Lessons from extreme human obesity: monogenic disorders

Endocrinol Metab Clin North Am. 2008 Sep;37(3):733-51, x. doi: 10.1016/j.ecl.2008.07.003.


Human obesity has a strong genetic component. Most genes that influence an individual's predisposition to gain weight are not yet known. However, the study of extreme human obesity caused by single gene defects has provided a glimpse into the long-term regulation of body weight. These monogenic obesity disorders have confirmed that the hypothalamic leptin-melanocortin system is critical for energy balance in humans, because disruption of these pathways causes the most severe obesity phenotypes. Approximately 20 different genes and at least three different mechanisms have been implicated in monogenic causes of obesity; however, they account for fewer than 5% of all severe obesity cases. This finding suggests that the genetic basis for human obesity is likely to be extremely heterogeneous, with contributions from numerous genes acting by various, yet undiscovered, molecular mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bardet-Biedl Syndrome / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Brain-Derived Neurotrophic Factor / genetics
  • Humans
  • Leptin / genetics
  • Mutation*
  • Obesity / genetics*
  • Pro-Opiomelanocortin / genetics
  • Proprotein Convertase 1 / genetics
  • Receptor, Melanocortin, Type 4 / genetics
  • Receptors, Leptin / genetics
  • Repressor Proteins / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • Brain-Derived Neurotrophic Factor
  • Leptin
  • MC4R protein, human
  • Receptor, Melanocortin, Type 4
  • Receptors, Leptin
  • Repressor Proteins
  • SIM1 protein, human
  • Pro-Opiomelanocortin
  • Proprotein Convertase 1