Dysregulation of the mesolimbic dopamine system and reward in MCH-/- mice.

BACKGROUND: The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays a critical role in energy homeostasis. Abundant expression of the MCH receptor is observed outside the hypothalamus, especially in the dorsal and the ventral striatum, raising the possibility that MCH modulates the function of the midbrain dopamine neurons and associated circuitry. METHODS: The MCH receptor 1 (MCHR1) expression was assessed by in situ hybridization. Expression of dopamine transporter (DAT) and the dopamine D1 and D2 receptor (D1R and D2R) subtypes in the caudate-putamen (CPu) and the nucleus accumbens (Acb) was evaluated by immunoblotting. Amperometry in ex vivo slices of the Acb was used to measure evoked-dopamine release in MCH-/ - mice. Catalepsy in MCH+/+ and MCH-/- mice was assessed by the bar test after haloperidol injection. Locomotor activity was measured after acute and chronic treatment with amphetamine and after dopamine reuptake inhibitor GBR 12909 administration. RESULTS: The psychostimulant amphetamine caused enhanced behavioral sensitization in MCH-/- mice. We found significantly elevated expression of the DAT in the Acb of MCH-/- mice. The DAT-mediated uptake of dopamine was also enhanced in MCH-/- mice consistent with increased expression of DAT. We also found that evoked dopamine release is significantly increased in the Acb shell of MCH-/- mice. The GBR 12909 administration increased the locomotor activity of MCH-/- mice significantly above that of MCH+/+ mice. CONCLUSIONS: These results demonstrate that MCH, in addition to its known role in feeding and weight regulation, plays a critical role in regulating Acb dopamine signaling and related behavioral responses.

MCH-/- mice are resistant to aging-associated increases in body weight and insulin resistance.

Ablation of the hypothalamic peptide, melanin-concentrating hormone (MCH), leads to a lean phenotype and resistance to diet-induced obesity. Observation of MCH(-/-) mice at older ages suggested that these effects persist in mice >1 year old. Leanness secondary to caloric restriction is known to be associated with improved glucose tolerance as well as an overall increase in life span. Because the MCH(-/-) model represents leanness secondary to increased energy expenditure rather than caloric restriction, we were interested in determining whether this model of leanness would be associated with beneficial metabolic effects at older ages. To assess the effects of MCH ablation over a more prolonged period, we monitored male and female MCH(-/-) mice up to 19 months. The lean phenotype of MCH(-/-) mice persisted over the duration of the study. At 19 months, MCH(-/-) male and female mice weighed 23.4 and 30.8% less than their wild-type counterparts, a result of reduced fat mass in MCH(-/-) mice. Aged MCH(-/-) mice exhibited better glucose tolerance and were more insulin sensitive compared with wild-type controls. Aging-associated decreases in locomotor activity were also attenuated in MCH(-/-) mice. We also evaluated two molecules implicated in the pathophysiology of aging, p53 and silent inflammatory regulator 2 (Sir2). We found that expression of the tumor suppressor protein p53 was higher in MCH(-/-) mice at 9 and 19 months of age. In contrast, expression of Sir2 was unchanged. In aggregate, these findings suggest that MCH ablation improves the long-term outcome for several indicators of the aging process.

Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms.

Genetics and environment contribute to the development of obesity, in both humans and rodents. However, the potential interaction between genes important in energy balance, strain background, and dietary environment has been only minimally explored. We investigated the effects of genetic ablation of melanin-concentrating hormone (MCH), a neuropeptide with a key role in energy balance, with chow and a high-fat diet (HFD) in two different mouse strains, one obesity-prone (C57BL/6) and the other obesity-resistant (129). Substantial differences were seen in wild-type (WT) animals of different strains. 129 animals had significantly lower levels of spontaneous locomotor activity than C57BL/6; however, 129 mice gained less weight on both chow and HFD. In both strains, deletion of MCH led to attenuated weight gain compared with WT counterparts, an effect secondary to increased energy expenditure. In both strains, feeding a HFD led to further increases in energy expenditure in both WT and MCH-KO mice; however, this increase was more pronounced in 129 mice. In addition, mice lacking MCH have a phenotype of increased locomotor activity, an effect also seen in both strains. The relative increase in activity in MCH(-/-) mice is modest in animals fed chow but increases substantially when animals are placed on HFD. These studies reinforce the important role of MCH in energy homeostasis and indicate that MCH is a plausible target for antiobesity therapy.