SIRT6 protects against pathological damage caused by diet‐induced obesity

Summary The NAD+‐dependent SIRT6 deacetylase is a therapeutic candidate against the emerging metabolic syndrome epidemic. SIRT6, whose deficiency in mice results in premature aging phenotypes and metabolic defects, was implicated in a calorie restriction response that showed an opposite set of pheno...

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Published in:Aging cell 2010-04, Vol.9 (2), p.162-173
Main Authors: Kanfi, Yariv, Peshti, Victoria, Gil, Reuven, Naiman, Shoshana, Nahum, Liat, Levin, Eran, Kronfeld‐Schor, Noga, Cohen, Haim Y.
Format: Article
Language:English
Subjects:
Animal Feed - adverse effects
Animals
diet‐induced obesity
Fats - administration & dosage
Fats - adverse effects
Gene Expression Regulation
Homeostasis
Lipid Metabolism
Male
metabolic syndrome
Mice
Mice, Transgenic
Obesity - etiology
Obesity - genetics
Obesity - metabolism
Obesity - pathology
PPAR gamma - metabolism
SIRT6
Sirtuins - genetics
Sirtuins - metabolism
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Summary:Summary The NAD+‐dependent SIRT6 deacetylase is a therapeutic candidate against the emerging metabolic syndrome epidemic. SIRT6, whose deficiency in mice results in premature aging phenotypes and metabolic defects, was implicated in a calorie restriction response that showed an opposite set of phenotypes from the metabolic syndrome. To explore the role of SIRT6 in metabolic stress, wild type and transgenic (TG) mice overexpressing SIRT6 were fed a high fat diet. In comparison to their wild‐type littermates, SIRT6 TG mice accumulated significantly less visceral fat, LDL‐cholesterol, and triglycerides. TG mice displayed enhanced glucose tolerance along with increased glucose‐stimulated insulin secretion. Gene expression analysis of adipose tissue revealed that the positive effect of SIRT6 overexpression is associated with down regulation of a selective set of peroxisome proliferator‐activated receptor‐responsive genes, and genes associated with lipid storage, such as angiopoietin‐like protein 4, adipocyte fatty acid‐binding protein, and diacylglycerol acyltransferase 1, which were suggested as potential targets for drugs to control metabolic syndrome. These results demonstrate a protective role for SIRT6 against the metabolic consequences of diet‐induced obesity and suggest a potentially beneficial effect of SIRT6 activation on age‐related metabolic diseases.
ISSN:1474-9718
1474-9726
DOI:10.1111/j.1474-9726.2009.00544.x