Both GLP-1 and GLP-2 are produced in the brain, predominantly in brainstem neurons, following which the peptides are transported to diverse regions of the CNS. The GLP-2 receptor, originally cloned from the GI tract and brain, has been detected in the rodent brain using both RT-PCR and in situ hybridization techniques. In the rat, the GLP-2R is most abundant in the hypothalamic DMH.

Does GLP-2 control food intake? Intriguing  data from Tang-Christensen and colleagues suggest that GLP-2 like GLP-1, may regulate feeding behavior when injected into the brain of rats. Icv GLP-2 inhibited food intake in the rat, and surprisingly, the actions of GLP-2 were blocked by the GLP-1 receptor antagonist, exendin(9-39). To review the original data, see The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake. Nat Med 2000 Jul;6(7):802-7.

To assess the distribution of CNS GLP-2 receptor expression in mice, as well as the actions of GLP-2 in the murine brain, Lovshin and colleagues used RT-PCR and X-Gal staining to study the expression of the endogenous murine GLP-2R, as well as the expression pattern of a GLP-2R promoter-LacZ transgene. Unlike a previous report suggesting restriction of the rat CNS GLP-2R to the DMH, the mouse GLP-2R was more widely distributed in various CNS nuclei. Although large doses of icv GLP-2 also inhibited food intake in the mouse, these actions were not blocked by exendin(9-39). Furthermore, GLP-2 still inhibited food intake in GLP-1R-/- mice, indicating that the GLP-1R was not essential for transduction of an anorectic GLP-2 signal. See Glucagon-like peptide-2 action in the murine central nervous system is enhanced by elimination of GLP-1 receptor signaling.

Subsequent studies in rats using a combination of both RT-PCR and in situ hybridization analyses confirmed low level but detectable expression of the GLP-2 receptor in extrahypothalamic regions of both the developing and adult rodent central nervous system. Moreover, the GLP-2:GLP-2R system was functional in the CNS, coupled to activation of adenylyl cyclase, and GLP-2 protected cultured hippocampal cells from glutamate-induced cytotoxicity in vitro, as outlined in Extrahypothalamic expression of the Glucagon-like Peptide-2 (GLP-2) receptor is coupled to reduction of glutamate-induced cell death in cultured hippocampal cells. Endocrinology. 2004 Apr 1 [Epub ahead of print]

Unlike GLP-1 or exendin-4, which does inhibit food intake when administered peripherally to rodents or humans, peripheral administration of GLP-2 in human subjects has no effect on food intake, as observed in Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology. 2001 Mar;120(4):806-15. and No effect of physiological concentrations of glucagon-like peptide-2 on appetite and energy intake in normal weight subjects. Int J Obes Relat Metab Disord. 2003 Apr;27(4):450-6 and Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety. Regul Pept. 2003 Nov 15;116(1-3):21-5.

Does GLP-2 regulate cell proliferation in the brain? Previous studies have shown that the GLP-1 receptor is induced at the site of brain injury in the rat, and activation of the CNS GLP-1receptor may promote cell proliferation or protect cells from cytotoxic injury. Velazquez and colleagues have shown that the GLP-2 receptor is expressed in the rat cerebral cortex and in cultured rat astrocytes. Furthermore, GLP-2 stimulates cell proliferation and cAMP formation, and induced fos and jun expression in astrocyte cell cultures. See Glucagon-like peptide-2 stimulates the proliferation of cultured rat astrocytes. Eur J Biochem. 2003 Jul; 270(14):3001-9.

Disruption of the Glp2r gene in POMC neurons reveals a role for endogenous CNS GLP-2R signaling in the control of insulin sensitivity and glucose homeostasis as deletion of the GLP-2R impaired insulin action and glucose homeostasis whereas exogenous central GLP-2-2 enhanced insulin-mediated suppression of hepatic glucose homeostasis. Central GLP-2 Enhances Hepatic Insulin Sensitivity via Activating PI3K Signaling in POMC Neurons Cell Metab. 2013 Jul 2;18(1):86-98