SIRT1 metabolic actions: Integrating recent advances from mouse models

Abstract

SIRT1 has attracted a lot of interest since it was discovered as a mammalian homolog of Sir2, a protein that influences longevity in yeast. Intensive early research suggested a key role of SIRT1 in mammalian development, metabolic flexibility and oxidative metabolism. However, it is the growing body of transgenic models that are allowing us to clearly define the true range of SIRT1 actions. In this review we aim to summarize the most recent lessons that transgenic animal models have taught us about the role of SIRT1 in mammalian metabolic homeostasis and lifespan.

Keywords: Energy homeostasis; Insulin resistance; SIRT1; Transgenic models.

Figure 1

Schematic representation of the actions of SIRT1 in liver, based on genetically engineered mouse models. Through direct deacetylation, SIRT1 enhances the transcriptional activity of a series of regulators, such as PGC-1α, the FOXO family of transcription factors, and the Liver X Receptor (LXR) or the Farnesoid X receptor (FXR). However, a series of other transcriptional regulators, such as SREBP-1c and CRTC2 are downregulated through deacetylation by SIRT1. Overall, SIRT1 activation favors lipid catabolism vs. anabolism, leading to protection against oxidative stress and sustainable glucose production during prolonged fasting.

Figure 2

Schematic representation of the actions of SIRT1 in skeletal muscle, based on genetically engineered mouse models. SIRT1 activation in muscle favours lipid catabolism through the activation of lipid oxidation and mitochondrial biogenesis gene sets by PGC-1α and the FOXO family of transcription factors, mostly FOXO3a. SIRT1 also enhances insulin action through the repression of proteins that downregulate insulin signaling, either through direct deacetylation, as with STAT3, or by transcriptional means (dashed line), as with PTP1b. SIRT1 might also impact on muscle differentiation through the repression of MyoD, even though this has not been properly tested in vivo.

Figure 3

Schematic representation of the actions of SIRT1 in white adipose tissue, based on genetically engineered mouse models. SIRT1 activation can target PPARγ activity in white adipose tissue. On the one hand, SIRT1 docks the NCoR1 to PPARγ, repressing the expression of genes linked to lipid anabolism and storage. On the other, SIRT1 directly deacetylates PPARγ, which allows the recruitment of PRDM16 to drive “browning” of white fat. Similar actions might be mediated through the activation of PGC-1α by SIRT1.