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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 &amp;gt;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.

MCH−/− Mice Are Resistant to Aging-Associated Increases in Body Weight and Insulin Resistance