The nuclear and mitochondrial sirtuins, Sirt6 and Sirt3, regulate each other's activity and protect the heart from developing obesity‐mediated diabetic cardiomyopathy

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, Sirtβ, and mitochondrial Sirt, Sirt3, regulate each other's activity and protect the heart from developing diabetic cardiomyopathy. We found that expression of both Sirtβ 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 Sirtβ transgenic (Tg.Sirtβ) mice were protected from developing obesity and insulin resistance when fed with the same HF‐HS diet. The hearts of Tg.Sirtβ mice were also protected from mitochondrial fragmentation and decline of Sirt3, resulting otherwise from HF‐HS diet feeding. Mechanistic studies showed that Sirt3 preserves Sirtβ levels by reducing oxidative stress, whereas Sirtβ maintains Sirt3 levels by up‐regulating nuclear respiratory factor 2 (Nrf2)‐dependent Sirt3 gene transcription. We found that Sirtβ regulates Nrf2‐mediated cardiac gene expression in 2 ways; first, Sirtβ suppresses expression of Kelch‐like ECH‐associated protein 1 (Keapl), a negative regulator of Nrf2, and second, Sirtβ binds to Nrf2 and antagonizes its interaction with Keapl, thereby stabilizing Nrf2 levels in cardiomyocytes. Together, these studies demonstrate that Sirtβ 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, Sirtβ and Sirt3, regulate each other's activity and protect the heart from developing obesity‐mediated diabetic cardiomyopathy. FASEB J. 33, 10872–10888 (2019). www.fasebj.org