A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance

Yung Seng Lee; Ben G. Challis; Darren A. Thompson; Giles S.H. Yeo; Julia M. Keogh; Michael E. Madonna; Vicki Wraight; Matthew Sims; Vincent Vatin; David Meyre; Julian Shield; Christine Burren; Zala Ibrahim; Tim Cheetham; Peter Swift; Anthea Blackwood; Chiao Chien Connie Hung; Nicholas J. Wareham; Philippe Froguel; Glenn L. Millhauser; Stephen O'Rahilly; I. Sadaf Farooqi

doi:10.1016/j.cmet.2006.01.006

A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance

Yung Seng Lee, Ben G. Challis, Darren A. Thompson, Giles S.H. Yeo, Julia M. Keogh, Michael E. Madonna, Vicki Wraight, Matthew Sims, Vincent Vatin, David Meyre, Julian Shield, Christine Burren, Zala Ibrahim, Tim Cheetham, Peter Swift, Anthea Blackwood, Chiao Chien Connie Hung, Nicholas J. Wareham, Philippe Froguel, Glenn L. MillhauserStephen O'Rahilly^*, I. Sadaf Farooqi

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, α- and β-MSH, the majority of attention has focused on α-MSH, partly reflecting the absence of β-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding β-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type β-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for β-MSH in the control of human energy homeostasis.

Original language	English
Pages (from-to)	135-140
Number of pages	6
Journal	Cell Metabolism
Volume	3
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2006.01.006
Publication status	Published - Feb 2006

Bibliographical note

Funding Information:
Y.S.L. was supported by an International Fellowship from The Agency for Science, Technology and Research, Singapore. This work was supported by the Wellcome Trust (G.S.H.Y., I.S.F., and S.O.R.) and the Medical Research Council (S.O.R., N.J.W., and P.F.) and the U.S. National Institutes of Health (G.L.M., DK64265). We are indebted to the patients and their families for their participation and to the physicians involved in the Genetics of Obesity Study (GOOS).

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

Keywords

Humdisease
Molneuro

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lee, Y. S., Challis, B. G., Thompson, D. A., Yeo, G. S. H., Keogh, J. M., Madonna, M. E., Wraight, V., Sims, M., Vatin, V., Meyre, D., Shield, J., Burren, C., Ibrahim, Z., Cheetham, T., Swift, P., Blackwood, A., Hung, C. C. C., Wareham, N. J., Froguel, P., ... Farooqi, I. S. (2006). A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance. Cell Metabolism, 3(2), 135-140. https://doi.org/10.1016/j.cmet.2006.01.006

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title = "A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance",

abstract = "The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, α- and β-MSH, the majority of attention has focused on α-MSH, partly reflecting the absence of β-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding β-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type β-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for β-MSH in the control of human energy homeostasis.",

keywords = "Humdisease, Molneuro",

author = "Lee, {Yung Seng} and Challis, {Ben G.} and Thompson, {Darren A.} and Yeo, {Giles S.H.} and Keogh, {Julia M.} and Madonna, {Michael E.} and Vicki Wraight and Matthew Sims and Vincent Vatin and David Meyre and Julian Shield and Christine Burren and Zala Ibrahim and Tim Cheetham and Peter Swift and Anthea Blackwood and Hung, {Chiao Chien Connie} and Wareham, {Nicholas J.} and Philippe Froguel and Millhauser, {Glenn L.} and Stephen O'Rahilly and Farooqi, {I. Sadaf}",

note = "Funding Information: Y.S.L. was supported by an International Fellowship from The Agency for Science, Technology and Research, Singapore. This work was supported by the Wellcome Trust (G.S.H.Y., I.S.F., and S.O.R.) and the Medical Research Council (S.O.R., N.J.W., and P.F.) and the U.S. National Institutes of Health (G.L.M., DK64265). We are indebted to the patients and their families for their participation and to the physicians involved in the Genetics of Obesity Study (GOOS). Copyright: Copyright 2008 Elsevier B.V., All rights reserved.",

year = "2006",

month = feb,

doi = "10.1016/j.cmet.2006.01.006",

language = "English",

volume = "3",

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Lee, YS, Challis, BG, Thompson, DA, Yeo, GSH, Keogh, JM, Madonna, ME, Wraight, V, Sims, M, Vatin, V, Meyre, D, Shield, J , Burren, C, Ibrahim, Z, Cheetham, T, Swift, P, Blackwood, A, Hung, CCC, Wareham, NJ, Froguel, P, Millhauser, GL, O'Rahilly, S & Farooqi, IS 2006, 'A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance', Cell Metabolism, vol. 3, no. 2, pp. 135-140. https://doi.org/10.1016/j.cmet.2006.01.006

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T1 - A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance

AU - Lee, Yung Seng

AU - Challis, Ben G.

AU - Thompson, Darren A.

AU - Yeo, Giles S.H.

AU - Keogh, Julia M.

AU - Madonna, Michael E.

AU - Wraight, Vicki

AU - Sims, Matthew

AU - Vatin, Vincent

AU - Meyre, David

AU - Shield, Julian

AU - Burren, Christine

AU - Ibrahim, Zala

AU - Cheetham, Tim

AU - Swift, Peter

AU - Blackwood, Anthea

AU - Hung, Chiao Chien Connie

AU - Wareham, Nicholas J.

AU - Froguel, Philippe

AU - Millhauser, Glenn L.

AU - O'Rahilly, Stephen

AU - Farooqi, I. Sadaf

N1 - Funding Information: Y.S.L. was supported by an International Fellowship from The Agency for Science, Technology and Research, Singapore. This work was supported by the Wellcome Trust (G.S.H.Y., I.S.F., and S.O.R.) and the Medical Research Council (S.O.R., N.J.W., and P.F.) and the U.S. National Institutes of Health (G.L.M., DK64265). We are indebted to the patients and their families for their participation and to the physicians involved in the Genetics of Obesity Study (GOOS). Copyright: Copyright 2008 Elsevier B.V., All rights reserved.

PY - 2006/2

Y1 - 2006/2

N2 - The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, α- and β-MSH, the majority of attention has focused on α-MSH, partly reflecting the absence of β-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding β-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type β-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for β-MSH in the control of human energy homeostasis.

AB - The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, α- and β-MSH, the majority of attention has focused on α-MSH, partly reflecting the absence of β-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding β-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type β-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for β-MSH in the control of human energy homeostasis.

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DO - 10.1016/j.cmet.2006.01.006

M3 - Article (Academic Journal)

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AN - SCOPUS:33645048441

SN - 1550-4131

VL - 3

SP - 135

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JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance

Abstract

Bibliographical note

Keywords

UN SDGs

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