title: 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.
authors.affiliation: Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, Belgrade, Serbia. Electronic address: julijana1008@gmail.com.
authors.forename: Julijana
authors.initials: J
authors.lastname: Stanimirovic
authors.affiliation: Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, Belgrade, Serbia. Electronic address: obradovicmilan@hotmail.com.
authors.forename: Milan
authors.initials: M
authors.lastname: Obradovic
authors.affiliation: Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, Belgrade, Serbia. Electronic address: jovsale@gmail.com.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Jovanovic
authors.affiliation: Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, Belgrade, Serbia. Electronic address: emma_crash@yahoo.com.
authors.forename: Emina
authors.initials: E
authors.lastname: Sudar-Milovanovic
authors.affiliation: Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, Belgrade, Serbia. Electronic address: sonjazafirovic@hotmail.com.
authors.forename: Sonja
authors.initials: S
authors.lastname: Zafirovic
authors.affiliation: School of Medicine, University of St Andrews, North Haugh, St Andrews, KY16 9TF, United Kingdom. Electronic address: sjp24@st-andrews.ac.uk.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Pitt
authors.affiliation: School of Medicine, University of St Andrews, North Haugh, St Andrews, KY16 9TF, United Kingdom. Electronic address: ajs21@st-andrews.ac.uk.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Stewart
authors.affiliation: Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, Belgrade, Serbia. Electronic address: isenovic@yahoo.com.
authors.forename: Esma R
authors.initials: ER
authors.lastname: Isenovic
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D005260:Female; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009566:Nitrates / Q000097:blood*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000097:blood*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D009566:Nitrates; D009573:Nitrites; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C546845:mTOR protein, rat; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578579:Pdpk1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: High fat diet; Insulin resistance; Liver metabolism; Nitrite/nitrate; Sex differences