title: F-DIO obesity-prone rat is insulin resistant before obesity onset.
abstract: We previously created a novel F-DIO rat strain derived by crossing rats selectively bred for the diet-induced obesity (DIO) phenotype with obesity-resistant Fischer F344 rats. The offspring retained the DIO phenotype through 3 backcrosses with F344 rats but also had exaggerated insulin responses to oral glucose before they became obese on a 31% fat high-energy (HE) diet. Here, we demonstrate that chow-fed rats from the subsequent randomly bred progeny required 57% lower glucose infusions to maintain euglycemia during a hyperinsulinemic clamp in association with 45% less insulin-induced hepatic glucose output inhibition and 80% lower insulin-induced glucose uptake than F344 rats. The DIO phenotype and exaggerated insulin response to oral glucose in the nonobese, chow-fed state persisted in the F6 generation. Also, compared with F344 rats, chow-fed F-DIO rats had 68% higher arcuate nucleus proopiomelanocortin mRNA expression which, unlike the increase in F344 rats, was decreased by 26% on HE diet. Further, F-DIO lateral hypothalamic orexin expression was 18% lower than in F344 rats and was increased rather than decreased by HE diet intake. Finally, both maternal obesity and 30% caloric restriction during the third week of gestation produced F-DIO offspring which were heavier and had higher leptin and insulin levels than lean F-DIO dam offspring. Third-gestational week dexamethasone also produced offspring with higher leptin and insulin levels but with lower body weight. Thus F-DIO rats represent a novel and potentially useful model for the study of DIO, insulin resistance, and perinatal factors that influence the development and persistence of obesity.
authors.affiliation: Neurology Service (127C), VA Medical Center, 385 Tremont Avenue, E. Orange, NJ 07018-1095, USA. levin@umdnj.edu
authors.forename: Barry E
authors.initials: BE
authors.lastname: Levin
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Migrenne
authors.forename: Streamson C
authors.initials: SC
authors.lastname: Chua
authors.forename: Ambrose A
authors.initials: AA
authors.lastname: Dunn-Meynell
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology; D007026:Hypothalamic Area, Lateral / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D000068797:Orexins; D010641:Phenotype; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D011333:Pro-Opiomelanocortin; D005947:Glucose