Melanin-concentrating hormone receptor 1 deficiency increases insulin sensitivity in obese leptin-deficient mice without affecting body weight.

The hypothalamic peptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis. Animals overexpressing MCH develop hyperphagia, obesity, and insulin resistance. In this study, mice lacking both the MCH receptor-1 (MCHr1 knockout) and leptin (ob/ob) double-null mice (MCHr1 knockout ob/ob) were generated to investigate whether the obesity and/or the insulin resistance linked to the obese phenotype of ob/ob mice was attenuated by ablation of the MCHr1 gene. In MCHr1 knockout ob/ob mice an oral glucose load resulted in a lower blood glucose response and markedly lower insulin levels compared with the ob/ob mice despite no differences in body weight, food intake, or energy expenditure. In addition, MCHr1 knockout ob/ob mice had higher locomotor activity and lean body mass, lower body fat mass, and altered body temperature regulation compared with ob/ob mice. In conclusion, MCHr1 is important for insulin sensitivity and/or secretion via a mechanism not dependent on decreased body weight.