Abstract
High phenotypic variation in diet-induced obesity in male C57BL/6J inbred mice suggests a molecular model to investigate non-genetic mechanisms of obesity. Feeding mice a high-fat diet beginning at 8 wk of age resulted in a 4-fold difference in adiposity. The phenotypes of mice characteristic of high or low gainers were evident by 6 wk of age, when mice were still on a low-fat diet; they were amplified after being switched to the high-fat diet and persisted even after the obesogenic protocol was interrupted with a calorically restricted, low-fat chow diet. Accordingly, susceptibility to diet-induced obesity in genetically identical mice is a stable phenotype that can be detected in mice shortly after weaning. Chronologically, differences in adiposity preceded those of feeding efficiency and food intake, suggesting that observed difference in leptin secretion is a factor in determining phenotypes related to food intake. Gene expression analyses of adipose tissue and hypothalamus from mice with low and high weight gain, by microarray and qRT-PCR, showed major changes in the expression of genes of Wnt signaling and tissue re-modeling in adipose tissue. In particular, elevated expression of SFRP5, an inhibitor of Wnt signaling, the imprinted gene MEST and BMP3 may be causally linked to fat mass expansion, since differences in gene expression observed in biopsies of epididymal fat at 7 wk of age (before the high-fat diet) correlated with adiposity after 8 wk on a high-fat diet. We propose that C57BL/6J mice have the phenotypic characteristics suitable for a model to investigate epigenetic mechanisms within adipose tissue that underlie diet-induced obesity.
Highlights
Obesity is a multifactorial disease in which inherited allelic variation, together with environmental variation, determines the predisposition of an individual to developing the disease
The evidence in support of a genetic component to the development of obesity is overwhelming [1,2,3], and a number of promising candidate genes are being tested as underlying causes of obesity [4], it remains difficult to quantify the genetic contribution to the obesity epidemic during the past 25 y, a period too short for the accumulation of additional obesogenic alleles
Regression analysis of body weight at weaning versus changes in adiposity and analysis of variance (ANOVA) of litter size versus changes in adiposity (DFM/lean mass (LM)) at 12 wk (Figure 1D and 1E) barely reached significance and the R2 indicated that the variation in wean weight contributed about 3 % to the variance in adiposity
Summary
Obesity is a multifactorial disease in which inherited allelic variation, together with environmental variation, determines the predisposition of an individual to developing the disease. The evidence in support of a genetic component to the development of obesity is overwhelming [1,2,3], and a number of promising candidate genes are being tested as underlying causes of obesity [4], it remains difficult to quantify the genetic contribution to the obesity epidemic during the past 25 y, a period too short for the accumulation of additional obesogenic alleles. Determining how allelic and environment variations interact to determine obesity phenotypes are critical for an understanding of the obesity epidemic
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