Credit: Biophoto Associates / Photo Researchers, Inc.

The deactylase sirtuin 1 (Sirt1) seems to be a linchpin for the metabolic benefits of calorie restriction. In two new studies, more insight is gained about the importance of Sirt1 and its role in metabolic homeostasis.

In the first paper (Cell Metab. 16, 180–188), Chalkiadaki and Guarente show that high-fat diet–induced activation of the inflammasome in adipocytes results in caspase-1–mediated cleavage of Sirt1. They also found that genetic knockout of Sirt1 specifically in adipocytes leads to increased adiposity and whole-body insulin resistance. And transcriptome analysis showed that these knockout cells are quite similar to adipocytes from mice on a high-fat diet. These results point to a link between dietary stress and the development of obesity that involves Sirt1.

Although these findings place adipocyte-expressed Sirt1 front and center in the proper regulation of whole-body metabolism, it is still unclear how Sirt1 activity achieves this regulation. In a second study (Cell 150, 620–632), Li Qiang et al. may have uncovered at least part of this downstream mechanism. They found that in white adipocytes Sirt1 deacetylates the liganded form of the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ), thus allowing it to interact with PRDM16 and potentiate a genetic program that leads to the 'browning' of these cells. This cellular conversion improved energy expenditure and whole-body insulin sensitivity.

Together, these results give further credence to pursuing pharmacological activators of Sirt1 as a means of improving metabolic health. They also suggest that their combined use with low concentrations of PPAR-γ agonists, such as thiazolidinediones, may be even further efficacious.