The Role of Mitochondria in Sex-Dependent Differences in Hepatic Steatosis and Oxidative Stress in Response to Cafeteria Diet-Induced Obesity in Mice.

Juliana Morais Mewes,Tiago Yoshida,Byanca Thais Lima De Souza,Marcio Shigueaki Mito,Rodrigo Polimeni Constantin,Karina Sayuri Utsunomiya,Jorgete Constantin,Eduardo Makiyama Klosowski,Mariana Amâncio Daniel Da Silva,Paulo Francisco Veiga Bizerra,Emy Luiza Ishii-Iwamoto,Gislaine Cristiane Mantovanelli,Eduardo Hideo Gilglioni,Fabiana Rodrigues Silva Gasparin,Maria Raquel Marçal Natali

doi:10.3390/nu11071618

Juliana Morais Mewes, Tiago Yoshida + Show 13 more

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https://doi.org/10.3390/nu11071618

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Journal: Nutrients	Publication Date: Jul 16, 2019
Citations: 5	License type: CC BY 4.0

Affiliation: Universidade Estadual de Maringá

Abstract

Female mice fed a cafeteria diet (FCaf) develop higher liver steatosis and oxidative stress than males (MCaf) as a consequence of unresolved ER stress. Here, we investigated whether mitochondria play a role in this sex difference. The isolated mitochondria from FCaf showed more signs of oxidative stress than those of MCaf, correlated with a reduced content of GSH, increased amount of reactive oxygen species (ROS), and lower activities of enzymes involved in ROS neutralisation. Mitochondria from FCaf and MCaf livers exhibited lower rates of succinate-driven state III respiration and reduced ATPase activity in intact coupled mitochondria compared to their controls fed a standard diet (FC and MC), with no differences between the sexes. Fatty acid oxidation in mitochondria and peroxisomes was higher in MCaf and FCaf compared to their respective controls. In the intact perfused liver, there was no difference between sex or diet regarding the fatty acid oxidation rate. These results indicated that cafeteria diet did not affect mitochondrial energy metabolism, even in FCaf livers, which have higher steatosis and cellular oxidative stress. Nevertheless, the increase in mitochondrial ROS generation associated with a decrease in the antioxidant defence capacity, probably contributes to inducing or reinforcing the ER stress in FCaf livers.

Highlights

The westernised lifestyle is often associated with the consumption of diets that offer an overload of nutrients, leading to obesity and several related metabolic disturbances, including non-alcoholic fatty liver disease (NAFLD)
As previously reported in cafeteria diet-induced obese mice [1], there was no significant difference in the initial weight between the groups (Figure 1A); at the end of the experimental period (14th week), a significant increase in body weight was found in the cafeteria diet-fed groups, of 21.7% for males fed a cafeteria diet (MCaf) and 26.7% for fed a cafeteria diet (FCaf), compared to their respective counterparts (MC and FC), with no effect of sex between the groups (Figure 1B)
The cafeteria diet induced a significant increase in the percentage of body fat (Figure 1C) in both sexes, and the relative increase was higher in males (+65.4%) and females (+41.6%) compared to MC and FC, respectively

Summary

Introduction

The westernised lifestyle is often associated with the consumption of diets that offer an overload of nutrients, leading to obesity and several related metabolic disturbances, including non-alcoholic fatty liver disease (NAFLD). The observation that such changes in FGF21 levels do not occur in obese females, which instead exhibit features of unresolved ER (endoplasmic reticulum) stress, led us to suggest that the hepatic steatosis induced by the cafeteria diet in mice is directly related to ER stress [1]. This assumption is in line with recent evidence that the ER acts as a sensor of metabolic derangement associated with an imbalanced diet, which activates an adaptive UPR (unfolded protein response), directing cells for either survival or death [2,3]. We have collected evidence that the branch of UPR involving Fgf up-regulation, in order to resolve the ER stress, seems to be effective in males but not in females under cafeteria diet-induced nutritional stress, which makes the females susceptible to the development of hepatic steatosis and cellular oxidative stress [1]

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