Chronic Rapamycin Treatment Causes Glucose Intolerance and Hyperlipidemia by Upregulating Hepatic Gluconeogenesis and Impairing Lipid Deposition in Adipose Tissue

Houde, Vanessa P.; Brûlé, Sophie; Festuccia, William T.; Blanchard, Pierre‐Gilles; Bellmann, Kerstin; Deshaies, Yves; Marette, André

doi:10.2337/db09-1324

Cited by 402 publications

(387 citation statements)

References 52 publications

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“…2A). One treatment cycle later, we performed a pyruvate tolerance test (PTT); pyruvate can be utilized as a substrate for gluconeogenesis by the liver, permitting us to assess hepatic gluconeogenesis (Houde et al ., 2010; Lamming et al ., 2012). As expected, daily rapamycin treatment induced significant pyruvate intolerance (Fig.…”

Section: Resultsmentioning

confidence: 99%

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

et al. 2015

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SummaryInhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA‐approved drug rapamycin has been shown to promote lifespan and delay age‐related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long‐term prophylactic use of rapamycin as a therapy for age‐related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR‐containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA‐approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA‐approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.

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Section: Resultsmentioning

confidence: 99%

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

et al. 2015

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“…Western analyses Western blots were performed as described [19]. Briefly, equal amounts of proteins were separated by SDS-PAGE (7.5% [wt/vol.])…”

Section: Methodsmentioning

confidence: 99%

“…Nuclear extracts Liver nuclear extracts were prepared as previously described [19] and subjected to immunoblotting as described above.…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction and quantitative PCR analysis RNA extraction and quantitative PCR analysis were performed as described previously [19] (see ESM Methods).…”

Section: Methodsmentioning

confidence: 99%

“…However, chronic rapamycin treatment causes diabetes-like symptoms due to alterations in hepatic gluconeogenic genes and lipid storage in fat [9,19,20]. However, no studies have yet evaluated the effect of specifically inhibiting S6K1 on cellular insulin signalling, glucose metabolism and whole-body glucose homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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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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mTOR signaling in liver disease

Cornu

Coquereaumont

Hall

2015

Signaling Pathways in Liver Diseases

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Chronic Rapamycin Treatment Causes Glucose Intolerance and Hyperlipidemia by Upregulating Hepatic Gluconeogenesis and Impairing Lipid Deposition in Adipose Tissue

Cited by 402 publications

References 52 publications

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

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

mTOR signaling in liver disease

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