Reduced Adipose Tissue Macrophage Content Is Associated With Improved Insulin Sensitivity in Thiazolidinedione-Treated Diabetic Humans

Abstract

Obesity is associated with increased adipose tissue macrophage (ATM) infiltration, and rodent studies suggest that inflammatory factors produced by ATMs contribute to insulin resistance and type 2 diabetes. However, a relationship between ATM content and insulin resistance has not been clearly established in humans. Since thiazolidinediones attenuate adipose tissue inflammation and improve insulin sensitivity, we examined the temporal relationship of the effects of pioglitazone on these two parameters. The effect of 10 and 21 days of pioglitazone treatment on insulin sensitivity in 26 diabetic subjects was assessed by hyperinsulinemic-euglycemic clamp studies. Because chemoattractant factors, cytokines, and immune cells have been implicated in regulating the recruitment of ATMs, we studied their temporal relationship to changes in ATM content. Improved hepatic and peripheral insulin sensitivity was seen after 21 days of pioglitazone. We found early reductions in macrophage chemoattractant factors after only 10 days of pioglitazone, followed by a 69% reduction in ATM content at 21 days and reduced ATM activation at both time points. Although markers for dendritic cells and neutrophils were reduced at both time points, there were no significant changes in regulatory T cells. These results are consistent with an association between adipose macrophage content and systemic insulin resistance in humans.

Macrophage functions in lean and obese adipose tissue

“…The combination of rosiglitazone and dexamethasone inhibits ATM accumulation in murine epididymal fat 28 . Similarly, pioglitazone in humans reduces macrophage chemoattractant factors after 10 and 21 days, reduces adipose tissue macrophage content by 69% after 21 days, and improves insulin sensitivity 29 . Pioglitazone induced apoptosis in subcutaneous adipose tissue macrophages in humans with impaired glucose tolerance, but in this study M1 and M2 macrophages were not distinguished 30 .…”

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

“…Common glucose-lowering medications, including metformin and thiazolidinediones, stimulate autophagy and prevent NEFA toxicity to beta cells [78,98]. Consistent with stimulated autophagy, thiazolidinediones promote adiposity, attenuate adipose tissue inflammation and enhance insulin action in type 2 diabetes [99]; however, it is unknown whether these effects are mediated via these drugs' ability to stimulate autophagy.…”

Obesity: An Immunometabolic Perspective

“…Anti-IL-1β monoclonal antibody therapy improved glycemic condition and β-cell insulin secretion (117–119). The antidiabetic thiazolidinediones (e.g., rosiglitazone and pioglitazone) decreased adipose tissue macrophage content (120, 121) and increase circulating levels of adiponectin and FGF21, thereby mediating redistribution of adipose tissue lipid stores (122, 123). Orexin-1 receptor antagonist has been shown to exert anti-obesity effects in obese leptin-deficient ob/ob mice (124, 125).…”