Depletion Of Visceral Tissue Macrophage By Clodronate Liposomes And The Effect On Insulin Sensitivity In DIO Mice

Background:Obesity-related adipose inflammation has been thought to be a causal factor for the development of insulin resistance and type2diabetes. Infiltrated macrophages in adipose tissue of obese animals and humans are an important source for inflammatory cytokines. Clodronate liposomes can ablate macrophages by inducing apoptosis. The aim of this study is to determine the effect of peritoneal injection of clodronate liposomes on macrophage levels in visceral adipose tissue and systemic glucose homeostasis and insulin sensitivity in diet-induced obese (DIO) mice.Methodology/Princioal Findings:Clodronate liposomes were used to deplete macrophages in lean and DIO mice. Macrophage levels in visceral adipose tissue, metabolic parameters, glucose and insulin tolerance, adipose and liver histology, adipokine and cytokine production were examined. Hyperinsulinemic-euglycemic clamp study was also performed to assess systemic insulin sensitivity. The results demonstrated that, peritoneal injection of clodronate liposomes significantly reduced blood glucose and insulin levels in DIO mice and lean mice, improved systemic glucose tolerance and insulin sensitivity, alleviated hepatosteatosis dramatically, and suppressed hepatic glucose output markedly in DIO mice. Macrophage levels in visceral adipose tissue of DIO mice was effectively decreased without affecting subcutaneous adipose tissue. Interestingly, levelss of insulin sensitizing hormone adiponectin, including the high molecular weight form, were significantly elevated in circulation.Conclusions:Intraperitoneal injection of clodronate liposomes reduces visceral adipose tissue macrophages, improves systemic glucose homeostasis and insulin sensitivity in DIO mice, which can be partially attributable to increased adiponectin levelss.