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1 Neurology Service, Department of Veterans Affairs Medical Center, E. Orange, NJ, USA; Neurosciences, New Jersey Medical School, Newark, NJ, USA
2 Department of Pediatrics, Division of Molecular Genetics, Columbia University, New York, NY, USA
* To whom correspondence should be addressed. E-mail: levin{at}umdnj.edu.
Previous breeding for the diet-induced obese (DIO) trait from outbred Sprague-Dawley rats produced a substrain with selection characteristics suggesting a polygenic mode of inheritance. To assess this issue further, selectively bred DIO male rats were crossed with obesity-resistant inbred Fisher F344 dams. Male offspring were crossed twice more against female F344 dams. The resultant N3 (F.DIO) rats were then inbred 3 more times. On low fat chow, 10wk old male and female DIO rats weighed 86% and 59% more than respective F344 rats. By the N3 (F.DIO) generation, they were only 12% and 10% heavier, respectively. After 3 additional inbreeding cycles, chow-fed F.DIO males had an exaggerated insulin response to oral glucose compared to F344 rats. Following 3wk on a 31% fat (HE) diet, male N3 F.DIO rats gained 16-20% more carcass and adipose weight with 98% higher plasma leptin levels, while F.DIO females gained 36-54% more carcass and adipose weight with 130% higher leptin levels than comparable F344 rats. After 3 inbreeding cycles, F.DIO males still gained more weight on HE diet and developed a 3-fold greater insulin response to oral glucose than F344 males. Preservation of the DIO and glucose intolerance traits through successive backcrosses and inbreeding cycles to produce the F.DIO strain lends further support to he idea that they inherited in a polygenic fashion.
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