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This Article Full Text Full Text (PDF) All Versions of this Article: 289/3/R704    most recent 00216.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Levin, B. E. Articles by Dunn-Meynell, A. A. Search for Related Content PubMed PubMed Citation Articles by Levin, B. E. Articles by Dunn-Meynell, A. A.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

F-DIO obesity-prone rat is insulin resistant before obesity onset

¹Neurology Service, Veterans Administration Medical Center, East Orange, New Jersey; ²Department of Neurology and Neurosciences, New Jersey Medical School, Newark, New Jersey; ³Universite Paris 7, Centre National de la Recherche Scientifique Unite Mixte de Recherche, Paris, France; ⁴Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York

Submitted 28 March 2005 ; accepted in final form 3 May 2005

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.

neuropeptide Y; proopiomelanocortin; orexin; diabetes; development

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