Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver

Chukijrungroat, Natsasi; Khamphaya, Tanaporn; Weerachayaphorn, Jittima; Songserm, Thaweesak; Saengsirisuwan, Vitoon

doi:10.1152/ajpendo.00076.2017

Cited by 56 publications

(51 citation statements)

References 33 publications

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“…Finally, differences in age, adiposity and background diets may also have contributed to the discrepant findings between these studies. In support of our findings, studies in a rodent model feeding a high-fat high-fructose diet (HFFD) for 12 weeks found the hepatic protein level of acetyl-CoA carboxylase and fatty acid synthase, which would suggest higher DNL, were significantly upregulated in female rats on the HFFD compared to the control diet whilst there was no change in male rats between the HFFD and control diets (Chukijrungroat et al 2017). Couchepin et al (2008) compared the sex-specific metabolic effects of 6 days' fructose overfeeding (3.5 g fructose/kg fat-free mass/day; 130% energy requirements); body weight increased in both males and females.…”

Section: Fructose and Sex-specific Effectssupporting

confidence: 84%

“…In support of our findings, studies in a rodent model feeding a high‐fat high‐fructose diet (HFFD) for 12 weeks found the hepatic protein level of acetyl‐CoA carboxylase and fatty acid synthase, which would suggest higher DNL, were significantly upregulated in female rats on the HFFD compared to the control diet whilst there was no change in male rats between the HFFD and control diets (Chukijrungroat et al . ).…”

Section: Introductionmentioning

confidence: 99%

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Challenging metabolic tissues with fructose: tissue‐specific and sex‐specific responses

Pinnick

Hodson

2019

The Journal of Physiology

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Excessive consumption of free sugars (which typically includes a composite of glucose and fructose) is associated with an increased risk of developing chronic metabolic diseases including obesity, non‐alcoholic fatty liver disease (NAFLD), type 2 diabetes and cardiovascular disease. Determining the utilisation, storage and fate of dietary sugars in metabolically relevant tissues is fundamental to understanding their contribution to metabolic disease risk. To date, the study of fructose metabolism has primarily focused on the liver, where it has been implicated in impaired insulin sensitivity, increased fat accumulation and dyslipidaemia. Yet we still have only a limited understanding of the mechanisms by which consumption of fructose, as part of a mixed meal, may alter hepatic fatty acid synthesis and partitioning. Moreover, surprisingly little is known about the metabolism of fructose within other organs, specifically subcutaneous adipose tissue, which is the largest metabolically active organ in the human body and is consistently exposed to nutrient fluxes. This review summarises what is known about fructose metabolism in the liver and adipose tissue and examines evidence for tissue‐specific and sex‐specific responses to fructose.

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Section: Fructose and Sex-specific Effectssupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Challenging metabolic tissues with fructose: tissue‐specific and sex‐specific responses

Pinnick

Hodson

2019

The Journal of Physiology

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“…Sex differences in the metabolic effects of fructose and/or copper de ciency have been noted in rodents (23)(24)(25)(26) as well as in humans (27,28), with more harmful effects reported in males and more protective effects in females, which is consistent with the sex differences in NAFLD (7). In fact, sex differences in fructose-induced metabolic effects are more complex and vary by tissue and organ (14,29,30). Although sex hormones are one of the factors leading to sex differences in copper-fructose interaction-induced metabolic disorders (26), the underlying mechanisms are largely unknown.…”

Section: Introductionsupporting

confidence: 58%

“…In contrast, liver injury was improved by hormone replacement therapy in postmenopausal women with type 2 diabetes (13). Ovariectomized (OVX) female rats exhibit exacerbated hepatic steatosis when exposed to high-fat high-fructose diet (HFFD), which was reversed by estrogen replacement (14). A four core genotypes mouse model (XX gonadal male and female, XY gonadal male and female) allows for the identi cation of whether sex differences arise from the sex chromosome complement.…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Dietary Copper-Fructose Interaction-Induced Alterations of Gut Microbial Activity are Not Correlated to Hepatic Steatosis

Song

Fang

et al. 2020

Preprint

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Abstract Background: Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the US. Diet copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner, and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. Methods: Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6mg/kg and 1.5mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma ALT, AST and liver histology were evaluated. Fecal microbial contents were analyzed by 16S rRNA sequencing. Fecal and cecal short chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS).Results: Male and female rats exhibit similar trends of changes in the body weight, body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. Conclusions: Our data demonstrated sex differences in the alterations of gut microbial activities and hepatic steatosis in response to dietary copper-fructose interaction in rats. Tissue-specific responses to dietary copper and fructose likely contribute to the sex differences in gut microbial activity and metabolic phenotype.

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“…Wang et al (2017) found that higher serum FGF21 levels were associated with an increased risk of type 2 diabetes in Chinese women but not in men. Diets that induce NAFLD also affected hepatic Fgf21 expression in sex-specific manners: highfat high-fructose diet increased Fgf21 expression only in male rats (Chukijrungroat et al, 2017), methioninecholine deficient diet only increased expression in female mice (Lee et al, 2016) and cafeteria obesogenic diet only increased expression in male mice. It is unknown whether the sex differences in the expression of FGF21 are manifested only in metabolic diseases and, possibly, are a consequence of these diseases, or if the activation of Fgf21 expression is sex-specific under natural physiological adaptations to nutritional stresses.…”

Section: Introductionmentioning

confidence: 99%

Sex Dimorphism in the Fgf21 Gene Expression in Liver and Adipose Tissues is Dependent on the Metabolic Condition

Бажан¹,

Jakovleva²,

Balyibina³

et al. 2019

OnLine Journal of Biological Sciences

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Fibroblast growth factor-21 (FGF21) beneficially affects carbohydrate and lipid metabolism. Previously, a sex-specific activation of Fgf21 expression was observed in humans and animals with metabolic diseases. It is unknown whether the sex differences in the Fgf21 expression are manifested in response to the natural physiological situations of fasting and refeeding. The aim of this work was to determine liver, White Adipose Tissue (WAT) and Brown Adipose Tissue (BAT) expression of genes related to FGF21 signaling in response to 24 h fasting, 6 h refeeding (after 24 h fasting) and Diet-Induced Obesity (DIO) in C57Bl mice of both sexes. Obesity was induced by the consumption of palatable food for 10 weeks. mRNA levels of peroxisome proliferator-activated receptor-a and-γ (Pparα, Pparγ), FGF21 (Fgf21), coactivator of FGF receptors (Klb) and transcriptional coactivator (Pgc-1α) were measured by RT-PCR. The study showed that the fasting-induced increases in hepatic Fgf21 gene expression and circulating FGF21 levels, as well as refeeding-induced increases in local WAT and BAT Fgf21 gene expression, were biased toward females. DIO-induced increase in circulating FGF21 levels, as well as in Fgf21 gene expression in the liver and BAT, were biased toward males. Considering that FGF21 is a novel metabolic regulator of energy homeostasis, sex differences in the responses to anabolic and catabolic stimulus could have translational implications for novel therapeutic outcomes.

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Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver

Cited by 56 publications

References 33 publications

Challenging metabolic tissues with fructose: tissue‐specific and sex‐specific responses

Challenging metabolic tissues with fructose: tissue‐specific and sex‐specific responses

Sex Differences in Dietary Copper-Fructose Interaction-Induced Alterations of Gut Microbial Activity are Not Correlated to Hepatic Steatosis

Sex Dimorphism in the Fgf21 Gene Expression in Liver and Adipose Tissues is Dependent on the Metabolic Condition

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