Melanin-Concentrating Hormone Receptor 1 Deficiency Increases Insulin Sensitivity in Obese Leptin-Deficient Mice Without Affecting Body Weight

Abstract

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. Diabetes 55:725-733, 2006 I t is well known that obesity is a major contributing factor to the development of insulin resistance and type 2 diabetes. Diabetic patients can often reverse their insulin resistance by decreasing their body weight. However, the mechanism linking obesity and insulin sensitivity is poorly understood. Mutations in the ob gene results in obesity and insulin resistance, and this may serve as a model for increased food intake leading to obesity and insulin resistance.Melanin-concentrating hormone (MCH) was originally isolated and sequenced from salmon pituitary and was named MCH due to its role in fish pigmentation (1). In rodents, MCH is predominantly expressed in the lateral hypothalamus and zona incerta, areas involved in the regulation of energy homeostasis and ingestive behavior. MCH fibers project broadly throughout the central nervous system, suggesting that MCH may function as a neurotransmittor and/or a neuromodulator to regulate behavioral functions (2,3). There is much data to support a role for MCH in the regulation of food intake, body weight, and energy balance. This includes the expression profile of MCH in the lateral hypothalamus and the fact that both fasting and leptin deficiency result in elevated MCH levels (4). Overexpression of MCH in transgenic mice given high-fat diet results in weight gain, hyperphagia, obesity, and insulin resistance (5). Chronic infusion of MCH results in hyperphagia and obesity in mice (6). Mice deficient of MCH are hypophagic, lean, and have an increased metabolic rate (7). Also, treatment of rats with an MCH receptor antagonist results in inhibition of food intake and weight loss (8). Furthermore, the central role of MCH and the MCH receptor-1 (MCHr1) for energy balance is supported by the phenotypes of MCHr1 knockout mice (9 -11). One important difference between the MCH knockout and MCHr1 knockout mice is that the latter are slightly hyperphagic but still lean due to increased energy expenditure. The rodent receptor for MCH, MCHr1 (or SL...

Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists

“…They were also less insulinresistant and had improved glucose tolerance. In contrast to the double KO mentioned above, when the MCHR1 KO was crossed with lep ob/ob mice (R1 ob/ob KO), a slightly different phenotype emerged (Bjursell et al, 2006). The R1 ob/ob KO mice were not different in body weight than lep ob/ob controls, food intake or energy expenditure than lep ob/ob , but were more insulin sensitive.…”

Mice with experimental colitis show an altered metabolism with decreased metabolic rate

“…The gross energy content was determined in a bomb calorimeter (C 5000, IKA, Werke, Germany). A tablet of benzoic acid (IKA, Werke, Germany) was used as a combustion aid when the material was not sufficient (1).…”

Acutely reduced locomotor activity is a major contributor to Western diet-induced obesity in mice

“…Leptin increases uncoupling protein-1 (UCP1) expression in brown adipose tissue (BAT) (10,38), and leptin-deficient mice have a lower body temperature (4,39). Administration of leptin increases the activity of the sympathetic nervous system (8), which is known to alter diet-induced thermogenesis (2) that is linked to UCP activity in BAT [reviewed in (13)].…”