Obesity is a heritable trait caused by complex interactions between genes and environment, including diet. Gene-by-diet interactions are difficult to study in humans because the human diet is hard to control. Here, we used mice to study dietary obesity genes, by four methods. First, we bred 213 F2 mice from strains that are susceptible [C57BL/6ByJ (B6)] or resistant [129P3/J (129)] to dietary obesity. Percent body fat was assessed after mice ate low-energy diet and again after the same mice ate high-energy diet for 8 weeks. Linkage analyses identified QTLs associated with dietary obesity. Three methods were used to filter candidate genes within the QTL regions: (a) association mapping was conducted using >40 strains; (b) differential gene expression and (c) comparison of genomic DNA sequence, using two strains closely related to the progenitor strains from Experiment 1. The QTL effects depended on whether the mice were male or female or which diet they were recently fed. After feeding a low-energy diet, percent body fat was linked to chr 7 (LOD=3.42). After feeding a high-energy diet, percent body fat was linked to chr 9 (Obq5; LOD=3.88), chr 12 (Obq34; LOD=3.88), and chr 17 (LOD=4.56). The Chr 7 and 12 QTLs were sex dependent and all QTL were diet-dependent. The combination of filtering methods highlighted seven candidate genes within the QTL locus boundaries: Crx, Dmpk, Ahr, Mrpl28, Glo1, Tubb5, and Mut. However, these filtering methods have limitations so gene identification will require alternative strategies, such as the construction of congenics with very small donor regions.
Calcium retention varies with developmental state, which may be partially under the control of insulin-like growth factor 1 (IGF-1). IGF-1 levels can be manipulated through dietary and therapeutic interventions. We investigated the relationship between IGF-1 endogenous production and calcium utilization and bone accretion during growth as well as the effects of IGF-1 treatment on calcium utilization during rapid and slowed growth in intact female Sprague-Dawley rats. In 33 rats killed at 11 time points (n = 3 each) from age 4 to 24 wk, femoral and vertebral bone mass were paralleled by plasma IGF-1 up to 9 wk. Fractional calcium absorption was maximal at 9 wk, reduced by one-half at 12 wk, and there was no further change at 20 wk. From this study, we selected 2 stages of growth, rapid and slow, for a subsequent intervention study. A 4-wk intervention was initiated at 6 or 8 wk when rats (n = 15/group) received either continuous rhIGF-1/IGF binding protein 3 (IGFBP3) infusion (0.3 mg/d) or vehicle (control) by osmotic mini-pumps. In rapidly growing IGF-1/IGFBP3-treated rats compared to controls, but not in slowly growing treated compared to control rats, IGF-1 treatment increased (P < 0.05) calcium absorption (35 vs. 21%), bone calcium balance (0.55 vs. 0.3 mmol/d), and femoral calcium content (31 vs. 24% of dry weight). Exogenous IGF-1/IGFBP3 treatment increased calcium accretion during rapid growth, but rats past rapid growth were no longer as sensitive to this dose of IGF-1/IGFBP3. Thus, interventions designed to improve bone mass through increased IGF-1 will have the greatest impact during rapid growth.
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