Glucagon-Like Peptide-2 Directly Regulates Hypothalamic Neurons Expressing Neuropeptides Linked to Appetite Control in Vivo and in Vitro

Mar 15, 2012Endocrinology

Glucagon-like peptide-2 directly affects brain neurons that control appetite in living animals and lab tests

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Abstract

Central administration of h(Gly(2))GLP-2 in mice significantly suppressed food and water intake with acute weight loss at 2 hours.

h(Gly(2))GLP-2 administration activated specific brain regions associated with appetite regulation, as indicated by c-Fos expression.
Differential colocalization of neuropeptides with c-Fos was observed in various hypothalamic nuclei.
In vitro studies showed that h(Gly(2))GLP-2 treatment increased neurotensin and ghrelin mRNA levels by 50% and 95%, respectively.
The increase in neuropeptide levels is linked to protein kinase A pathway activation.
GLP-2 may influence appetite regulation through its effects on hypothalamic neuropeptides.

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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.

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Glucagon-Like Peptide-2 Directly Regulates Hypothalamic Neurons Expressing Neuropeptides Linked to Appetite Control in Vivo and in Vitro

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