title: Sex-dependent hepatic transcripts and metabolites in the development of glucose intolerance and insulin resistance in Zucker diabetic fatty rats.
abstract: Male Zucker diabetic fatty (mZDF) rats spontaneously develop type 2 diabetes, whereas females only become diabetic when fed a diabetogenic high-fat diet (high-fat-fed female ZDF rat, HF-fZDF). The aim of this study was to investigate if differences in liver functions could provide clues to this sex difference. Non-diabetic obese fZDF rats were compared with either mZDF or HF-fZDF regarding hepatic molecular profiles, to single out those components that might be protective in the females. High-fat feeding in fZDF led to enhanced weight gain, increased blood glucose and insulin levels, reduced insulin sensitivity and a trend towards reduced glucose tolerance, indicative of a prediabetic state. mZDF rats were diabetic, with low levels of insulin, high levels of glucose, reduced insulin sensitivity and impaired glucose tolerance. Transcript profiling and capillary electrophoresis time-of-flight mass spectrometry were used to indentify hepatic transcripts and metabolites that might be related to this. Many diet-induced alterations in transcript and metabolite levels in female rats were towards a 'male-like' phenotype, including reduced lipogenesis, increased fatty acid (FA) oxidation and increased oxidative stress responses. Alterations detected at the level of hepatic metabolites, indicated lower capacity for glutathione (GSH) production in male rats, and higher GSH turnover in females. Taken together, this could be interpreted as if anabolic pathways involving lipogenesis and lipid output might limit the degree of FA oxidation and oxidative stress in female rats. Together with a greater capacity to produce GSH, these hepatic sex differences might contribute to the sex-different development of diabetes in ZDF rats.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gustavsson
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Erik
authors.initials: E
authors.lastname: Wahlström
authors.forename: Mattias
authors.initials: M
authors.lastname: Vesterlund
authors.forename: Alireza
authors.initials: A
authors.lastname: Azimi
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norstedt
authors.forename: Petra
authors.initials: P
authors.lastname: Tollet-Egnell
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D004041:Dietary Fats / Q000009:adverse effects; D005260:Female; D020869:Gene Expression Profiling; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D015151:Immunoblotting; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats