mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function

Paschoal, Vivian A.; Amano, Mariane Tami; Belchior, Thiago; Magdalon, Juliana; Chimin, Patrícia; Andrade, Mauro Figueiredo Carvalho de; Ortiz‐Silva, Milene; Castro, Érique; Yamashita, Alex Shimura; Neto, José Cesar Rosa; Câmara, Niels Olsen Saraiva; Festuccia, William T.

doi:10.1016/j.imbio.2016.09.014

Cited by 43 publications

(60 citation statements)

References 40 publications

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“…Clearly, our findings highlight the importance of mTOR in polarization of M2 cells and M2-mediated chronic allograft rejection. In certain transplant models, the mTOR inhibitor rapamycin has been shown to inhibit neointimal formation and chronic graft rejection (17, 35, 39) and our data argue for the importance of M2 suppression by rapamycin, in addition to its effects on T cells, in chronic rejection. However, mechanisms of acute and chronic rejection are so different in that some form of immunosuppression therapies to inhibit T cells is often required for chronic rejection to develop, but how T cell suppression reagents, such as CTLA4-Ig, are inherently linked to chronic rejection are currently unknown and certainly require further investigation.…”

Section: Discussionsupporting

confidence: 55%

“…On the other hand, M2 polarization depends on IL-4 and IL-13, and these cytokines signal through the JAK/STAT pathway, which usually leads to the activation of mTOR and other downstream signaling events (16). In fact, pharmacological inhibition of mTOR Complex 1 (mTORC1) by rapamycin or specific deletion of mTORC2 in macrophages can markedly reduce IL-4/IL-13-mediated M2 polarization (17, 18). Therefore, TRAF6 and mTOR are pivotal signaling molecules in orchestrating M1 and M2 polarization.…”

Section: Introductionmentioning

confidence: 99%

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Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

Zhao

Chen

Lan

et al. 2018

American Journal of Transplantation

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Macrophages infiltrating the allografts are heterogeneous, consisting of proinflammatory (M1 cells) as well as antiinflammatory and fibrogenic phenotypes (M2 cells); they affect transplantation outcomes via diverse mechanisms. Here we found that macrophage polarization into M1 and M2 subsets was critically dependent on tumor necrosis factor receptor-associated factor 6 (TRAF6) and mammalian target of rapamycin (mTOR), respectively. In a heart transplant model we showed that macrophage-specific deletion of TRAF6 (LysM Traf6 ) or mTOR (LysM Mtor ) did not affect acute allograft rejection. However, treatment of LysM Mtor recipients with CTLA4-Ig induced long-term allograft survival (>100 days) without histological signs of chronic rejection, whereas the similarly treated LysM Traf6 recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4-Ig-treated LysM Traf6 mice was similar to that of CTLA4-Ig-treated wild-type B6 recipients. Mechanistically, we found that the graft-infiltrating macrophages in LysM Mtor recipients expressed high levels of PD-L1, and that PD-L1 blockade readily induced rejection of otherwise survival grafts in the LysM Mtor recipients. Our findings demonstrate that targeting mTOR-dependent M2 cells is critical for preventing chronic allograft rejection, and that graft survival under such conditions is dependent on the PD-1/PD-L1 coinhibitory pathway.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

Zhao

Chen

Lan

et al. 2018

American Journal of Transplantation

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“…It has been reported that there is an interaction between PICs activation and mTOR signal pathway [22]. It has also been reported that mTOR can positively regulate IL-6 and TNF-α and negatively regulate other PICs [23, 24]. In our study, we observed that rapamycin amplified the expression of IL-6 and TNF-α.…”

Section: Discussionsupporting

confidence: 75%

Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer’s disease rats

Wang

et al. 2016

Translational Neuroscience

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As a part of Alzheimer’s disease (AD) development the mammalian target of rapamycin (mTOR) has been reported to play a crucial role in regulating cognition and can be used as a neuronal marker. Neuro-inflammation is also a cause of the pathophysiological process in AD. Thus, we examined the protein expression levels of mTOR and its downstream pathways as well as pro-inflammatory cytokines (PICs) in the brain of AD rats. We further examined the effects of blocking mTOR on PICs, namely IL-1β, IL-6 and TNF-α. Our results showed that the protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1) and p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in the hippocampus of AD rats compared with controls. Blocking mTOR by using rapamycin selectively enhanced activities of IL-6 and TNF-α signaling pathways, which was accompanied with an increase of Caspase-3, indicating cellular apoptosis and worsened learning performance. In conclusion, our data for the first time revealed specific signaling pathways engaged in the development of AD, including a regulatory role by the activation of mTOR in PIC mechanisms. Stimulation of mTOR is likely to play a beneficial role in modulating neurological deficits in AD.Targeting one or more of these signaling molecules may present with new opportunities for treatment and clinical management of AD

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“…Most animal studies have commonly utilized short-term intraperitoneal rapamycin administered from 11–28 days in the setting of normal chow diets and have demonstrated weight loss, increase in plasma insulin levels, glucose intolerance and dyslipidemia. In a recent study, oral rapamycin administered in conjunction with high fat feeding over the course of 30 days worsened glucose tolerance and adipose tissue inflammation, with no changes in body weight in mice (Paschoal et al , 2017). Similarly, oral rapamycin administered to aged hybrid mice demonstrated impaired glucose tolerance after 4 weeks of rapamycin feeding (Yang et al , 2012).…”

Section: Discussionmentioning

confidence: 99%

Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat

Hartigh

Goodspeed

Wang

et al. 2018

Experimental Physiology

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Excess adiposity is commonly associated with insulin resistance, which can increase the risk of cardiovascular disease. However, the exact molecular mechanisms by which obesity results in insulin resistance are yet to be understood clearly. The intracellular nutrient-sensing protein, mechanistic target of rapamycin (mTOR), is a crucial signalling component in the development of obesity-associated insulin resistance. Given that increased tissue activation of mTOR complex-1 (mTORC1) occurs in obesity, diabetes and ageing, we hypothesized that pharmacological inhibition of mTORC1 would improve metabolic dysregulation in diet-induced obesity. We administered continuous rapamycin, a specific mTORC1 inhibitor, orally to C57BL/6J mice concurrently with a high-fat, high-sucrose (HFHS) diet for 20 weeks. The control group received placebo microcapsules. Rapamycin-treated mice showed significantly reduced weight gain and adiposity (33.6 ± 4.9 versus 40.4 ± 3.0% body fat, P < 0.001, n = 8 mice per group), despite increased or equivalent food intake compared with the placebo group. The rapamycin-fed mice also demonstrated reduced plasma glucose (252 ± 57 versus 297 ± 67 mg dl , P < 0.001) and improved insulin sensitivity during insulin and glucose tolerance testing. Rapamycin-treated mice also had lower plasma triglycerides (48 ± 13 versus 67 ± 11 mg/dL, P < 0.01) and hepatic triglyceride content (89 ± 15 versus 110 ± 19 mg/g liver, P < 0.05) compared with the placebo group. A moderately low dose of rapamycin decreased adiposity and improved the metabolic profile in a model of diet-induced obesity. These data suggest that low-grade chronic mTORC1 inhibition might be a potential strategy for anti-obesity therapies.

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mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function

Cited by 43 publications

References 40 publications

Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer’s disease rats

Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat

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