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SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72\u201379% of AL (group 2), DR at 68\u201372% of AL (group 3) or DR at 47\u201348% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Body weights, organ weights, carcass analysis, in-life data including estrous cyclicity, and histopathology were determined. At 6\u20137 weeks of age SD rats had 6% body fat. AL-feeding resulted in hypertriglyceridemia, hypercholesterolemia, and dietary-induced obesity (DIO) by study week 14, with 25% body fat that progressed to 36\u201342% body fat by 106 weeks. As early as 14 weeks, key biomarkers developed for spontaneous nephropathy, cardiomyopathy, and degenerative changes in multiple organ systems. Early endocrine disruption was indicated by changes in metabolic and endocrine profiles and the early development and progression of lesions in the pituitary, pancreatic islets, adrenals, thyroids, parathyroids, liver, kidneys, and other tissues. Reproductive senescence was seen by 9 months with declines in estrous cyclicity and pathological changes in the reproductive organs of both sexes fed AL or moderate DR, but not marked DR. The diabesity syndrome in AL-fed, DIO SD rats was readily modulated or prevented by moderate to marked DR. Moderate DR of balanced diets resulted in a better toxicology model by significantly improving survival, controlling adult body weight and obesity, reducing the onset, severity, and morbidity of age-related renal, endocrine, metabolic, and cardiac diseases. Moderate DR feeding reduces study-to-study variability, increases treatment exposure time, and increases the ability to distinguish true treatment effects from spontaneous aging. The structural and metabolic differences between the phenotypes of DIO and DR SD rats indicated changes of polygenic expression over time in this outbred stock. AL-overfeeding of SD rats produces a needed model of DIO and diabesity that needs further study of its patterns of polygenic expression and phenotype.<\/jats:p>","DOI":"10.1080\/01926230500311222","type":"journal-article","created":{"date-parts":[[2006,2,7]],"date-time":"2006-02-07T14:02:03Z","timestamp":1139320923000},"page":"650-674","source":"Crossref","is-referenced-by-count":30,"title":["Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague\u2013Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction"],"prefix":"10.1177","volume":"33","author":[{"given":"Kevin P.","family":"Keenan","sequence":"first","affiliation":[{"name":"Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Min","family":"Hoe","sequence":"additional","affiliation":[{"name":"Merck Research Laboratories, Department of Biometrics, West Point, 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