Obesity is associated with increased susceptibility to dyslipidemia, insulin resistance, and hypertension, a combination of traits that comprise the traditional definition of the metabolic syndrome. Recent evidence suggests that obesity is also associated with the development of nonalcoholic fatty liver disease (NAFLD). Despite the high prevalence of obesity and its related conditions, their etiologies and pathophysiology remains unknown. Both genetic and environmental factors contribute to the development of obesity and NAFLD. Previous genetic analysis of high-fat, diet-induced obesity in C57BL/6J (B6) and A/J male mice using a panel of B6-ChrA/J/NaJ chromosome substitution strains (CSSs) demonstrated that 17 CSSs conferred resistance to high-fat, diet-induced obesity. One of these CSS strains, CSS-17, which is homosomic for A/J-derived chromosome 17, was analyzed further and found to be resistant to diet-induced steatosis. In the current study we generated seven congenic strains derived from CCS-17, fed them either a high-fat, simple-carbohydrate (HFSC) or low-fat, simple-carbohydrate (LFSC) diet for 16 weeks and then analyzed body weight and related traits. From this study we identified several quantitative trait loci (QTLs). On a HFSC diet, Obrq13 protects against diet-induced obesity, steatosis, and elevated fasting insulin and glucose levels. On the LFSC diet, Obrq13 confers lower hepatic triglycerides, suggesting that this QTL regulates liver triglycerides regardless of diet. Obrq15 protects against diet-induced obesity and steatosis on the HFSC diet, and Obrq14 confers increased final body weight and results in steatosis and insulin resistance on the HFSC diet. In addition, on the LFSC diet, Obrq 16 confers decreased hepatic triglycerides and Obrq17 confers lower plasma triglycerides on the LFSC diet. These congenic strains provide mouse models to identify genes and metabolic pathways that are involved in the development of NAFLD and aspects of diet-induced metabolic syndrome.
Mammalian Genome – Springer Journals
Published: Jan 10, 2009
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