Received for publication August 14, 2008.
Revised October 9, 2008.
Accepted for publication October 28, 2008.

Mechanism-Based Modeling of Nutritional and Leptin Influences on Growth in Normal and Type 2 Diabetic Rats

Abstract

Influences of genetic and nutritional factors on body weight, fat mass, and leptin production, and effects of leptin were assessed in normal (WKY) and diabetic (GK) rats by mechanism-based modeling. The study included 60 WKY and 60 GK rats: half received high-fat diet (HF), the others 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 measured by ELISA. All data were co-modeled using NONMEM VI (FOCE-I). 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 LBM^0.75) 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 about three-fold higher in GK vs. WKY, indicating leptin resistance for the effect on food consumption in GK. The GK had similar kcal intake, but lower body weights and fat mass than WKY, possibly due to 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.

Key words: Abdominal fat, Food intake, Leptin, Metabolic rate, PK/PD modeling, Type 2 Diabetes