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Ghrelin, obesity and diabetes

Abstract

The high prevalence of obesity and diabetes will lead to higher rates of morbidity and mortality. The search for drugs to treat these metabolic disorders has, therefore, intensified. The stomach-derived peptide ghrelin regulates food intake and body weight. Recent work suggests that ghrelin also controls glucose metabolism. In addition, current evidence suggests that most of the actions of ghrelin could contribute to the metabolic syndrome. The ghrelin signaling system is, therefore, a promising target for the development of new drugs for the treatment of obesity and diabetes. Agents that block the ghrelin signaling system might be especially useful targets. This Review summarizes the potential and the limitations of ghrelin as a tool to better understand, prevent and treat obesity and diabetes.

Key Points

  • Ghrelin is a peptide hormone derived from the stomach and gastrointestinal tract that predominantly controls energy balance and glucose homeostasis

  • Ghrelin mainly affects metabolism through the G-protein-coupled growth hormone secretagogue receptor 1a (GHS-R1a) in the brain

  • Pharmacologic ghrelin treatment in rodents leads to sustained gain of fat mass induced by increased food intake, decreased fat oxidation rates, altered nutrient partitioning, increased lipogenesis in adipose tissue and decreased thermogenesis

  • Ghrelin-deficient mouse models possess improved peripheral insulin sensitivity, and descriptive studies in humans and rodents suggest an inverse relationship between plasma ghrelin levels and insulin resistance and type 2 diabetes

  • Constituting a classical combination of a peptide hormone and a G-protein-coupled receptor (with additional ligands and receptors possibly to be discovered), there is reasonable potential to target the ghrelin–GHS-R system pharmacologically, whereas possible GHS-R1a-independent ghrelin effects represent a less defined and more complicated target

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Figure 1: The effects of ghrelin on the CNS, and subsequent glucose, lipid and energy metabolism.

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Acknowledgements

R Nogueiras is a recipient of a Marie Curie Outgoing International Fellowship.

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Wiedmer, P., Nogueiras, R., Broglio, F. et al. Ghrelin, obesity and diabetes. Nat Rev Endocrinol 3, 705–712 (2007). https://doi.org/10.1038/ncpendmet0625

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