MCH

MCH activates MCHR1, a Gi/Go-coupled GPCR highly expressed in the nucleus accumbens, cortex, hippocampus, and hypothalamus. Receptor activation reduces cAMP, activates MAPK, and modulates neuronal excitability. In the nucleus accumbens, MCHR1 activation enhances reward-related feeding behavior, while hypothalamic activation promotes energy conservation.

MCH neurons fire exclusively during REM sleep and are quiescent during wakefulness, in contrast to orexin neurons which fire during wakefulness. MCH promotes REM sleep when administered ICV and increases hippocampal theta oscillations. MCHR1 antagonists reduce REM sleep duration. This opposing relationship with orexin suggests MCH and orexin balance sleep-wake cycling.

MCH-null mice are lean with increased metabolic rate despite normal food intake. MCH overexpressing mice develop obesity even on a normal diet. Peripheral MCHR1 antagonists reduce body weight in rodent obesity models by 5-15% without the food intake effects of central MCHR1 blockade, suggesting peripheral MCH signaling contributes to fat storage and thermogenesis.

Several MCHR1 antagonists (including ATC0065 and AZD1979) have entered Phase 1/2 clinical trials for obesity. Modest weight loss of 3-5% was observed in early trials, though effects were less robust than expected from rodent models. The disconnect between species may reflect the absence of MCHR2 in rodents, which complicates translational modeling.