Metabolic syndrome, a complex of highly debilitating disorders that includes insulin resistance, hypertension, and dyslipidemia, is associated with the development of obesity in humans, as well as in rodent models. White adipose tissue (WAT) inflammation, caused in part by macrophage infiltration, and fat accumulation in the liver are both linked to development of the metabolic syndrome.

Despite large increases in body fat, melanocortin 3-receptor (MC3-R) deficient mice do not get fatty liver disease or severe insulin resistance. This is in contrast to obese melanocortin 4-receptor (MC4-R) deficient mice and diet-induced obese (DIO) mice which show increased adiposity, fatty liver disease and insulin resistance. We hypothesized that defects in the inflammatory response to obesity may underlie the protection from metabolic syndrome seen in MC3-R null mice. MC4-R mice fed a chow diet show increased pro-inflammatory gene expression and macrophage infiltration in WAT, as do WT DIO mice. In contrast MC3-R deficient mice fed a normal chow diet show neither of these inflammatory changes, despite their elevated adiposity, and a comparable degree of adipocyte hypertrophy to the MC4-R null and DIO mice.

Furthermore, even when challenged with high-fat chow for 4 weeks, a period of time shown to induce an inflammatory response in WAT of WT animals, MC3-R nulls showed an attenuated upregulation in both monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor alpha (TNF) mRNA in WAT compared to WT high-fat fed animals.