Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity

Lamming, Dudley W.; Ye, Lan; Katajisto, Pekka; Goncalves, Marcus D.; Saitoh, Maki; Stevens, Deanna; Davis, James G.; Salmon, Adam B.; Richardson, Arlan; Ahima, Rexford S.; Guertin, David A.; Sabatini, David M.; Baur, Joseph A.

doi:10.1126/science.1215135

Cited by 1,050 publications

(1,045 citation statements)

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“…1C). As we previously reported (Lamming et al ., 2012), daily treatment with 2 mg/kg rapamycin efficiently inhibited the phosphorylation of both S6 S240/244, a readout of mTORC1 signaling, and AKT S473, an mTORC2 substrate. Rapamycin was equally efficacious in inhibiting phosphorylation of S6 in mice treated daily with rapamycin as in mice treated weekly (1×/7d) and sacrificed on the day following treatment (D1).…”

Section: Resultsmentioning

confidence: 94%

“…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%

“…2B), indicating increased hepatic gluconeogenesis. The different outcomes of these two tests were unexpected, as we have previously observed that chronic rapamycin treatment induces both glucose and pyruvate intolerance due to increased hepatic gluconeogenesis and hepatic insulin resistance (Lamming et al ., 2012, 2013a). Rictor is an essential protein component of mTORC2, and we showed that the effects of rapamycin on hepatic insulin resistance are mediated by disruption of mTORC2 utilizing a whole‐body tamoxifen‐inducible Rictor knockout mouse (Lamming et al ., 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Rapamycin is an acute inhibitor of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a protein kinase which regulates numerous cellular processes including ribosomal biogenesis, protein translation, and autophagy through the phosphorylation of substrates that include S6K1, 4E‐BP1, and Ulk1. Mice lacking S6K1 or with decreased mTORC1 activity have extended longevity, demonstrating that decreased mTORC1 signaling is sufficient to promote longevity, especially in females (Selman et al ., 2009; Lamming et al ., 2012; Wu et al ., 2013). …”

Section: Introductionmentioning

confidence: 99%

“…While investigating the mechanistic basis for the effect of rapamycin on glucose tolerance, we discovered that long‐term treatment with rapamycin also inhibits a second mTOR complex, mTORC2, in vivo , resulting in hepatic insulin resistance (Lamming et al ., 2012, 2013a). mTORC2 has also recently been shown to have an important role in promoting immune function, which suggests that the immunosuppressive effects of rapamycin may be due in part to the inhibition of mTORC2 signaling (Powell et al ., 2012; Byles et al ., 2013; Festuccia et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

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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: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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Metabolic reprogramming: a bridge between aging and tumorigenesis

2022

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Aging is the most robust risk factor for cancer development, with more than 60% of cancers occurring in those aged 60 and above. However, how aging and tumorigenesis are intertwined is poorly understood and a matter of significant debate. Metabolic changes are hallmarks of both aging and tumorigenesis. The deleterious consequences of aging include dysfunctional cellular processes, the build-up of metabolic byproducts and waste molecules in circulation and within tissues, and stiffer connective tissues that impede blood flow and oxygenation. Collectively, these age-driven changes lead to metabolic reprogramming in different cell types of a given tissue that significantly affects their cellular functions. Here, we put forward the idea that metabolic changes that happen during aging help create a favorable environment for tumorigenesis. We review parallels in metabolic changes that happen during aging and how these changes function both as adaptive mechanisms that enable the development of malignant phenotypes in a cell-autonomous manner and as mechanisms that suppress immune surveillance, collectively creating the perfect environment for cancers to thrive. Hence, antiaging therapeutic strategies that target the metabolic reprogramming that occurs as we age might provide new opportunities to prevent cancer initiation and/or improve responses to standard-of-care anticancer therapies.

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mTOR inhibition by rapamycin increases ceramide synthesis by promoting transforming growth factor‐β1/Smad signaling in the skin

et al. 2016

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Although mammalian target of rapamycin (mTOR) mediates a wide variety of biological functions, little information is available on the effect of mTOR on the functions of skin cells. In this study, we investigated effects of mTOR inhibition by rapamycin on ceramide synthesis in the skin of rats and human keratinocytes and its regulatory mechanisms. The phosphorylation of p70 S6 kinase, which indicates mTOR activation, was induced in the skin of rats fed a high‐fat diet, but this abnormality was reversed by supplementation with rapamycin. Ceramide levels and the mRNA levels of serine palmitoyltransferase (SPT) and transforming growth factor (TGF)‐β1 were suppressed in the skin of rats fed high‐fat diets, but this abnormality was reversed by supplementation with rapamycin. TGF‐β1‐induced SPT mRNA expression was blocked by SB525334, an inhibitor of TGF‐β1‐induced Smad2/3 nuclear localization, in human keratinocytes. Rapamycin‐induced SPT mRNA expression was blocked by an anti‐TGF‐β1 antibody or SB525334 in human keratinocytes. These results show that mTOR inhibition by rapamycin increases ceramide synthesis by promoting TGF‐β1/Smad signaling in the skin.

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Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity

Cited by 1,050 publications

References 39 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

Metabolic reprogramming: a bridge between aging and tumorigenesis

mTOR inhibition by rapamycin increases ceramide synthesis by promoting transforming growth factor‐β1/Smad signaling in the skin

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