Ubiquitous Sirt1 overexpression is associated with preserved cardiac diastolic function and mitochondrial respiratory capacity in mice on a high-fat diet

Background Chronic high-fat diet (HFD) induces obesity, insulin resistance, and mitochondrial dysfunction, serving as a critical driver of diabetic cardiomyopathy. In turn, the NAD+-dependent deacetylase Sirt1 regulates metabolic flexibility and cellular survival, making it a promising therapeutic target to counteract this diet-induced cardiovascular damage. Methods Here, we investigated the impact of a moderate, systemic Sirt1 overexpression (∼3-fold via a BAC transgenic mouse model; Sirt1 OE ) on HFD-induced metabolic and cardiac remodeling. Sirt1 OE and wild-type (WT) male mice were fed a HFD for 8 weeks. Whole-body glucose homeostasis, cardiac function, cardiac insulin signaling, and complex I-supported mitochondrial state 3 respiration (via Clark electrode) were assessed. Results HFD-fed WT mice developed obesity, fasting hyperglycemia, impaired glucose tolerance, isolated diastolic dysfunction (pre-HFpEF phenotype), and cardiac insulin resistance, characterized by blunted Akt phosphorylation. In Sirt1 OE mice, HFD-induced diastolic dysfunction was significantly mitigated, and maximal mitochondrial respiratory capacity remained preserved. This protection was associated with a selectively maintained downstream Akt (Ser473) activation despite upstream insulin receptor inhibition. On a systemic level, Sirt1 OE mice exhibited accelerated glucose clearance and a marked reduction in fat mass accumulation. Conclusion Moderate systemic Sirt1 overexpression protects against HFD-induced myocardial mitochondrial respiratory dysfunction and partially mitigates diastolic dysfunction. This cardioprotection is apparently cell-autonomously supported by the preservation of downstream insulin-Akt signaling, though partly facilitated by a reduced systemic adiposity and metabolic load. Strategies augmenting Sirt1 pathways warrant further investigation as therapeutic approaches against metabolic cardiomyopathies.