Abstract
Influences of genetic and nutritional factors on body weight, fat mass, and leptin production and effects of leptin were assessed in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats by mechanism-based modeling. The study included 60 WKY and 60 GK rats; half received high-fat diet (HF), and the others received normal rat chow (N). Body weights and food consumption were measured twice weekly. Six rats per group were sacrificed at 4, 8, 12, 16, and 20 weeks. Abdominal fat was weighed, and plasma leptin was measured by enzyme-linked immunosorbent assay. All data were comodeled using NONMEM version VI level 1.1 (first-order conditional estimation with interaction) (Beal SL, Boeckmann AJ, Sheiner LB, and NONMEM Project Group, NONMEM Users Guides, University of California, San Francisco, CA, 2007). Weight gain was modeled as differences between energy intake and metabolic rate based on allometrically scaled lean body mass (LBM). The GK had higher metabolic rates (1.15 kcal/day/g LBM0.75) than WKY-N (0.92) and WKY-HF (1.02) rats and higher efficiency in transforming energy into body weight. Leptin effect was modeled as inhibition of food consumption. Total body fat was estimated from abdominal fat. Leptin production from fat was 4.7-fold higher for GK (3.03 ng/ml/day/g) than WKY (0.66 ng/ml/day/g). Leptin production rate from LBM was 0.53 ng/ml/day/g for all groups. The IC50 for inhibition of food intake by leptin was approximately 3-fold higher in GK versus WKY, indicating leptin resistance for the effect on food consumption in GK. The GK had similar intake of kilocalories but lower body weights and fat mass than WKY, possibly because of higher metabolic rates. Our mechanism-based model explains intrinsic reasons for differences in growth, food intake, and leptin concentrations among these two strains of rats.
Footnotes
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This work was supported by the UB-Pfizer Strategic Alliance.
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This work was previously presented in part at: Landersdorfer CB, DuBois DC, Almon RR, and Jusko WJ (2007) Mechanism-based modeling of nutritional and leptin influences on growth in normal and type 2 diabetic rats. Annual Meeting of the American Association of Pharmaceutical Scientists; 2007 Nov 12–15; San Diego, CA. American Association of Pharmaceutical Scientists, Arlington, VA.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.144766.
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ABBREVIATIONS: T2DM, type 2 diabetes mellitus; GK, Goto-Kakizaki; WKY, Wistar-Kyoto; N, normal diet; HF, high-fat diet; WT, total body weight; LBM, lean body mass; AFat, abdominal fat mass; CLept, leptin concentration; kin Food, zero order input constant for food; kout Food, loss parameter for food.
- Received August 13, 2008.
- Accepted October 28, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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