Role of Sirt3 in Differential Sex-Related Responses to a High-Fat Diet in Mice

• Main Authors: Marija Pinterić, Iva I. Podgorski, Marijana Popović Hadžija, Ivana Tartaro Bujak, Ana Dekanić, Robert Bagarić, Vladimir Farkaš, Sandra Sobočanec, Tihomir Balog
• Format: Article
• Language: English
• Published: MDPI AG 2020-02-01
• Series: Antioxidants
• Subjects: sirtuin 3; high fat diet; sex differences; mice; oxidative stress; metabolic stress
• Online Access: https://www.mdpi.com/2076-3921/9/2/174

Metabolic homeostasis is differently regulated in males and females. Little is known about the mitochondrial Sirtuin 3 (Sirt3) protein in the context of sex-related differences in the development of metabolic dysregulation. To test our hypothesis that the role of Sirt3 in response to a high-fat diet (HFD) is sex-related, we measured metabolic, antioxidative, and mitochondrial parameters in the liver of Sirt3 wild-type (WT) and knockout (KO) mice of both sexes fed with a standard or HFD for ten weeks. We found that the combined effect of Sirt3 and an HFD was evident in more parameters in males (lipid content, glucose uptake, <i>ppar&#947;</i>, <i>cyp2e1</i>, <i>cyp4a14</i>, Nrf2, MnSOD activity) than in females (protein damage and mitochondrial respiration), pointing towards a higher reliance of males on the effect of Sirt3 against HFD-induced metabolic dysregulation. The male-specific effects of an HFD also include reduced Sirt3 expression in WT and alleviated lipid accumulation and reduced glucose uptake in KO mice. In females, with a generally higher expression of genes involved in lipid homeostasis, either the HFD or Sirt3 depletion compromised mitochondrial respiration and increased protein oxidative damage. This work presents new insights into sex-related differences in the various physiological parameters with respect to nutritive excess and Sirt3.