Hypothalamic mTORC2 is essential for metabolic health and longevity

Chellappa, Karthikeyani; Brinkman, Jacqueline A.; Mukherjee, Sarmistha; Morrison, Mark A.; Alotaibi, Mohammed T.; Carbajal, Kathryn; Alhadeff, Amber L.; Perron, Isaac J.; Yao, Rebecca; Purdy, Cole S.; DeFelice, Denise M.; Wakai, Matthew H.; Tomasiewicz, Jay L.; Lin, Amy; Meyer, Emma; Peng, Yi; Apelo, Sebastian I. Arriola; Puglielli, Luigi; Betley, J. Nicholas; Paschos, Georgios K.; Baur, Joseph A.; Lamming, Dudley W.

doi:10.1111/acel.13014

Cited by 50 publications

(31 citation statements)

References 130 publications

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“…We have previously shown that diminishing mTORC2 activity specifically in the liver or in the whole body reduces male lifespan by at least 30% (Lamming et al, 2014b), while deletion of Rictor specifically in the hypothalamus reduces male lifespan by 10% and increases frailty in both sexes (Chellappa et al, 2019). Fitness was also reduced when Rictor was inducibly deleted in adult mice, which resulted in a progeroid phenotype.…”

Section: Discussionmentioning

confidence: 99%

Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension

Tomasiewicz

Yang

et al. 2019

Cell Reports

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SUMMARY Calorie restriction (CR) extends the healthspan and lifespan of diverse species. In mammals, a broadly conserved metabolic effect of CR is improved insulin sensitivity, which may mediate the beneficial effects of a CR diet. This model has been challenged by the identification of interventions that extend lifespan and healthspan, yet promote insulin resistance. These include rapamycin, which extends mouse lifespan yet induces insulin resistance by disrupting mTORC2 (mechanistic Target Of Rapamycin Complex 2). Here, we induce insulin resistance by genetically disrupting adipose mTORC2 via tissue-specific deletion of the mTORC2 component Rictor (AQ-RKO). Loss of adipose mTORC2 blunts the metabolic adaptation to CR, and prevents whole-body sensitization to insulin. Despite this, AQ-RKO mice subject to CR experience the same increase in fitness and lifespan on a CR diet as wild-type mice. We conclude that the CR-induced improvement in insulin sensitivity is dispensable for the effects of CR on fitness and longevity.

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Section: Discussionmentioning

confidence: 99%

Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension

Tomasiewicz

Yang

et al. 2019

Cell Reports

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“…We show that castration reduced the expression levels of hypothalamic ERα in 17aE2 treated males, and significantly increased mTORC1 signaling in the ARC. While the molecular mechanisms underlying this relationship require further investigation, such an interaction could be related to the altered activity of mTORC2 signaling in the ARC neurons (Chellappa et al 2019). Understanding the effect of hypothalamic mTOR signaling in the control of neuroinflammatory responses may provide significant insight into the causes of sexspecific differences in aging.…”

Section: Discussionmentioning

confidence: 99%

Sex hormones underlying 17a-Estradiol effects on neuroinflammation

Debarba

Jayarathne

Miller

et al. 2020

Preprint

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Phone: 64 3 479 5465 Email: mike.garratt@otago.ac.nz Abbreviations: ACA, acarbose; 17aE2, 17-a-estradiol; CNS, central nervous system; ERα, estrogen receptor alpha; ARC, arcuate nucleus of the hypothalamus.Abstract 17-α-estradiol (17aE2) treatment extends lifespan in male mice and can reduce neuroinflammatory responses in the hypothalamus of 12-month-old males. Although 17aE2 improves longevity in males, female mice are unaffected, suggesting a sexually dimorphic pattern of lifespan regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are mediated by sex hormones and whether hypothalamic changes extend to other brain regions in old age. Manipulating sex hormone levels through gonadectomy, we show that sex-specific effects of 17aE2 on age-associated gliosis are brain region-specific and are partially dependent on gonadal hormone production. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration prior to 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis. By contrast, sex-specific changes in microgliosis with 17aE2 were not significantly affected by castration in males. While 17aE2 treatment had no effect of hypothalamic astrocytes or microglia in intact females, ovariectomy significantly increased the occurrence of hypothalamic gliosis evaluated in 25-month-old females, which was partially reduced by 17aE2. In the hippocampus, both male and female gonadally-derived hormones influenced the severity of gliosis and the responsiveness to 17aE2 in a regiondependent manner. The male-specific effects of 17aE2 correlate with changes in hypothalamic ERα expression, highlighting a receptor through which 17aE2 could act. The results of this study demonstrate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex-specific gonads. Interactions between sex-steroids and neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in aging.

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“…The GSEA assay on the effects of SMAD2 showed that it can in uence the energy dependent regulation of mTOR by LKB1 AMPK pathway, and RNA polymerase. The mTORassociated signaling pathway acts as a nutrition sensor of nutrition, and regulates cell differentiation and senescence [27] , whose disorder may cause spermogenesis arrest. Similarly, spermogenesis depends on the energy metabolism balance, which also indicated that energy dependent regulation of mTOR by LKB1 AMPK pathway.…”

Section: Discussionmentioning

confidence: 99%

Weighted Gene Co-Expression Network Analysis Revealed The Cellular Senescence Signaling Pathway Associated With Non-Obstructive Azoospermia

Wang¹,

Xia²,

Yi³

et al. 2020

Preprint

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BackgroundNon-obstructive azoospermia (NOA) in males is a disease commonly associated with infertility, and is characterized by a disorder in spermogenesis, which may be caused by chromosomal abnormalities, orchitis, or chemical therapy. Spermogenesis is a process tightly regulated by precise gene expression patterns. However, the key genes and signaling pathways contributing to NOA remain unclear.MethodsIn this study, weighted gene co-expression network analysis was performed to identify NOA-associated gene clusters, and combined with the KEGG pathway assay and biological research.ResultsOur results revealed that the cellular senescence signaling pathway may play important roles in NOA. Indeed, cellular senescence is a complex biological process, often associated with disorder in cellular function. Using different expression genes (DEGs), the core, NOA-associated gene set in the cellular senescence pathway was identified; it contained SMAD2, which was upregulated, and HIPK4, which was downregulated. Consequently, the database was divided based on the expression levels of SMAD2 and HIPK4, and the GSEA (Gene Set Enrichment Analysis) assay, as well as the GO and KEGG assays of genes co-expressing with SMAD2 and HIPK4, showed that these two genes may take part in the regulation of cellular senescence, sperm differentiation and development, and energy metabolism.ConclusionsThe two genes, SMAD2 and HIPK4, took part in the regulation of senescence, and indicated that the cellular senescence of sertoli cells may play important roles in the NOA. This research can help us understand the mechanisms underlying NOA, and suggest anti-senescence therapeutic approaches that target these associated genes, especially SMAD2 and HIPK4.

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Hypothalamic mTORC2 is essential for metabolic health and longevity

Cited by 50 publications

References 130 publications

Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension

Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension

Sex hormones underlying 17a-Estradiol effects on neuroinflammation

Weighted Gene Co-Expression Network Analysis Revealed The Cellular Senescence Signaling Pathway Associated With Non-Obstructive Azoospermia

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