Incretin hormones and the satiation signal

Abstract

Recent research has indicated that appetite-regulating hormones from the gut may have therapeutic potential. The incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral and central pathways mediating satiation. Several studies have also indicated that GLP-1 levels and responses to meals may be altered in obese subjects. Clinical trial results have shown further that two GLP-1 receptor agonists (GLP-1 RAs), exenatide and liraglutide, which are approved for the treatment of hyperglycemia in patients with type 2 diabetes, also produce weight loss in overweight subjects without diabetes. Thus, GLP-1 RAs may provide a new option for pharmacological treatment of obesity.

Figure 1

Physiological effects of GLP-1. Reprinted with permission from Drucker and Nauck, 2006.

Figure 2

The neural pathway for the actions of GLP-1. GLP-1 secretion is stimulated by nutrients in (a) the gut lumen, and newly released GLP-1 diffuses across the basal lamina into the lamina propria. On its way to the capillary, however, it may bind to and activate (f) sensory afferent neurons originating in the (c) nodose ganglion, which may, in turn, activate neurons of the NTS (a). The same pathway may be activated by sensory neurons in (e) the hepatoportal region or in (d) the liver tissue. Ascending fibers from the NTS may generate reflexes in the hypothalamus, and descending impulses (from neurons in the PVN?) may activate (b) vagal motor neurons, that send (h) stimulatory or (g) inhibitory impulses to the pancreas and the gastrointestinal tract. Interactions between ascending sensory nerve fibers and vagal motor neurons may also take place at the level of the brain stem. Reprinted with permission from Holst, 2007.

Figure 3

Mean changes in body weight with liraglutide, orlistat or placebo. Reprinted with permission from Astrup, 2009.