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Biochim Biophys Acta Mol Basis Dis. 2018 Jul;1864(7):2495-2509. doi: 10.1016/j.bbadis.2018.04.004. Epub 2018 Apr 10.

Sex differences in the development of hepatic steatosis in cafeteria diet-induced obesity in young mice.

Author information

1
Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, University of Maringá, Maringá, Paraná, Brazil.
2
Department of Physiological Sciences, University of Maringá, Maringá, Paraná, Brazil.
3
Department of Morphophysiological Sciences, University of Maringá, Maringá, Paraná, Brazil.
4
Laboratory of Bioenergetics, Faculty of Pharmaceutical Sciences, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
5
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
6
Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, University of Maringá, Maringá, Paraná, Brazil. Electronic address: eliiwamoto@uem.br.

Abstract

The present study was planned to improve our understanding about sex differences in the development of hepatic steatosis in cafeteria diet-induced obesity in young mice. Female (FCaf) and male (MCaf) mice fed a cafeteria diet had similar body weight gain and adiposity index, but FCaf had a more extensive steatosis than MCaf. FCaf livers exhibited a higher non-alcoholic fatty liver disease activity score, elevated lipid percentage area (+34%) in Sudan III staining and increased TG content (+25%) compared to MCaf. Steatosis in FCaf was not correlated with changes in the transcript levels of lipid metabolism-related genes, but a reduced VLDL release rate was observed. Signs of oxidative stress were found in FCaf livers, as elevated malondialdehyde content (+110%), reduced catalase activity (-36%) and increased Nrf2 and Hif1a mRNA expression compared to MCaf. Interestingly, fibroblast growth factor 21 (Fgf21) mRNA expression was found to be exclusively induced in MCaf, which also exhibited higher FGF21 serum levels (+416%) and hepatic protein abundance (+163%) than FCaf. Moreover, cafeteria diet increased Fgfr1, Fsp27 and Ucp1 mRNA expression in brown adipose tissue of males (MCaf), but not females (FCaf). FGF21 hepatic production by male mice seems to be part of a complex network of responses to the nutritional stress of the cafeteria diet, probably related to the unfolded protein response activation. Although aimed at the restoration of hepatic metabolic homeostasis, the branch involving Fgf21 upregulation seems to be impaired in females, rendering them incapable of reducing the hepatic lipid content and cellular oxidative stress.

KEYWORDS:

Adipose tissue; FGF21; Hepatic steatosis; Oxidative stress; Sex dimorphism; Western diet

PMID:
29653185
DOI:
10.1016/j.bbadis.2018.04.004
[Indexed for MEDLINE]

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