Central pre-proglucagon derived peptides: opportunities for treatment of obesity

Curr Pharm Des. 2003;9(17):1373-82. doi: 10.2174/1381612033454775.


Modern societies have moved from famine to feast and obesity and its co-morbidities now sweep the world as a global epidemic. Numerous scientific laboratories and pharmaceutical companies have taken the challenge and are now exploiting novel molecular targets for treatment of obesity. The pre-proglucagon system constitutes interesting candidates as potential targets for new anti-obesity drugs. In the periphery, pre-proglucagon derived peptides, Glucagon-Like Peptide-1 (GLP-1), Glucagon-Like Peptide-2 (GLP-2) and oxyntomodulin (OXM) are involved in a wide variety of physiological functions, including glucose homeostasis, gastric emptying, intestinal growth, insulin secretion as well as the regulation of food intake. Peripheral administration of GLP-1 derivatives and analogues to both rodents and man have shown promising effects on food intake and body weight suggesting that such therapies constitute potential anti-obesity treatment. In the central nervous system, pre-proglucagon and hence GLP-1, GLP-2 and OXM are exclusively found in a small population of nerve cells in the nucleus of the solitary tract. These constitute a neural pathway linking the "viscero-sensory" brainstem to hypothalamic nuclei involved in energy homeostasis. Intracerebroventricular administration of all of the three derived peptides robustly decrease food intake. It is evident that central GLP-1 agonism probably in combination with GLP-2 and/or OXM agonism constitute a potential pharmacological tool to reduce food intake and maybe also enhance energy expenditure. This and other aspects of the current state of the role of central pre-proglucagon in energy homeostasis are reviewed.

Publication types

  • Review

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Central Nervous System / metabolism*
  • Eating / drug effects
  • Glucagon / agonists
  • Glucagon / metabolism
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptides / agonists
  • Glucagon-Like Peptides / metabolism
  • Glucagon-Like Peptides / pharmacology
  • Humans
  • Obesity / drug therapy*
  • Oxyntomodulin
  • Peptide Fragments / agonists
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology
  • Peptides / agonists
  • Peptides / metabolism
  • Peptides / pharmacology
  • Proglucagon
  • Protein Precursors / agonists
  • Protein Precursors / metabolism
  • Protein Precursors / pharmacology*
  • Receptors, Glucagon / physiology


  • GLP1R protein, human
  • Glucagon-Like Peptide 2
  • Glucagon-Like Peptide-1 Receptor
  • Oxyntomodulin
  • Peptide Fragments
  • Peptides
  • Protein Precursors
  • Receptors, Glucagon
  • Proglucagon
  • Glucagon-Like Peptides
  • Glucagon-Like Peptide 1
  • Glucagon