Duration of Rapamycin Treatment Has Differential Effects on Metabolism in Mice

Fang, Yimin; Westbrook, Reyhan; Hill, Cristal M.; Boparai, Ravneet K.; Arum, Oge; Spong, Adam; Wang, Feiya; Javors, Martin A.; Chen, Jiawen; Sun, Liou Y.; Bartke, Andrzej

doi:10.1016/j.cmet.2013.02.008

Cited by 171 publications

(208 citation statements)

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“…Rapamycin (4 mg kg −1 body weight) was administered to WT and Nrf2KO mice via i.p. injection every other day for 6 weeks (Fang et al ., 2013), and several markers of cellular senescence were measured in fat and lung tissues. We found that in fat tissue from Nrf2KO mice at basal state showed higher levels of β‐gal staining and proinflammatory cytokines (measured by mRNA) than WT controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…with rapamycin at a dose of 4 mg kg −1 body weight (dissolved in ethanol then diluted with vehicle containing 5% Tween‐80 and 5% PEG400) or same volume ethanol diluted with vehicle as controls. The dosing was given at every other day for 6 weeks (Fang et al ., 2013). The mice were euthanized at 48 h after last dose of rapamycin and a thorough necropsy was performed.…”

Section: Methodsmentioning

confidence: 99%

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Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

et al. 2017

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SummarySenescent cells contribute to age‐related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. In wild‐type (WT) mouse fibroblasts, rapamycin increased the levels of Nrf2, and this correlates with the activation of autophagy and a reduction in the induction of cell senescence, as measured by SA‐β‐galactosidase (β‐gal) staining, senescence‐associated secretory phenotype (SASP), and p16 and p21 molecular markers. In Nrf2KO fibroblasts, however, rapamycin still decreased β‐gal staining and the SASP, but rapamycin did not activate the autophagy pathway or decrease p16 and p21 levels. These observations were further confirmed in vivo using Nrf2KO mice, where rapamycin treatment led to a decrease in β‐gal staining and pro‐inflammatory cytokines in serum and fat tissue; however, p16 levels were not significantly decreased in fat tissue. Consistent with literature demonstrating that the Stat3 pathway is linked to the production of SASP, we found that rapamycin decreased activation of the Stat3 pathway in cells or tissue samples from both WT and Nrf2KO mice. Our data thus suggest that cell senescence is a complex process that involves at least two arms, and rapamycin uses Nrf2 to regulate cell cycle arrest, but not the production of SASP.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

et al. 2017

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“…3). In addition, it has been demonstrated very recently that the duration of mTOR inhibition with rapamycin is of critical importance for regulating metabolic homeostasis (65). While short-term treatment with rapamycin exerts detrimental effects on glucose homeostasis in mice, prolonged treatment (i.e.…”

Section: Effects Of Mtor Inhibitors On Lipids "mentioning

confidence: 99%

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

Vergès

Walter

Cariou

2014

European Journal of Endocrinology

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During the past years, targeted therapies for cancer have been developed using drugs that have significant metabolic consequences. Among them, the mammalian target of rapamycin (mTOR) inhibitors and, to a much lesser extent, the tyrosine kinase inhibitors (TKIs) are involved. mTOR plays a key role in the regulation of cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a significant increase in plasma triglycerides and LDL cholesterol. mTOR inhibitors seem to increase plasma triglycerides by reducing the activity of the lipoprotein lipase which is in charge of the catabolism of triglyceride-rich lipoproteins. The increase in LDL cholesterol observed with mTOR inhibitors seems to be due to a decrease in LDL catabolism secondary to a reduction of LDL receptor expression. In addition, treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia, ranging from 13 to 50% in the clinical trials. The mechanisms responsible for hyperglycemia with new onset diabetes are not clear, but are likely due to the combination of impaired insulin secretion and insulin resistance. TKIs do not induce hyperlipidemia but alter glucose homeostasis. Treatment with TKIs may be associated either with hyperglycemia or hypoglycemia. The molecular mechanism by which TKIs control glucose homeostasis remains unknown. Owing to the metabolic consequences of these agents used as targeted anti-cancer therapies, a specific and personalized follow-up of blood glucose and lipids is recommended when using mTOR inhibitors and of blood glucose when using TKIs.

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“…Interestingly, only 1 week of PF-4708671 treatment was found to improve fasting glucose whereas rapamycin further increased fasting hyperglycaemia in obese mice. In addition to fasting glucose, rapamycin treatment was also found to increase fasting insulinaemia as previously reported in various rodent models [19,20,28,29]. To determine the impact of S6K1 inhibition on glucose homeostasis, we next performed a glucose tolerance test (GTT).…”

Section: S6k1 Inhibition Increases Glucose Uptake In L6 Myocytesmentioning

confidence: 99%

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

et al. 2016

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Aims/hypothesis The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo. Methods We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo. Results Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice. Conclusions/interpretation Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.

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Duration of Rapamycin Treatment Has Differential Effects on Metabolism in Mice

Cited by 171 publications

References 22 publications

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

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