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Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.

ABSTRACT: Chronic activation of mammalian target of rapamycin complex 1 (mTORC1) and p70 S6 kinase (S6K) in response to hypernutrition contributes to obesity-associated metabolic pathologies, including hepatosteatosis and insulin resistance. Sestrins are stress-inducible proteins that activate AMP-activated protein kinase (AMPK) and suppress mTORC1-S6K activity, but their role in mammalian physiology and metabolism has not been investigated. We show that Sestrin2--encoded by the Sesn2 locus, whose expression is induced upon hypernutrition--maintains metabolic homeostasis in liver of obese mice. Sesn2 ablation exacerbates obesity-induced mTORC1-S6K activation, glucose intolerance, insulin resistance, and hepatosteatosis, all of which are reversed by AMPK activation. Furthermore, concomitant ablation of Sesn2 and Sesn3 provokes hepatic mTORC1-S6K activation and insulin resistance even in the absence of nutritional overload and obesity. These results demonstrate an important homeostatic function for the stress-inducible Sestrin protein family in the control of mammalian lipid and glucose metabolism.

SUBMITTER: Lee JH

PROVIDER: S-EPMC3687365 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.

Lee Jun Hee JH Budanov Andrei V AV Talukdar Saswata S Park Eek Joong EJ Park Hae Li HL Park Hwan-Woo HW Bandyopadhyay Gautam G Li Ning N Aghajan Mariam M Jang Insook I Wolfe Amber M AM Perkins Guy A GA Ellisman Mark H MH Bier Ethan E Scadeng Miriam M Foretz Marc M Viollet Benoit B Olefsky Jerrold J Karin Michael M

Cell metabolism 20120901 3

Chronic activation of mammalian target of rapamycin complex 1 (mTORC1) and p70 S6 kinase (S6K) in response to hypernutrition contributes to obesity-associated metabolic pathologies, including hepatosteatosis and insulin resistance. Sestrins are stress-inducible proteins that activate AMP-activated protein kinase (AMPK) and suppress mTORC1-S6K activity, but their role in mammalian physiology and metabolism has not been investigated. We show that Sestrin2--encoded by the Sesn2 locus, whose express ...[more]

PMID: 22958918

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Project description:Cellular damage produced by conditions generating oxidative stress have far-reaching implications in human disease that encompass, but are not restricted to aging, cardiovascular disease, type 2 diabetes, airway inflammation/asthma, cancer, and metabolic syndrome including visceral obesity, insulin resistance, fatty liver disease, and dyslipidemia. Although there are numerous sources and cellular targets of oxidative stress, this review will highlight literature that has investigated downstream consequences of oxidatively-induced DNA damage in both nuclear and mitochondrial genomes. The presence of such damage can in turn, directly and indirectly modulate cellular transcriptional and repair responses to such stressors. As such, the persistence of base damage can serve as a key regulator in coordinated gene-response cascades. Conversely, repair of these DNA lesions serves as both a suppressor of mutagenesis and by inference carcinogenesis, and as a signal for the cessation of ongoing oxidative stress. A key enzyme in all these processes is 8-oxoguanine DNA glycosylase (OGG1), which, via non-catalytic binding to oxidatively-induced DNA damage in promoter regions, serves as a nucleation site around which changes in large-scale regulation of inflammation-associated gene expression can occur. Further, the catalytic function of OGG1 can alter the three-dimensional structure of specialized DNA sequences, leading to changes in transcriptional profiles. This review will concentrate on adverse deleterious health effects that are associated with both the diminution of OGG1 activity via population-specific polymorphic variants and the complete loss of OGG1 in murine models. This mouse model displays diet- and age-related induction of metabolic syndrome, highlighting a key role for OGG1 in protecting against these phenotypes. Conversely, recent investigations using murine models having enhanced global expression of a mitochondrial-targeted OGG1 demonstrate that they are highly resistant to diet-induced disease. These data suggest strategies through which therapeutic interventions could be designed for reducing or limiting adverse human health consequences to these ubiquitous stressors.

Project description:BackgroundEnergy-dissipating brown adipocytes have significant potential for improving systemic metabolism. Vanin-1, a membrane-bound pantetheinase, is involved in various biological processes in mice. However, its role in BAT mitochondrial function is still unclear. In this study, we aimed to elucidate the impact of Vanin-1 on BAT function and contribution during overnutrition-induced obesity.MethodsVanin-1 expression was analyzed in different adipose depots in mice. The cellular localization of Vanin-1 was analyzed by confocal microscopy and western blots. Mice lacking Vanin-1 (Vanin-1-/-) were continuously fed either a chow diet or a high-fat diet (HFD) to establish an obesity model. RNA-seq analysis was performed to identify the molecular changes associated with Vanin-1 deficiency during obesity. BAT-specific Vanin-1 overexpression mice were established to determine the effects of Vanin-1 in vivo. Cysteamine treatment was used to examine the effect of enzymatic reaction products of Vanin-1 on BAT mitochondria function in Vanin-1-/- mice.ResultsThe results indicate that the expression of Vanin-1 is reduced in BAT from both diet-induced and leptin-deficient obese mice. Study on the subcellular location of Vanin-1 shows that it has a mitochondrial localization. Vanin-1 deficiency results in increased adiposity, BAT dysfunction, aberrant mitochondrial structure, and promotes HFD induced-BAT whitening. This is attributed to the impairment of the electron transport chain (ETC) in mitochondria due to Vanin-1 deficiency, resulting in reduced mitochondrial respiration. Overexpression of Vanin-1 significantly enhances energy expenditure and thermogenesis in BAT, renders mice resistant to diet-induced obesity. Furthermore, treatment with cysteamine rescue the mitochondrial dysfunction in Vanin-1-/- mice.ConclusionsCollectively, these findings suggest that Vanin-1 plays a crucial role in promoting mitochondrial respiration to counteract diet-induced obesity, making it a potential therapeutic target for obesity.

Dataset Information

Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.

Publications

Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3.

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