Glucagon-like peptide-2 directly regulates hypothalamic neurons expressing neuropeptides linked to appetite control in vivo and in vitro.

Abstract

Glucagon-like peptide-2 (GLP-2), a proglucagon-derived peptide, has been postulated to affect appetite at the level of the hypothalamus. To gain better insight into this process, a degradation-resistant GLP-2 analog, human (Gly(2))GLP-2(1-33) [h(Gly(2))GLP-2] was intracerebroventricularly injected into mice to examine its action on food and water intake and also activation of hypothalamic anorexigenic α-melanocyte-stimulating hormone/proopiomelanocortin, neurotensin, and orexigenic neuropeptide Y, and ghrelin neurons. Central h(Gly(2))GLP-2 administration significantly suppressed food and water intake with acute weight loss at 2 h. Further, central h(Gly(2))GLP-2 robustly induced c-Fos activation in the hypothalamic arcuate, dorsomedial, ventromedial, paraventricular, and the lateral hypothalamic nuclei. We found differential colocalization of neuropeptides with c-Fos in specific regions of the hypothalamus. To assess whether hypothalamic neuropeptides are directly regulated by GLP-2 in vitro, we used an adult-derived clonal, immortalized hypothalamic cell line, mHypoA-2/30, that endogenously expresses functional GLP-2 receptors (GLP-2R) and two of the feeding-related neuropeptides linked to GLP-2R activation in vivo: neurotensin and ghrelin. Treatment with h(Gly(2))GLP-2 stimulated c-Fos expression and phosphorylation of cAMP response element-binding protein/activating transcription factor-1. In addition, treatment with h(Gly(2))GLP-2 significantly increased neurotensin and ghrelin mRNA transcript levels by 50 and 95%, respectively, at 24 h after treatment in protein kinase A-dependent manner. Taken together, these findings implicate the protein kinase A pathway as the means by which GLP-2 can up-regulate hypothalamic neuropeptide mRNA levels and provide evidence for a link between central GLP-2R activation and specific hypothalamic neuropeptides involved in appetite regulation.

• Authors: Prasad S Dalvi, Denise D Belsham
• Journal: Endocrinology (Endocrinology) Vol. 153 Issue 5 Pg. 2385-97 (May 2012) ISSN: 1945-7170 [Electronic] United States
• PMID: 22416082 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ghrelin
• Glucagon-Like Peptide 2
• Neuropeptide Y
• Proto-Oncogene Proteins c-fos
• Neurotensin
• Pro-Opiomelanocortin

Topics

• Animals
• Dose-Response Relationship, Drug
• Drinking (drug effects, physiology)
• Eating (drug effects, physiology)
• Ghrelin (genetics, metabolism)
• Glucagon-Like Peptide 2 (pharmacology)
• Hypothalamus (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microinjections
• Neurons (drug effects, metabolism)
• Neuropeptide Y (genetics, metabolism)
• Neurotensin (genetics, metabolism)
• Pro-Opiomelanocortin (genetics, metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)