A high fat diet induces sex-specific differences in hepatic lipid metabolism and nitrite/nitrate in rats

Abstract

Men and women differ substantially with regard to the severity of insulin resistance (IR) but the underlying mechanism(s) of how this occurs is poorly characterized. We investigated whether a high fat (HF) diet resulted in sex-specific differences in nitrite/nitrate production and lipid metabolism and whether these variances may contribute to altered obesity-induced IR. Male and female Wistar rats were fed a standard laboratory diet or a HF diet for 10 weeks. The level of plasma nitrite/nitrate, as well as free fatty acid (FFA), in both plasma and liver lysates were assessed. The levels of inducible nitric oxide (NO) synthase (iNOS), p65 subunit of NFκB, total and phosphorylated forms of Akt, mTOR and PDK-1 in lysates, and the levels of glucose transporter 2 (Glut-2) and fatty acid translocase/cluster of differentiation 36 (FAT/CD36) in plasma membrane fractions of liver were assessed. HF-fed male rats exhibited a significant increase in plasma nitrite/nitrate, and hepatic FFA and FAT/CD36 levels compared with controls. They also displayed a relative decrease in iNOS and Glut-2 levels in the liver. Phosphorylation of Akt (at Ser(473) and Thr(308)), mTOR and PDK-1 was also reduced. HF-fed female rats exhibited increased levels of NFκB-p65 in liver compared with controls, while levels of Glut-2, FAT/CD36 and Akt phosphorylation at Thr(308) and PDK-1 were decreased. Our results reveal that altered lipid and glucose metabolism in obesity, lead to altered iNOS expression and nitrite/nitrate production. It is likely that this mechanism contributes to sex-specific differences in the development of IR.

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

“…We previously reported that a HF diet causes the development of an obese phenotype in both male and female rats [39,48,49]. In addition, our previous results show that the level total cholesterol was increased in the liver obese female, suggesting excessive intrahepatic lipid accumulation caused by obesity [39].…”

“…In addition, our previous results show that the level total cholesterol was increased in the liver obese female, suggesting excessive intrahepatic lipid accumulation caused by obesity [39]. However, only in male rats did a HF diet induce obesity leading to hyperlipidaemia, hyperglycaemia and IR [39,48].…”

“…Additionally, we have recently shown sex-specific differences in hepatic iNOS regulation in HF-diet fed rats [39]. There is limited knowledge as to the effects of a HF-diet on cardiac iNOS in female rats and the mechanisms by which obesity reverses the cardioprotective effects of oestradiol are poorly understood.…”

“…In this study we used adult HOMA-index of β-cell function (HOMA-β) and plasma nitrate/nitrite levels in control and obese female rats [39], and shown that our obese female rats did not develop IR (assessed by unchanged levels of HOMA-IR and HOMA β). Experimental protocols were approved by the Vinca Institute Ethical Committee for Experimental Animals.…”

Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high-fat diet

“…We have previously reported that a HF diet, despite causing the development of an obese phenotype in both male and female rats, only induces hyperlipidaemia, hyperglycaemia, and IR in male rats [39,30,40]. Furthermore, we have reported that in male rats, obesity accompanied with IR decreases cardiac Na + /K + -ATPase activity/expression, while estradiol administration as bolus injection achieved contrary effects.…”