Low resting metabolic rate and increased hunger due to β-MSH and β-endorphin deletion in a canine model
Marie T. Dittmann, Gabriella Lakatos, Jodie Wainwright, Jacek Mokrosiński, Eloise Cross, I. Sadaf Farooqi, Natalie Wallis, Lewis G. Halsey, Rory P. Wilson, Stephen O’Rahilly, Giles S.H. Yeo, Eleanor Raffan
Abstract
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 β–melanocyte-stimulating hormone (β-MSH) and β-endorphin but not α-MSH; humans, similar to dogs, produce α-MSH and β-MSH from the POMC propeptide, but rodents produce only α-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 β-MSH signals comparably to α-MSH at melanocortin receptors. These data implicate β-MSH and β-endorphin as important in determining hunger and moderating energy expenditure and suggest that this role is independent of the presence of α-MSH.