The Central Sirtuin 1/p53 Pathway Is Essential for the Orexigenic Action of Ghrelin
Open accessAbstract
OBJECTIVE: Ghrelin is a stomach-derived peptide that increases food intake through the activation of hypothalamic AMP-activated protein kinase (AMPK). However, the molecular mechanisms initiated by the activation of the ghrelin receptor, which in turn lead to AMPK activation, remain unclear. Sirtuin 1 (SIRT1) is a deacetylase activated in response to calorie restriction that acts through the tumor suppressor gene p53. We tested the hypothesis that the central SIRT1/p53 pathway might be mediating the orexigenic action of ghrelin. RESEARCH DESIGN AND METHODS: SIRT1 inhibitors, such as Ex527 and sirtinol, and AMPK activators, such as AICAR, were administered alongside ghrelin in the brain of rats and mice (wild-type versus p53 knockout [KO]). Their hypothalamic effects on lipid metabolism and changes in transcription factors and neuropeptides were assessed by Western blot and in situ hybridization. RESULTS: The central pretreatment with Ex527, a potent SIRT1 inhibitor, blunted the ghrelin-induced food intake in rats. Mice lacking p53, a target of SIRT1 action, failed to respond to ghrelin in feeding behavior. Ghrelin failed to phosphorylate hypothalamic AMPK when rats were pretreated with Ex527, as it did in p53 KO mice. It is noteworthy that the hypothalamic SIRT1/p53 pathway seems to be specific for mediating the orexigenic action of ghrelin, because central administration of AICAR, a potent AMPK activator, increased food intake in p53 KO mice. Finally, blockade of the central SIRT1 pathway did not modify ghrelin-induced growth hormone secretion. CONCLUSIONS: Ghrelin specifically triggers a central SIRT1/p53 pathway that is essential for its orexigenic action, but not for the release of growth hormone.
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SIRT1 activity is increased in the hypothalamus during starvation with high ghrelin levels.
“It is known that the SIRT1 activity is increased in hypothalamus during starvation with high ghrelin levels ([167](#B167)).”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [167]
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“, 2016) as well as the hypothalamus in adult rodents and mouse models of aging (Velasquez et al., 2011; Fujitsuka et al., 2016).”
BackgroundProtective effect of EX-527 against high-fat diet-induced diabetic nephropathy in Zucker rats
Kundu, A., Richa, S., Dey, P., Kim, K. S., Son, J. Y., Kim, H. R., Lee, S.-Y., Lee, B.-H., Lee, K. Y., Kacew, S., et al. (2020) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2020.114899 · Cited by 27 · see citing works
- Authors
- Velásquez, D. A., Martínez, G., Romero, A., Vázquez, M. J., Boit, K. D., Dopeso-Reyes, I. G., López, M., Vidal, A., Nogueiras, R., & Diéguez, C.
- Affiliations
- Department of Physiology, School of Medicine—Instituto de Investigaciones Sanitarias (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain
- Universidade de Santiago de Compostela (ES)
- Department of Cell Biology and Ecology, University of Santiago de Compostela, Santiago de Compostela, Spain
- Corresponding author
- Diéguez, Carlos
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-03-22
- Volume
- 60
- Issue
- 4
- Pages
- 1177-1185
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3064091
- OpenAlex
- W2140530719
- Cited by
- 161
- References
- 41
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 10 · 2023: 2 · 2022: 5 · 2021: 11 · 2020: 11 · 2019: 9 · 2018: 15 · 2017: 10 · 2016: 10 · 2015: 10 · 2014: 24 · 2013: 16 · 2012: 13
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- ghrelin, SIRT1, p53, AMPK, dietary intake, hypothalamus, EX527, sirtinol, AICAR, growth hormone secretion, caloric restriction, neuropeptides, lipid metabolism
- MeSH terms
- Animals, Benzamides, Carbazoles, Eating, Feeding Behavior, Male, Mice, Inbred C57BL, Naphthols, Phosphorylation, Blotting, Western, Tumor Suppressor Protein p53, Rats, Sprague-Dawley, In Situ Hybridization, Mice, Knockout, Mice, Rats, Ghrelin, AMP-Activated Protein Kinases, Sirtuin 1
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