A third report with unspecified amount of clodronate liposomes administered into DIO mice did not investigate the effect on glucose homeostasis/systemic insulin sensitivity or macrophage content in adipose tissue. Therefore, our work provides novel information regarding the beneficial effect of clodronate liposomes on glucose homeostasis which is associated with reduction of macrophage content in visceral but not subcutaneous adipose tissue. Dissection of mice revealed significant reduction of weights in epididymal, mesenteric and peri-nephric adipose tissue in lean mice injected with clodronate liposomes. Significant reduction of weights in peri-nephric fat depot was AbMole BioScience observed in DIO mice injected with clodronate liposomes. Liver weights were also significantly decreased in DIO mice injected with clodronate liposomes under fasted condition and trended lower under fed condition. The reduction of liver weights is most likely due to decrease in triglyceride content. Diet-induced obesity is associated with hepatosteatosis. To determine whether reduction in hepatic triglyceride content alleviated hepatotseatosis, histology studies were performed with livers from DIO mice. As shown in Figure 4C, massive amounts of lipid droplets were observed in the livers of DIO mice treated with PBS liposomes but were barely detectable in the livers of DIO mice treated with clodronate liposomes, indicating the absence of steatosis. Histology and real-time PCR studies showed depletion of macrophages in the livers of DIO mice treated with clodronate liposomes. A hyperinsulinemic-euglycemic clamp study revealed significantly increased percent suppression of hepatic glucose output, suggesting that the ability of insulin on repressing glucose production in the liver is enhanced in DIO mice treated with clodronate liposomes compared to control DIO mice treated with PBS liposomes. Glucose uptake in muscle and adipose tissue was not significantly altered in DIO mice treated with clodronate liposomes. It has been reported that depletion of macrophages in visceral adipose tissue in lean mice by clodronate liposomes increases lipolysis and leads to elevated circulating FFA levels. Increased FFA levels are known to be detrimental to systemic insulin sensitivity. Elevated plasma FFA levels are also observed in our DIO mice treated with clodronate liposomes, suggesting that the beneficial phenotype of adipose macrophage reduction on improving systemic insulin sensitivity could be attenuated by increased lipolysis. Macrophage infiltration, accumulation and activation in adipose tissue of obese animals have been considered to play an important role in the development of obesity-related insulin resistance and type 2 diabetes. Visceral adipose tissue is the fat depot correlated with obesity-related metabolic syndrome and reduction of macrophage content in visceral adipose tissue may be beneficial for improving metabolic syndrome in obese animals. Despite the fact that a genetic approach was used previously to deplete CD11c positive macrophages in adipose tissue and improved systemic insulin sensitivity was observed.