Key result
Moderate Sirt1 overexpression mitigates diet-induced diastolic dysfunction and preserves mitochondrial function in mice.
Why the study?
Chronic high-fat diet induces metabolic and cardiac dysfunction including diabetic cardiomyopathy, and the role of systemic Sirt1 overexpression in mitigating these effects is unclear.
Does moderate systemic Sirt1 overexpression protect against high-fat diet-induced metabolic and cardiac remodeling in male mice?
Does moderate systemic Sirt1 overexpression protect against high-fat diet-induced metabolic and cardiac remodeling in male mice?
Moderate systemic Sirt1 overexpression protects against high-fat diet-induced diastolic and mitochondrial dysfunction, suggesting Sirt1 pathways as a potential therapeutic target for metabolic cardiomyopathies.
Hypothesis-generating in obese mice; leaves open whether Sirt1 activation prevents human diabetic cardiomyopathy.
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.
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Schrepper et al. (2026) studied High-fat diet-induced metabolic and cardiac remodeling. Systemic Sirt1 overexpression vs. Wild-type (WT) mice was evaluated on Metabolic and cardiac remodeling (including glucose homeostasis, cardiac function, and mitochondrial respiration). Moderate (~3-fold) Sirt1 overexpression in male mice on an 8-week high-fat diet mitigated diastolic dysfunction and preserved mitochondrial respiratory capacity compared to wild-type mice.
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