Role of the glucagon-like-peptide-1 receptor in the control of energy balance

Abstract

The peripheral and central glucagon-like-peptide-1 (GLP-1) systems play an essential role in glycemic and energy balance regulation. Thus, pharmacological targeting of peripheral and/or central GLP-1 receptors (GLP-1R) may represent a potential long-term treatment option for both obesity and type-II diabetes mellitus (T2DM). Uncovering and understanding the neural pathways, physiological mechanisms, specific GLP-1R populations, and intracellular signaling cascades that mediate the food intake inhibitory and incretin effects produced by GLP-1R activation are vital to the development of these potential successful therapeutics. Particular focus will be given to the essential role of the nucleus tractus solitarius (NTS) in the caudal brainstem, as well as the gut-to-brain communication by vagal afferent fibers in mediating the physiological and behavioral responses following GLP-1R activation. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

Figure 1

Proposed intracellular signaling pathways in nucleus tractus solitarius (NTS) glucagon-like-peptide-1 receptor (GLP-1R)-expressing neurons mediating suppression of intake by GLP-1R activation. Gastric vagal afferent signaling increases endogenous NTS-derived GLP-1 that acts on endemic NTS GLP-1R-expressing neurons to engage a cyclic AMP (cAMP)-dependent increase in protein kinase-A (PKA) activity. An increase in PKA activity drives a simultaneous increases in the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and decreases in adenosine monophosphate protein kinase (AMPK) activity. An increase in PKA and p44/42 MAPK activity together with a decrease in AMPK activity drives an increase in cAMP response element binding (CREB)-mediated nuclear transcription and protein synthesis, thus allowing the NTS-GLP-1R-expressing neurons to potentially integrate various anorectic signals involved in meal-to-meal food intake control. mTOR = mammalian target of rapamycin; CAMKK = Calmodulin-dependent protein kinase kinase; CAMKII = calcium/calmodulin-dependent protein kinase II; VGCC = voltage gated calcium channel; MEK = mitogen-activated protein kinase kinase.