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  • Review Article
  • Published:

Sirtuins mediate mammalian metabolic responses to nutrient availability

Nature Reviews Endocrinology volume 8, pages 287–296 (2012)Cite this article

Subjects

Abstract

Metabolic diseases are an increasing threat in developed countries. Dysregulation of metabolic pathways, caused by imbalances in energy homeostasis, leads to obesity, diabetes and cardiovascular disease with devastating results for both individuals and societies. Sirtuins, a conserved family of NAD+-dependent deacetylase enzymes found in many species, regulate various metabolic pathways and have emerged as important sensors of energy status in mammals. The nuclear sirtuins, SIRT1, SIRT6 and SIRT7, regulate the activity of key transcription factors and cofactors of numerous metabolic pathways in almost all tissues by linking nutrient signals with the cellular responses to energy demands. The mitochondrial sirtuins, SIRT3, SIRT4 and SIRT5, regulate the activity of important mitochondrial enzymes and drive metabolic cycles in response to fasting and calorie restriction. Accumulating evidence indicates that sirtuins can be beneficial in the prevention of metabolic and age-related diseases and suggests that they can be pharmacologically activated to ameliorate such diseases. This Review describes the latest advances in the understanding of the function of sirtuins as regulators of mammalian metabolism and focuses on the role of these enzymes as mediators of nutrient availability.

Key Points

  • Sirtuins link NAD+ cleavage to deacetylation of target proteins that are important in metabolism

  • SIRT1 regulates key factors that influence hepatic carbohydrate and lipid metabolism

  • SIRT1 counteracts processes that result in cardiovascular disease and the metabolic syndrome

  • SIRT3 regulates oxidative metabolism and suppresses the production and the effects of reactive oxygen species

  • SIRT6 regulates glucose homeostasis

  • Sirtuins could be pharmacologically activated to protect against metabolic and age-related diseases

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Figure 1: Sirtuins affect multiple diseases.
Figure 2: Circadian cycle of NAD+ synthesis and SIRT1 activity.
Figure 3: SIRT1 regulates hepatic metabolism at multiple levels.
Figure 4: Sirtuin targets in mitochondria.

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Acknowledgements

A. Chalkiadaki's and L. Guarente's research work is supported by grants from the NIH and the Glenn Foundation for Medical Research. We apologize to researchers whose work was not cited due to space limitations.

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  1. Department of Biology, Paul F. Glenn Laboratory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 68, Cambridge, 02139, MA, USA

    Angeliki Chalkiadaki & Leonard Guarente

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Both authors contributed equally to all aspects of this article (researching data for the article, writing the manuscript, discussions of the content and review or editing of the manuscript before submission).

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Correspondence to Leonard Guarente.

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A. Chalkiadaki declares no competing interests. L. Guarente declares that he has acted as a consultant for Sirtris Pharmaceuticals (owned by GlaxoSmithKline) and is co-chair of the scientific advisory board of Sirtris–GlaxoSmithKline.

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Chalkiadaki, A., Guarente, L. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat Rev Endocrinol 8, 287–296 (2012). https://doi.org/10.1038/nrendo.2011.225

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