Abstract
Glucagon exerts pleiotropic actions on energy balance and has emerged as an attractive target for the treatment of diabetes and obesity in the last few years. Glucagon reduces body weight and adiposity by suppression of appetite and by modulation of lipid metabolism. Moreover, this hormone promotes weight loss by activation of energy expenditure and thermogenesis. In this review, we cover these metabolic actions elicited by glucagon beyond its canonical regulation of glucose metabolism. In addition, we discuss recent developments of therapeutic approaches in the treatment of obesity and diabetes by dual- and tri-agonist molecules based on combinations of glucagon with other peptides. New strategies using these unimolecular polyagonists targeting the glucagon receptor (GCGR), have become successful approaches to evaluate the multifaceted nature of glucagon signaling in energy balance and metabolic syndrome.
Highlights
BackgroundIn the early 1920s, Kimball and Murlin [1] reported that extracts of pancreatic tissue produced a hyperglycemic response, due to a circulating factor that was identified as glucagon
We have reviewed studies of glucagon action focusing on the energy balance regulation beyond glucose control
We summarized some of therapeutic efforts directed at manipulating glucagon receptor (GCGR) signaling for the treatment of metabolic diseases
Summary
In the early 1920s, Kimball and Murlin [1] reported that extracts of pancreatic tissue produced a hyperglycemic response, due to a circulating factor that was identified as glucagon. This pancreatic hormone is a 29-amino-acid peptide released from the α-cells of the islet of Langerhans, and has for long been recognized as the principal counter-regulatory hormone to insulin in response to low glucose [2,3]. Glucagon and glucagon-like peptides are transcribed from a common proglucagon gene, a peptide precursor of 160 amino acids, that is expressed in pancreatic islet α-cells, in a specific population of enteroendocrine cells (L-cells) of the intestinal mucosa, and in a set of neurons in the nucleus tractus solitarius (NTS) of the medulla oblongata [4,5]
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