Effects of a specific MCHR1 antagonist (GW803430) on energy budget and glucose metabolism in diet-induced obese mice

OBJECTIVE: The melanin-concentrating hormone (MCH) is a centrally acting peptide implicated in the regulation of energy homeostasis and body weight, although its role in glucose homeostasis is uncertain. Our objective was to determine effects of MCHR1 antagonism on energy budgets and glucose homeostasis in mice.

METHODS: Effects of chronic oral administration of a specific MCHR1 antagonist (GW803430) on energy budgets and glucose homeostasis in diet-induced obese (DIO) C57BL/6J mice were examined.

RESULTS: Oral administration of GW803430 for 30 days reduced food intake, body weight, and body fat. Circulating leptin and triglycerides were reduced but insulin and nonesterified fatty acids were unaffected. Despite weight loss there was no improvement in glucose homeostasis (insulin levels and intraperitoneal glucose tolerance tests). On day 4-6, mice receiving MCHR1 antagonist exhibited decreased metabolisable energy intake and increased daily energy expenditure. However these effects had disappeared by day 22-24. Physical activity during the dark phase was increased by MCHR1 antagonist treatment throughout the 30-day treatment.

CONCLUSIONS: GW803430 produced a persistent anti-obesity effect due to both a decrease in energy intake and an increase in energy expenditure via physical activity but did not improve glucose homeostasis.