Rapamycin-induced metabolic defects are reversible in both lean and obese mice
Open accessAbstract
The inhibition of mTOR (mechanistic target of rapamycin) by the macrolide rapamycin has many beneficial effects in mice, including extension of lifespan and reduction or prevention of several age-related diseases. At the same time, chronic rapamycin treatment causes impairments in glucose metabolism including hyperglycemia, glucose intolerance and insulin resistance. It is unknown whether these metabolic effects of rapamycin are permanent or whether they can be alleviated. Here, we confirmed that rapamycin causes glucose intolerance and insulin resistance in both inbred and genetically heterogeneous mice fed either low fat or high fat diets, suggesting that these effects of rapamycin are independent of genetic background. Importantly, we also found that these effects were almost completely lost within a few weeks of cessation of treatment, showing that chronic rapamycin treatment does not induce permanent impairment of glucose metabolism. Somewhat surprisingly, chronic rapamycin also promoted increased accumulation of adipose tissue in high fat fed mice. However, this effect too was lost when rapamycin treatment was ended suggesting that this effect of rapamycin is also not permanent. The reversible nature of rapamycin's alterations of metabolic function suggests that these potentially detrimental side-effects might be managed through alternative dosing strategies or concurrent treatment options.
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Rapamycin has been associated with prevention of age-related diseases and extension of lifespan in both obese and lean mice.
“rapamycin has been associated with the prevention of age-related diseases and the extension of lifespan in both, obese and lean mice (Liu et al., 2014)”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Liu et al., 2014
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“Although rapamycin has been associated with 21 the prevention of age-related diseases and the extension of lifespan in both, obese and lean mice (Liu et al., 2014) and to avoid hyperlipidemia and diabetes-like syndrome in aged obese rats (Scarpace et al., 2016), a recent paper indicate that…”
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- Authors
- Liu, Y., Diaz, V., Fernandez, E., Strong, R., Ye, L., Baur, J. A., Lamming, D. W., Richardson, A., & Salmon, A. B.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio TX 78245, USA
- University of Pennsylvania (US)
- University of Wisconsin–Madison (US)
- Oklahoma City VA Medical Center (US)
- Corresponding author
- Salmon, Adam B.
- ORCID
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2014-09-02
- Volume
- 6
- Issue
- 9
- Pages
- 742-754
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC4221917
- OpenAlex
- W2169210738
- Cited by
- 68
- References
- 50
- Citations by year
- 2026: 4 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 17 · 2015: 13 · 2014: 2
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Aging (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000547)
- American Federation for Aging Research
- Office of Research and Development
- National Institutes of Health (K99-R00)
- Geriatric Research Education and Clinical Center
- National Institute on Aging (R01AG043483, 1P30- AG13319, R00AG041765, AG036613, RC2AG036613, K99AG041765, P30AG013319)
- NIH Clinical Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- rapamycin, mTOR inhibition, impaired glucose tolerance, insulin resistance, hyperglycemia, adipose tissue accumulation, obesity, high-fat diet, genetic background, lifespan extension, adverse drug reactions
- MeSH terms
- Administration, Oral, Animals, Antibiotics, Antineoplastic, Male, Mice, Inbred C57BL, Sirolimus, Glucose Metabolism Disorders, Adiposity, Mice
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