The F-DIO Obesity-prone Rat is Insulin Resistant Prior to Obesity Onset

Running Title: Non-obese F-DIO rats are insulin resistant ABSTRACT 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.