Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4, Regulates Feeding-Associated Neuropeptides in Hypothalamic Neurons in Vivo and in Vitro

Dalvi, Prasad S.; Nazarians-Armavil, Anaies; Purser, Matthew J.; Belsham, Denise D.

doi:10.1210/en.2011-1795

Cited by 58 publications

(37 citation statements)

References 54 publications

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“…Acute EX-4-induced anorexia has been shown to be accompanied by activation of GLP-1R-expressing regions including the ARC, paraventricular nucleus, and dorsomedial nucleus of hypothalamus as assessed by c-Fos. Furthermore, double-labeling immunohistochemistry indicated that central EX-4 significantly activated POMC and NPY neurons in the ARC (56). In this study, we found that long-term EX-4 injection increased POMC and decreased NPY expression in both HF diet-fed rats and SC-fed rats.…”

Section: Discussionsupporting

confidence: 53%

Long Term Exendin-4 Treatment Reduces Food Intake and Body Weight and Alters Expression of Brain Homeostatic and Reward Markers

et al. 2014

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Repeated administration of the long-acting glucagon-like peptide 1 receptor agonist exendin-4 (EX-4) has been shown to reduce food intake and body weight and do so without a rebound increase in food intake after treatment termination. The current study examines the neural mechanisms underlying these actions. After 6 weeks of maintenance on a standard chow or a high-fat (HF) diet, male Sprague Dawley rats were treated with EX-4 (3.2 μg/kg, i.p., twice a day) or vehicle for 9 consecutive days. Food intake and body weight (BW) were monitored daily. Expression of the genes for the hypothalamic arcuate nucleus (ARC) peptides proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti gene-related protein was determined. Expression of the dopamine precursor tyrosine hydroxylase (TH) gene in the ventral tegmental area and genes for dopamine receptors 1 (D1R) and dopamine receptor 2 in the nucleus accumbens were also determined. Pair-fed groups were included to control for the effects of reduced food intake and BW. Treatment with EX-4 significantly decreased food intake and BW over the 9-day period in both the standard chow and HF groups. HF feeding decreased POMC without changing NPY/agouti gene-related protein gene expression in the ARC. Treatment with EX-4 increased POMC and decreased NPY expression independent of the reduction of food intake and BW. Mesolimbic TH and D1R gene expression were decreased significantly in chronic HF diet-fed rats, and these changes were reversed in both EX-4 and pair-fed conditions. These results suggest a role for increased POMC and decreased NPY expression in the ARC in the effects of EX-4 on food intake and BW. Our findings also suggest that EX-4 induced the recovery of mesolimbic TH and D1R expression in HF diet-fed rats may be secondary to HF intake reduction and/or weight loss.

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Section: Discussionsupporting

confidence: 53%

Long Term Exendin-4 Treatment Reduces Food Intake and Body Weight and Alters Expression of Brain Homeostatic and Reward Markers

et al. 2014

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“…Our findings indicate that GLP-2R activation involves complex interactions between several hypothalamic nuclei, acute activation of feeding-related neuropeptidergic neurons, and longer-term transcriptional regulation of downstream neuropeptides. Central h(Gly 2 )GLP-2 administration activated several hypothalamic regions with a distinct pattern of c-Fos expression in comparison with the long-acting GLP-1R agonist, exendin-4 (47). Not only the major nuclei that lie in the vicinity of the third ventricle were activated but also the lateral hypothalamus was activated.…”

Section: Discussionmentioning

confidence: 95%

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

Dalvi

Belsham²

2012

Endocrinology

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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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“…Numerous comprehensive studies aim to describe the GLP-1R population responsible for GLP-1-induced energy intake reduction (20,(33)(34)(35)(36)(37)(38)(39)(40)(41). This task has been hampered by the widespread distribution of the GLP-1R in the brain and in the periphery on neurons that could rapidly signal to the brain.…”

Section: Discussionmentioning

confidence: 99%

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

Secher¹,

Jelsing²,

Baquero³

et al. 2014

J. Clin. Invest.

693

673

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Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4, Regulates Feeding-Associated Neuropeptides in Hypothalamic Neurons in Vivo and in Vitro

Cited by 58 publications

References 54 publications

Long Term Exendin-4 Treatment Reduces Food Intake and Body Weight and Alters Expression of Brain Homeostatic and Reward Markers

Long Term Exendin-4 Treatment Reduces Food Intake and Body Weight and Alters Expression of Brain Homeostatic and Reward Markers

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

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

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