Enhancing the levels or activity of an enzyme previously implicated in protecting against neurodegeneration that occurs in Alzheimer’s, Huntington’s, and Parkinson’s disease could represent a new approach to halting the development of obesity-related metabolic disorders such as diabetes. The protein, SIRT1, is a deacetylase enzyme that in mice has already been shown to protect against the development of liver steatosis and insulin resistance as a result of a high-fat diet (HFD).

New research by two Massachusetts Institute of Technology (MIT) scientists has shown that mice engineered to lack SIRT1 specifically in adipocytes are more prone to becoming obese and developing metabolic dysfunction. Most notably, the white fat cells in these modified animals exhibited an altered gene expression profile that was very similar to that observed in the adipocytes of wild-type mice fed a HFD. This indicated that in wild-type animals dietary stress causes inhibition of SIRT1, preventing the protein from doing its job of regulating metabolic function.

Mice lacking SIRT1 in their fat cells are thus “poised for metabolic dysfunction,” comments Leonard Guarente, M.D., who carried out the work with colleague Angeliki Chalkiadaki, M.D. “You’ve removed one of the safeguards against metabolic decline, so you now give them the trigger of a high-fat diet, they’re much more sensitive than the normal mouse.”

Further studies showed that in normal mice given a HFD, the SIRT1 protein is cleaved by caspase-1, an enzyme induced by inflammation. “What our study shows is that once you induce the inflammatory response, the consequence in the fat cells is that SIRT1 will be cleaved,” Drs. Guarente and Chalkiadaki write in their published Cell Metabolism paper.

The researchers say their studies thus demonstrate that SIRT1 is required for the maintenance of metabolic health in adipose tissue under normal conditions. The results also provide further evidence for the link between a high-fat diet and inflammation. “Our findings lead to a two-stage model for the effects of HFD in wild-type mice,” they add. “In the first stage, SIRT1 protein is at least partially inactivated in adipose tissue, causing a unique transcriptional profile and a predisposition to metabolic disease. Under prolonged metabolic stress, loss of SIRT1 function from adipose tissue leads to a diabetic phenotype, manifested by whole-body glucose intolerance and insulin resistance.”

Interestingly, the studies also showed that aging mice were more susceptible to the detrimental effects of a HFD than younger mice, suggesting that aging is accompanied by a gradual loss in the protective effects of SIRT1. As aging is also known to increase inflammation, Dr. Guarante is now studying whether age-related inflammation also triggers SIRT1 loss.

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