Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS

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   Figure 1

   Proposed routes of action of GLP-1 in the central regulation of feeding and glucose metabolism. Gut-derived GLP-1 may affect the brain by several routes of action, i.e. indirectly, via neural afferents, and directly, by entering the brain via the systemic circulation and by crossing the blood-brain barrier. Other potential mediators constituting the gut–brain axis include nutrients and signals arising from meal-related gastric distension. GLP-1 secreted from intestinal L-cells in response to meal-ingestion, diffuses across the basal lamina into the lamina propria, at which level the uptake by capillaries and the degradation by DPP-4 occurs. Subsequently, endogenous GLP-1 activates intestinal vagal afferents, located in the gut or portal circulation, partly belonging to the enteric nervous system (ENS), which may activate GLP-1-producing neurons in the nucleus tractus solitarii (NTS). Additional activation of intestinal or portal vagal afferents by nutrients, other gut-hormones or gastric distension may also activate these GLP-1-producing neurons. These neurons project to several food-regulating areas, most of which contain GLP-1 receptors. These areas include the ventral tegmental area (VTA), the nucleus accumbens (NAc) and the hypothalamus (Hyp). Throughout the hypothalamus, the GLP-1 receptor is present, particularly in the paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH) and the arcuate nucleus (ARC), with a greater density on pro-opiomelanocortin (POMC) neurons (anorexigenic neurons) than on the agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons (orexigenic neurons). To date, no receptors have been found in the ventromedial hypothalamus (VMH). Less is known about the higher cortical centres that extend the circuitry beyond the hypothalamus, VTA and nucleus accumbens. Only 25% of the gut-derived GLP-1 reaches the portal circulation, where it can activate afferent hepatic vagal nerves, while merely 10–15% of gut-derived GLP-1 enters the systemic circulation and may access the brain through areas with a permeable blood-brain barrier, such as the area postrema (AP) and ARC. Efferent pathways, among others, originating in the brain stem (BS), subsequently signal to peripheral organs to close the loop of feeding behaviour and glucose metabolism regulation, both of which may be partly interlinked. Accordingly, GLP-1 lowers blood glucose by stimulating pancreatic insulin secretion and production, and by suppressing glucagon secretion from the pancreas and by enhancing hepatic insulin action in a glucose-dependent manner. Also, GLP-1-related effects promoting gastric emptying delay seem to be part of this regulatory loop. These actions may be due to direct effects of circulating gut-derived GLP-1 but, given the short circulating half-life of the incretin hormone, indirect, neurally mediated effects may contribute, even to a greater extent, to the efferent output to these organs.

• © 2014 Society for Endocrinology