Ghrelin, the proglucagon-derived peptides and peptide YY in nutrient homeostasis

Abstract

Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2 diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide (GLP)-1, GLP-2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in the clinic for the treatment of obesity and type 2 diabetes mellitus.

β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

“…It is also noteworthy that signals from the autonomic nervous system so prominently impact ghrelin secretion, especially given the inherent nutrient-sensing, enteroendocrine nature of most ghrelin cells (71,72). While recognition by ghrelin cells of dietary metabolites -and, in particular, their sensing of low glucose levels -could drive the modest increase in plasma ghrelin levels observed in GC-β1AR -/-mice upon a 24-hour fast or severe caloric restriction, the levels achieved are far lower than those in mice with intact ghrelin cell β 1 AR signaling.…”

Murine GLUTag Cells

“…Furthermore, GLP-1 secretion is stimulated by long-chain monounsaturated fatty acids, such as oleic acid, but not by similar length saturated fatty acids such as palmitic acid, in agreement with previous observations in primary L-cell cultures. The effects of oleic acid on GLP-1 secretion are known to be mediated by the atypical isozyme protein kinase C ζ in GLUTag cells, as also found in vivo (Iakoubov et al 2007 ;Dong and Brubaker 2012 ), while a role for fatty acid transport protein 4 in the uptake of oleic acid by GLUTag cells has also been demonstrated (Poreba et al 2012 ).…”

“…Such indirect actions are particularly important to GLP-1 release, since L-cells are mainly concentrated in the distal ileum and colon (Dong and Brubaker 2012 ), and nutrients have not reached this area of the gastrointestinal tract when the initial phase of prandial GLP-1 secretion is triggered. Initially, a neurohormonal mechanism, involving the vagus nerve, was shown to mediate the very rapid rise in GLP-1 levels after nutrient ingestion (Dong and Brubaker 2012 ). Consistent with this hypothesis, a stimulatory effect of two muscarinic agonists, bethanechol and carbachol, has been found in GLUTag cells (Brubaker et al 1998 ), although expression of muscarinic receptors by this cell line has not been reported to date.…”

“…Nutrient ingestion is the most powerful mechanism for triggering GLP-1 secretion by the intestinal L-cell (Dong and Brubaker 2012 Carbohydrates GLUTag cells are highly sensitive to glucose, such that cells that are propagated at 5 mmol/L concentration of glucose become quiescent and hyperpolarized when this monosaccharide is removed from the medium. Accordingly, when glucose is added back to the bath solution, the membrane conductance decreases, and the frequency of action potentials in the cells, as well as the secretion of GLP-1 are strongly enhanced, even at very low glucose concentrations (Reimann and Gribble 2002 ).…”

“…Overall, these effects made GLP-1 a promising novel therapeutic tool for the treatment of type 2 diabetes mellitus, and GLP-1 derivative drugs have been successfully used to reduce glycemia in patients with type 2 diabetes since 2005. These anti-diabetic agents include agonists of the GLP-1 receptor long-lasting analogues of the native peptide and inhibitors of the enzyme responsible for the rapid degradation of the active forms of GLP-1 (Dong and Brubaker 2012 ). Interestingly, potentiation of the endogenous secretion of the peptide is another possible therapeutic approach which has gained much attention lately; however, a better understanding of the processes regulating GLP-1 secretion by the intestinal L-cell (an enteroendocrine type of cell which is the major source of circulating GLP-1 in the body) is still required.…”