Abstract 3922: A Potent Anti-Inflammatory CCR2/CCR5 Dual Antagonist Abrogates Adipose Inflammation and Glucose Intolerance, and Reduces Fat Mass in a Preclinical Model of Diet Induced Obesity
Adipose inflammation is emerging as an important player in the pathogenesis of insulin resistance, diabetes and obesity. Macrophage accumulation and the expression of inflammatory chemokines MCP-1 and RANTES are elevated in obese humans and animals. Furthermore, reduced adipose inflammation and improved insulin sensitivity have been observed in mice deficient in macrophage recruitment proteins MCP-1 or CCR2. In the present study we show that pharmacological reduction of adipose macrophage content by treatment with a potent CCR2/CCR5 dual antagonist ( LYSN 2238290 ) was associated with reduced body weight and adipose mass, and a normalization of glucose tolerance in diet induced obese mice. Mice (C57BL6) were fed high fat diet and the antagonist was administered subcutaneously daily starting two weeks after the initiation of diet. At the end of 6 weeks, the animals treated with LYSN2238290 exhibited >90% reduction in the expression of macrophage marker genes in adipose. Reduced adipose inflammation was associated with reduced body weight gain and a reduction (37%, P<0.05) in white adipose fat which occurred without significant effect on food intake. Measurement of glucose tolerance at the end of six weeks showed a dose dependent improvement in glucose disposal in the treated groups. At 30 mg/kg of LYSN 2238290, the glucose disposal rate was similar to that of the normal lean animals. In addition, LYSN2238290 produced 40 % reduction ( p<0.05) in liver triglycerides. These data show that in a preclinical model of diet induced obesity, a potent CCR2/CCR5 dual antagonist produced a major reduction in body weight and adipose fat mass, and improvement in insulin sensitivity. These data suggest that pharmacological targeting of adipose inflammation may represent a novel approach to the prevention and treatment of diabetes and obesity.