MCH

MCH activates MCHR1, a Gi/Go-coupled GPCR that inhibits adenylyl cyclase and activates ERK/MAPK pathways. In the arcuate nucleus and other hypothalamic energy balance centers, MCHR1 activation inhibits NPY/AgRP neuron inhibition and reduces POMC neuron activity, producing a net pro-feeding state. MCHR1 activation also modulates dopamine release in the nucleus accumbens, contributing to reward-driven eating.

MCH neuronal activity increases during fasting and decreases after feeding. Central MCH injection rapidly and potently increases food intake and, with chronic administration, produces obesity. MCH overexpressing transgenic mice develop obesity and insulin resistance, while MCH or MCHR1 knockout mice are lean with increased metabolic rate. These genetic data establish MCH as a major orexigenic driver of energy surplus.

Multiple MCHR1 antagonists (ALB-127158, GW803430, ATC0175) have been evaluated in Phase I/II trials for obesity. While animal data strongly supported the approach, human trials showed modest weight loss results, complicated by CNS side effects (mood, anxiety) reflecting MCH's broad limbic system expression. Development of peripherally restricted MCHR1 antagonists continues.

MCH neurons are active during REM sleep and MCHR1 activation promotes REM sleep. MCH knockout mice show reduced REM sleep and sleep fragmentation. Conversely, MCH neuronal activation promotes sleep onset. These findings position the MCH system as a therapeutic target for REM sleep disorders and insomnia.

MCHR1 antagonists produce antidepressant and anxiolytic effects in rodent behavioral models without sedation. MCH overexpression in limbic circuits produces depression-like and anxiety-like behaviors. The MCH/MCHR1 system overlaps with circuits governing stress responses and reward, making it a candidate for mood disorder treatment.