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 F. Wainwright; Jacek Mokrosinski; Eloise Cross; I. Sadaf Farooqi; Natalie J.  Wallis; Lewis G. Halsey; Rory Wilson; Stephen O’Rahilly; Giles S.H.  Yeo; Eleanor Raffan

doi:10.1126/sciadv.adj3823

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 F. Wainwright, Jacek Mokrosinski, Eloise Cross, I. Sadaf Farooqi, Natalie J. Wallis, Lewis G. Halsey, Rory Wilson, Stephen O’Rahilly, Giles S.H. Yeo, Eleanor Raffan

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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.

Original language	English
Article number	adj3823
Pages (from-to)	1-12
Number of pages	12
Journal	Science Advances
Volume	10
Issue number	10
Early online date	6 Mar 2024
DOIs	https://doi.org/10.1126/sciadv.adj3823
Publication status	E-pub ahead of print - 6 Mar 2024

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© 2024 The Author(s), some rights reserved; exclusive licensee American Association for the Advancement of Science. This is an open access article distributed under the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/
Final published version, 1.2 MBLicence: CC BY

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Dittmann, M. T., Lakatos, G., Wainwright, J. F., Mokrosinski, J., Cross, E., Farooqi, I. S., Wallis, N. J., Halsey, L. G., Wilson, R., O’Rahilly, S., Yeo, G. S. H., & Raffan, E. (2024). Low resting metabolic rate and increased hunger due to β-MSH and β-endorphin deletion in a canine model. Science Advances, 10(10), 1-12. Article adj3823. Advance online publication. https://doi.org/10.1126/sciadv.adj3823

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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 alsohave 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 andmoderating energy expenditure and suggest that this role is independent of the presence of α-MSH.",

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AU - Mokrosinski, Jacek

AU - Cross, Eloise

AU - Farooqi, I. Sadaf

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AU - O’Rahilly, Stephen

AU - Yeo, Giles S.H.

AU - Raffan, Eleanor

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N2 - 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 alsohave 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 andmoderating energy expenditure and suggest that this role is independent of the presence of α-MSH.

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

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