Identification of Akt-independent Regulation of Hepatic Lipogenesis by Mammalian Target of Rapamycin (mTOR) Complex 2

Yuan, Minsheng; Pino, Elizabeth C; Wu, Lianfeng; Kacergis, Michael C.; Soukas, Alexander A.

doi:10.1074/jbc.m112.386854

Cited by 138 publications

(146 citation statements)

References 44 publications

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“…As mTORC2 directly activates Akt downstream of insulin/PI3K signaling, it is not surprising that mTORC2 inhibition disrupts the physiological response to insulin. Consistent with this, liver specific Rictor knockout mice have severe insulin resistance and glucose intolerance (Hagiwara et al, 2012;Yuan et al, 2012), as do mice lacking Rictor in the muscle or fat (Kumar et al, 2008(Kumar et al, & 2010.…”

Section: Glucose Homeostasismentioning

confidence: 56%

mTOR Signaling in Growth, Metabolism, and Disease

Saxton

Sabatini

2017

Cell

2,224

2,558

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The mechanistic Target of Rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR-signaling network contributes to human disease, and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

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Section: Glucose Homeostasismentioning

confidence: 56%

mTOR Signaling in Growth, Metabolism, and Disease

Saxton

Sabatini

2017

Cell

2,224

2,558

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“…To test whether local insulin resistance causes inflammation in the liver, we examined hepatic macrophages in liver-specific Rictor-knockout mice (LiRiKO: Alb-Cre, Rictor fl/fl ), which have hepatic insulin resistance due to loss of insulin/mTORC2 signaling in liver (35)(36)(37). HFD-fed LiRiKO mice had a moderate but nonsignificant increase in the number of hepatic macrophages compared with HFD-fed control mice (Supplemental Figure 6D).…”

Section: Resultsmentioning

confidence: 99%

“…In mammals, mTORC2 consists of mTOR, rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinaseinteracting protein 1 (mSIN1), and mammalian lethal with SEC thirteen 8 (mLST8) (26)(27)(28)(29)(30)(31). Insulin stimulates mTORC2 to promote glucose uptake in adipose tissue (32)(33)(34), liver (35)(36)(37), and skeletal muscle (38,39). Previously, we and others have shown that adipose-specific Rictor knockout (AdRiKO) exacerbates obesity-related complications in mice, such as systemic insulin resistance and hepatic steatosis (32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Insulin resistance causes inflammation in adipose tissue

Shimobayashi

Albert

Woelnerhanssen³

et al. 2018

Journal of Clinical Investigation

351

232

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“…Mammalian TORC2 (mTORC2) also phosphorylates and activates Sgk (García-Martínez and Alessi, 2008), though key differences between mammals and lower eukaryotes exist. In knockout mice, it is the protein kinase Akt that mediates many of the metabolic effects of mTORC2 (Bhaskar and Hay, 2007;Hagiwara et al, 2012;Lamming et al, 2012;Yuan et al, 2012). Whereas defects in glucose metabolism in mTORC2 knockout mice are the result of defective Akt signaling through FoxO (Hagiwara et al, 2012;Yuan et al, 2012), in C. elegans, the growth, reproductive and lifespanshortening phenotypes of TORC2 mutants do not depend upon AKT signaling through FoxO (Jones et al, 2009;Soukas et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…In knockout mice, it is the protein kinase Akt that mediates many of the metabolic effects of mTORC2 (Bhaskar and Hay, 2007;Hagiwara et al, 2012;Lamming et al, 2012;Yuan et al, 2012). Whereas defects in glucose metabolism in mTORC2 knockout mice are the result of defective Akt signaling through FoxO (Hagiwara et al, 2012;Yuan et al, 2012), in C. elegans, the growth, reproductive and lifespanshortening phenotypes of TORC2 mutants do not depend upon AKT signaling through FoxO (Jones et al, 2009;Soukas et al, 2009). Still, certain aspects of mammalian metabolic regulation by TORC2 cannot be fully explained by loss of Akt activation, indicating additional, unelucidated outputs of TORC2 signaling (Yuan et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2

Webster

Douglas

et al. 2013

Development

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SUMMARYThe target of rapamycin complex 2 (TORC2) pathway is evolutionarily conserved and regulates cellular energetics, growth and metabolism. Loss of function of the essential TORC2 subunit Rictor (RICT-1) in Caenorhabditis elegans results in slow developmental rate, reduced brood size, small body size, increased fat mass and truncated lifespan. We performed a rict-1 suppressor RNAi screen of genes encoding proteins that possess the phosphorylation sequence of the AGC family kinase SGK, a key downstream effector of TORC2. Only RNAi to dpy-21 suppressed rict-1 slow developmental rate. DPY-21 functions canonically in the ten-protein dosage compensation complex (DCC) to downregulate the expression of X-linked genes only in hermaphroditic worms. However, we find that dpy-21 functions outside of its canonical role, as RNAi to dpy-21 suppresses TORC2 mutant developmental delay in rict-1 males and hermaphrodites. RNAi to dpy-21 normalized brood size and fat storage phenotypes in rict-1 mutants, but failed to restore normal body size and normal lifespan. Further dissection of the DCC via RNAi revealed that other complex members phenocopy the dpy-21 suppression of rict-1, as did RNAi to the DCC effectors set-1 and set-4, which methylate histone 4 on lysine 20 (H4K20). TORC2/rict-1 animals show dysregulation of H4K20 mono-and tri-methyl silencing epigenetic marks, evidence of altered DCC, SET-1 and SET-4 activity. DPY-21 protein physically interacts with the protein kinase SGK-1, suggesting that TORC2 directly regulates the DCC. Together, the data suggest non-canonical, negative regulation of growth and reproduction by DPY-21 via DCC, SET-1 and SET-4 downstream of TORC2 in C. elegans.

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Identification of Akt-independent Regulation of Hepatic Lipogenesis by Mammalian Target of Rapamycin (mTOR) Complex 2

Cited by 138 publications

References 44 publications

mTOR Signaling in Growth, Metabolism, and Disease

mTOR Signaling in Growth, Metabolism, and Disease

Insulin resistance causes inflammation in adipose tissue

A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2

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