Abstract
BackgroundObesity-related adipose inflammation has been thought to be a causal factor for the development of insulin resistance and type 2 diabetes. 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. In this study, we aim to determine whether peritoneal injection of clodronate liposomes has any beneficial effect on systemic glucose homeostasis/insulin sensitivity and whether macrophage content in visceral adipose tissue will be reduced in diet-induced obese (DIO) mice.Methodology/Principal FindingsClodronate liposomes were used to deplete macrophages in lean and DIO mice. Macrophage content 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. Peritoneal injection of clodronate liposomes significantly reduced blood glucose and insulin levels in DIO mice. Systemic glucose tolerance and insulin sensitivity were mildly improved in both lean and DIO mice treated with clodronate liposomes by intraperitoneal (ip) injection. Hepatosteatosis was dramatically alleviated and suppression of hepatic glucose output was markedly increased in DIO mice treated with clodronate liposomes. Macrophage content in visceral adipose tissue of DIO mice was effectively decreased without affecting subcutaneous adipose tissue. Interestingly, levels of insulin sensitizing hormone adiponectin, including the high molecular weight form, were significantly elevated in circulation.Conclusions/SignificanceIntraperitoneal 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 levels.
Highlights
Obesity has become a huge public health burden since it is related to the development of many chronic diseases such as type 2 diabetes
Clodronate liposomes reduce macrophage content in visceral adipose tissue of DIO mice To determine whether reduced visceral adipose macrophage content will be associated with a beneficial effect on improving insulin resistance in diet-induced obese mice, a chemical approach was used to deplete macrophages
As shown in figure 1A–B, F4/80 positive cells are significantly decreased in adipose tissue from DIO mice treated with clodronate liposomes compared to control DIO mice injected with PBS liposomes
Summary
Obesity has become a huge public health burden since it is related to the development of many chronic diseases such as type 2 diabetes. Extensive studies have been performed to determine the role of adipose inflammation in development of obesity-related insulin resistance and type 2 diabetes [8,9,10,11]. Macrophages accumulated and activated in adipose tissue in obesity have been shown to secrete a variety of proinflammatory cytokines, which potentially contribute to obesity-related chronic inflammation [6,17]. Diet induced obese mice with reduced adipose macrophage infiltration have improved insulin sensitivity, as observed in mice deficient in CCR2, osteopontin and CXCL14 [19,20,21]. We aim to determine whether peritoneal injection of clodronate liposomes has any beneficial effect on systemic glucose homeostasis/insulin sensitivity and whether macrophage content in visceral adipose tissue will be reduced in diet-induced obese (DIO) mice
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