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

Yung Seng Lee1, Ben G Challis, Darren A Thompson

  • 1University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, CB2 2XY, United Kingdom.

Cell Metabolism
|February 7, 2006
PubMed

Insights

A rare genetic variant in beta-melanocyte-stimulating hormone (beta-MSH) is linked to severe obesity. This beta-MSH variant impairs receptor binding, affecting energy balance and causing hyperphagia in children.

Area of Science:

  • Endocrinology
  • Genetics
  • Metabolism

Background:

  • The melanocortin-4 receptor (MC4R) is crucial for regulating energy balance.
  • Pro-opiomelanocortin (POMC) yields two ligands: alpha-MSH and beta-MSH, with alpha-MSH historically receiving more research focus.
  • Beta-MSH's role in human energy homeostasis is less understood, partly due to its absence in rodents.

Purpose of the Study:

  • To investigate the role of beta-melanocyte-stimulating hormone (beta-MSH) in human energy homeostasis.
  • To screen for genetic variants in the POMC gene associated with severe, early-onset obesity.

Main Methods:

  • Screened the POMC gene in 538 patients with severe, early-onset obesity.
  • Identified and analyzed a rare missense variant, Tyr221Cys, in the beta-MSH region.
  • Assessed the variant peptide's binding and signaling capabilities at the MC4R.
  • Examined cosegregation of the variant with obesity in affected families.

Main Results:

  • A significantly increased frequency of the Tyr221Cys beta-MSH variant was found in obese patients compared to the general population (p < 0.001).
  • The Tyr221Cys variant peptide demonstrated impaired binding to and activation of the MC4R.
  • Obese children with the variant exhibited hyperphagia and increased linear growth, consistent with MC4R deficiency.

Conclusions:

  • The Tyr221Cys variant in beta-MSH is associated with severe, early-onset obesity.
  • Impaired MC4R signaling by the variant beta-MSH contributes to hyperphagia and altered energy balance.
  • These findings highlight beta-MSH's significant role in human energy homeostasis.

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