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

Marija Pinterić,Vladimir Farkaš,Robert Bagarić,Iva I Podgorski,Tihomir Balog,Ivana Tartaro Bujak,Ana Dekanić,Sandra Sobočanec,Marijana Popović Hadžija

doi:10.3390/antiox9020174

Marija Pinterić, Vladimir Farkaš + Show 7 more

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https://doi.org/10.3390/antiox9020174

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Journal: Antioxidants	Publication Date: Feb 20, 2020
Citations: 11	License type: CC BY 4.0

Affiliation: Rudjer Boskovic Institute

Abstract

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, pparγ, cyp2e1, cyp4a14, 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.

Highlights

The metabolic syndrome is metabolic derangement involving a cluster of risk factors primarily associated with obesity, type two diabetes, and a high risk of cardiovascular events, and with the development of inflammation, atherosclerosis, renal, liver and respiratory disease, cancer, and premature aging [1,2]
Sexual dimorphism exists in various physiological processes, with males and females differing with respect to their regulation of energy homeostasis, metabolic rate, or body weight gain [34]
We report the following novel observations in conditions of high fat diet (HFD) feeding and Sirtuin 3 (Sirt3) depletion in liver of 129S mice: (a) HFD reduces hepatic Sirt3 expression solely in males, but only partially; (b) HFD-induced lipid accumulation is alleviated in the absence of Sirt3 only in males, which may be attributed to impaired glucose uptake and an increased reliance on fatty acids; (c) in females, either an HFD or the absence of Sirt3 compromised mitochondrial respiration and increased protein oxidative damage, which could be associated with more efficient lipid metabolism

Summary

Introduction

The metabolic syndrome is metabolic derangement involving a cluster of risk factors primarily associated with obesity, type two diabetes, and a high risk of cardiovascular events, and with the development of inflammation, atherosclerosis, renal, liver and respiratory disease, cancer, and premature aging [1,2]. The increase in caloric food intake or consumption of diets high in both fat and carbohydrates ( known as a “western diet”) along with physical inactivity leads to increased obesity, a key factor in the development of metabolic syndrome. Human metabolic syndrome can be effectively mimicked in rodent models using dietary intervention, such as high-fat diets (HFDs) [3]. Oxidative stress is associated with the metabolic syndrome, but whether it is the cause or the consequence is a matter of debate. An HFD is Antioxidants 2020, 9, 174; doi:10.3390/antiox9020174 www.mdpi.com/journal/antioxidants

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