulin-induced glucose uptake in adipocytes. Finally, AT-MP CM from obese ZDF rats inhibited insulin-stimulated glucose uptake in adipocytes in contrast to AT-MP CM from lean ZDF rats. After treatment with SR141716, AT-MP CM rescued insulin-induced glucose uptake in adipocytes. In summary, our data indicate that CB1 receptor antagonism in macrophages modified their cytokine production and improved the insulin responsiveness of adipocytes that had been incubated with macrophage CM. Thus, SR141716 ameliorated adipose tissue insulin resistance by direct action on AT-MP demonstrating a novel peripheral mode of action of CB1 antagonism.
Miranville
Alexandra
A
Therapeutic Department Metabolism, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany. alexandra.miranville@sanofi-aventis.com
Herling
Andreas W
AW
Biemer-Daub
Gabriele
G
Voss
Marc D
MD
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D017077:Culture Media, Conditioned; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D019440:Anti-Obesity Agents; D001786:Blood Glucose; D017077:Culture Media, Conditioned; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D008070:Lipopolysaccharides; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000077285:Rimonabant