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

Lookup NU author(s): Professor Timothy Cheetham

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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, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-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 beta-MSH, Tyr221 Cys. 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 beta-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 beta-MSH in the control of human energy homeostasis.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Cell Metabolism

Year: 2006

Volume: 3

Issue: 2

Pages: 135-140

ISSN (print): 1550-4131

ISSN (electronic): 1932-7420

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.cmet.2006.01.006

DOI: 10.1016/j.cmet.2006.01.006

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