Low resting metabolic rate and increased hunger due to -MSH and -endorphin deletion in a canine model

Mutations that perturb leptin-melanocortin signaling are known to cause hyperphagia and obesity, but energy expenditure has not been well studied outside rodents. We report on a common canine mutation in pro-opiomelanocortin (POMC), which prevents production of beta-melanocyte-stimulating hormone (beta-MSH) and beta-endorphin but not alpha-MSH; humans, similar to dogs, produce alpha-MSH and beta-MSH from the POMC propeptide, but rodents produce only alpha-MSH. We show that energy expenditure is markedly lower in affected dogs, which also have increased motivational salience in response to a food cue, indicating increased wanting or hunger. There was no difference in satiety at a modified ad libitum meal or in their hedonic response to food, nor disruption of adrenocorticotropic hormone (ACTH) or thyroid axes. In vitro, we show that beta-MSH signals comparably to alpha-MSH at melanocortin receptors. These data implicate beta-MSH and beta-endorphin as important in determining hunger and moderating energy expenditure and suggest that this role is independent of the presence of alpha-MSH.