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1 Neurology Service (127C), Veterans Administration Medical Center, East Orange, New Jersey, USA; Neurology and Neurosciences, New Jersey Medical School/University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
2 CNRS UMR 7059, Universite Paris, Paris, France
3 Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York, USA
* To whom correspondence should be addressed. E-mail: levin{at}umdnj.edu.
We previously created a novel F-DIO rat strain derived by crossing rats selectively bred for the diet-induced obese (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 diet high energy (HE). 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 non-obese, chow-fed state persisted in the F6 generation. Also, in comparison to 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 which influence the development and persistence of obesity.
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