SIRT3 weighs heavily in the metabolic balance: a new role for SIRT3 in metabolic syndrome.

Eating a "Western diet" high in fat and sugars is associated with accelerated development of age-related metabolic diseases such as obesity, insulin resistance, and diabetes while incidences of these diseases are decreased on a low-calorie diet. The mitochondrial NAD(+)-dependent protein deacetylase SIRT3 has previously been shown to be important in adapting to metabolic stress brought on by fasting and calorie restriction. During times of metabolic stress, SIRT3 is upregulated and maintains homeostasis following nutrient deprivation by turning on pathways such as fatty acid oxidation, antioxidant production, and the urea cycle. New studies now demonstrate that SIRT3 is regulated during nutrient excess. During high-fat diet feeding, SIRT3 is downregulated leading to mitochondrial protein hyperacetylation. The consequence of this hyperacetylation is the accelerated development of metabolic syndrome. Thus, SIRT3 is emerging as an important metabolic sensor working to restore metabolic homeostasis during times of stress.