Sirtuins (
Sirts) are implicated in regulating a myriad of
biologic functions ranging from cell growth and metabolism to longevity. Here, we show that nuclear
Sirt, Sirt6, and mitochondrial
Sirt,
Sirt3, regulate each other's activity and protect the heart from developing
diabetic cardiomyopathy. We found that expression of both Sirt6 and
Sirt3 was reduced in cardiomyocytes treated with
palmitate and in hearts of mice fed with a high-fat, high-
sucrose (HF-HS) diet to develop
obesity and diabetes. Conversely, whole-body overexpressing Sirt6 transgenic (Tg.Sirt6) mice were protected from developing
obesity and
insulin resistance when fed with the same HF-HS diet. The hearts of Tg.Sirt6 mice were also protected from mitochondrial fragmentation and decline of
Sirt3, resulting otherwise from HF-HS diet feeding. Mechanistic studies showed that
Sirt3 preserves Sirt6 levels by reducing oxidative stress, whereas Sirt6 maintains
Sirt3 levels by up-regulating
nuclear respiratory factor 2 (Nrf2)-dependent
Sirt3 gene transcription. We found that Sirt6 regulates Nrf2-mediated cardiac gene expression in 2 ways; first, Sirt6 suppresses expression of
Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, and second, Sirt6 binds to Nrf2 and antagonizes its interaction with Keap1, thereby stabilizing Nrf2 levels in cardiomyocytes. Together, these studies demonstrate that Sirt6 and
Sirt3 maintain each other's activity and protect the heart from developing
diabetic cardiomyopathy.-Kanwal, A., Pillai, V. B., Samant, S., Gupta, M., Gupta, M. P. The nuclear and mitochondrial
sirtuins, Sirt6 and
Sirt3, regulate each other's activity and protect the heart from developing
obesity-mediated
diabetic cardiomyopathy.