Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1

Jung, Sung-Min; Hung, Chien-Min; Hildebrand, Samuel; Sanchez-Gurmaches, Joan; Martínez-Pastor, Bárbara; Gengatharan, Jivani M.; Wallace, Martina; Mukhopadhyay, Dimpi; Calejman, Camila Martínez; Luciano, Amelia K.; Hsiao, Wen-Yu; Tang, Yun‐Chi; Li, Huawei; Daniels, Danette L.; Mostoslavsky, Raúl; Metallo, Christian M.; Guertin, David A.

doi:10.1016/j.molcel.2019.07.023

Cited by 62 publications

(50 citation statements)

References 77 publications

(100 reference statements)

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“…These opposing functions of central and peripheral serotonin are consistent with findings from other highly conserved regulators of energy balance such as the AMP-activated protein kinase where genetic reductions of hypothalamic AMPK increases energy expenditure 35 , while reductions of AMPK in adipose tissue lower energy expenditure and iWAT browning 36 . A similar paradigm of opposing functions between central and adipose specific mTOR has also been observed [37][38][39] . Thus, there is a precedent by which central and peripheral pathways may exert opposing functions on energy expenditure.…”

Section: Discussionsupporting

confidence: 60%

Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance

et al. 2020

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Obesity is linked with insulin resistance and is characterized by excessive accumulation of adipose tissue due to chronic energy imbalance. Increasing thermogenic brown and beige adipose tissue futile cycling may be an important strategy to increase energy expenditure in obesity, however, brown adipose tissue metabolic activity is lower with obesity. Herein, we report that the exposure of mice to thermoneutrality promotes the infiltration of white adipose tissue with mast cells that are highly enriched with tryptophan hydroxylase 1 (Tph1), the rate limiting enzyme regulating peripheral serotonin synthesis. Engraftment of mast celldeficient mice with Tph1 −/− mast cells or selective mast cell deletion of Tph1 enhances uncoupling protein 1 (Ucp1) expression in white adipose tissue and protects mice from developing obesity and insulin resistance. These data suggest that therapies aimed at inhibiting mast cell Tph1 may represent a therapeutic approach for the treatment of obesity and type 2 diabetes.

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Section: Discussionsupporting

confidence: 60%

Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance

et al. 2020

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“…FOXO1 regulates a broad spectrum of transcriptional targets implicated in different aspects of adipocytes function. We and others showed that FOXO1 promotes the expression of Atgl (Chakrabarti and Kandror 2009b;Chakrabarti et al 2011;Jung et al 2019). Interestingly, a number of reports showed that FOXO1 suppresses the expression of genes regulating energy dissipation, including UCP1, in white and brown adipocytes (Nakae et al 2008(Nakae et al , 2012Liu et al 2016;Kita et al 2019;Peng et al 2019).…”

Section: Discussionmentioning

confidence: 95%

“…Interestingly, a number of reports showed that FOXO1 suppresses the expression of genes regulating energy dissipation, including UCP1, in white and brown adipocytes (Nakae et al 2008(Nakae et al , 2012Liu et al 2016;Kita et al 2019;Peng et al 2019). However, a recent study indicated that in brown adipose tissue of mice fed ND, FOXO1 does not affect UCP1 and in vitro under specific culture conditions deletion of FOXO1 might even decrease Ucp1 expression in brown adipocytes (Jung et al 2019). Another study also indicates that in the mice with decreased insulin signaling, FOXO1 might drive Ucp1 expression (Ortega-Molina et al 2012).…”

Section: Discussionmentioning

confidence: 99%

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

et al. 2020

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Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that β-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.These authors contributed equally to this work. Corresponding author: grzegorz.sumara@uni-wuerzburg.de Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.

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“…β-adrenergic stimulation of mTORC2 signaling induces lipid catabolism in brown adipocytes and glucose uptake into skeletal muscle or brown fat cells [56]. The function of rictor in lipid catabolism in brown adipocytes is independent of Akt but involves FoxO1 deacetylation via SIRT6 [57]. α-adrenergic signaling to mTORC2 also promotes glucose uptake in cardiomyocytes [58].…”

Section: Signaling To Mtormentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

154

108

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1

Abstract: Highlights d Inhibiting brown adipocyte mTORC2 protects against obesity at thermoneutrality d mTORC2 suppresses lipolysis and UCP1 expression d Inhibiting mTORC2 triggers FoxO1 deacetylation by SIRT6 d FoxO1 drives lipid catabolism upon mTORC2 loss

Cited by 62 publications

References 77 publications

Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance

Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

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