SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus
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Diet restriction retards aging and extends lifespan by triggering adaptive mechanisms that alter behavioral, physiological, and biochemical responses in mammals. Little is known about the molecular pathways evoking the corresponding central response. One factor that mediates the effects of diet restriction is the mammalian nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1. Here we demonstrate that diet restriction significantly increases SIRT1 protein levels and induces neural activation in the dorsomedial and lateral hypothalamic nuclei. Increasing SIRT1 in the brain of transgenic (BRASTO) mice enhances neural activity specifically in these hypothalamic nuclei, maintains a higher range of body temperature, and promotes physical activity in response to different diet-restricting paradigms. These responses are all abrogated in Sirt1-deficient mice. SIRT1 upregulates expression of the orexin type 2 receptor specifically in these hypothalamic nuclei in response to diet-restricting conditions, augmenting response to ghrelin, a gut hormone whose levels increase in these conditions. Our results suggest that in the hypothalamus, SIRT1 functions as a key mediator of the central response to low nutritional availability, providing insight into the role of the hypothalamus in the regulation of metabolism and aging in mammals.
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SIRT1 level is increased by dietary restriction in multiple brain regions, including hypothalamus, hippocampus, and cortex.
“Several lines of evidence have shown that SIRT1 level is increased by DR in multiple brain regions, including hypothalamus, hippocampus, and cortex [103,104,161,162].”
From Dietary Restriction and Neuroinflammation: A Potential Mechanistic Link (2019) · cites this paper as [104]
The Results section reports increased SIRT1 protein levels after dietary restriction in three hypothalamic nuclei. It also reports SIRT1 expression in the hippocampus and cortex, but does not show that dietary restriction increased its levels there; the reported absence of an increase in those regions concerns cFOS-positive cells, not SIRT1. Page numbers were not available in our copy. (LLM, conf=0.90)
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- Authors
- Satoh, A., Brace, C. S., Ben-Josef, G., West, T., Wozniak, D. F., Holtzman, D. M., Herzog, E. D., & Imai, S.-I.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Imai, Shin-ichiro
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-07-28
- Volume
- 30
- Issue
- 30
- Pages
- 10220-10232
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2922851
- OpenAlex
- W2082921977
- Cited by
- 237
- References
- 66
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 11 · 2023: 9 · 2022: 14 · 2021: 13 · 2020: 20 · 2019: 9 · 2018: 20 · 2017: 9 · 2016: 18 · 2015: 13 · 2014: 23 · 2013: 16 · 2012: 25
- FWCI
- 8.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- Ellison Medical Foundation
- Longer Life Foundation
- Japan Society for the Promotion of Science
- National Institute on Aging (R01AG024150, AG02150)
- National Institute of Mental Health (R01MH063104)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- SIRT1, dietary restriction, hypothalamus, dorsomedial hypothalamus, lateral hypothalamic nucleus, ghrelin, NAD+-dependent deacetylase, aging, lifespan extension, body temperature, physical activity, metabolic regulation, neuronal activation
- MeSH terms
- Adaptation, Physiological, Animals, Body Temperature, Brain, Dorsomedial Hypothalamic Nucleus, Enzyme-Linked Immunosorbent Assay, Female, Food Deprivation, Hypothalamic Area, Lateral, Male, Mice, Inbred C57BL, Motor Activity, Neurons, RNA, Messenger, Up-Regulation, Receptors, Neuropeptide, Statistics, Nonparametric, Microdissection, Receptors, G-Protein-Coupled, Chromatin Immunoprecipitation, Mice, Ghrelin, Sirtuin 1, Orexin Receptors
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