title: Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy.
abstract: We previously reported that prenatal and suckling exposure to a maternal diet rich in animal fat leads to cardiovascular dysfunction in young adult rat offspring with subsequent development of dyslipidemia and hyperglycemia. We have further investigated glucose homeostasis in adult female offspring by euglycemic-hyperinsulinemic clamp and by dynamic assessment of glucose-stimulated insulin secretion in isolated, perifused pancreatic islet cells. Additionally, given the link between reduced mitochondrial DNA (mtDNA) content and the development of type 2 diabetes mellitus, we have measured mtDNA in organs from young adult animals. Sprague-Dawley rats were fed a diet rich in animal fat or normal chow throughout pregnancy and weaning. Infusion of insulin (5 mU.kg(-1).min(-1)) resulted in a higher steady-state plasma insulin concentration in 1-year-old offspring of fat-fed dams (OHF, n = 4) vs. offspring of control dams (OC, n = 4, P < 0.01). Glucose-stimulated insulin secretion in isolated islets from 9-mo-old OHF was significantly reduced compared with OC (n = 4, P < 0.05). Transmission electron micrography showed altered insulin secretory granule morphology in OHF pancreatic beta-cells. Kidney mtDNA was reduced in 3-mo-old OHF [16S-to-18S gene ratio: OC (n = 10) 1.05 +/- 0.19 vs. OHF (n = 10) 0.66 +/- 0.06, P < 0.05]. At 6 mo, gene chip microarray of OHF aorta showed reduced expression of the mitochondrial genome. Prenatal and suckling exposure to a diet rich in animal fat leads to whole body insulin resistance and pancreatic beta-cell dysfunction in adulthood, which is preceded by reduced tissue mtDNA content and altered mitochondrial gene expression.
authors.affiliation: Division of Reproductive Health, Endocrinology and Development, King's College London, United Kingdom. paul.taylor@kcl.ac.uk
authors.forename: Paul D
authors.initials: PD
authors.lastname: Taylor
authors.forename: Josie
authors.initials: J
authors.lastname: McConnell
authors.forename: Imran Y
authors.initials: IY
authors.lastname: Khan
authors.forename: Kathleen
authors.initials: K
authors.lastname: Holemans
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Lawrence
authors.forename: Henry
authors.initials: H
authors.lastname: Asare-Anane
authors.forename: Shanta J
authors.initials: SJ
authors.lastname: Persaud
authors.forename: Peter M
authors.initials: PM
authors.lastname: Jones
authors.forename: Linda
authors.initials: L
authors.lastname: Petrie
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hanson
authors.forename: Lucilla
authors.initials: L
authors.lastname: Poston
mesh_terms: D000273:Adipose Tissue / Q000254:growth & development; D000818:Animals; D001786:Blood Glucose / Q000502:physiology*; D001835:Body Weight; D004041:Dietary Fats / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D007515:Islets of Langerhans / Q000502:physiology; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D024821:Metabolic Syndrome / Q000196:embryology; D008928:Mitochondria / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D039401:Prenatal Nutritional Physiological Phenomena / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; D008055:Lipids