Changes in Gene Expression Foreshadow Diet-Induced Obesity in Genetically Identical Mice

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. Genetic models to explain the obesity epidemic are inadequate because the emergence of this epidemic over the past 30 y has been too rapid to allow for the appearance of new mutant genes. The authors show that diet-induced obesity among genetically identical mice is characterized by highly variable and stable phenotypes that are established in mice early in life, even before they become exposed to an obesogenic environment. Furthermore, strong associations occur between susceptibility to obesity and the expression of genes implicated in processes that regulate cellular development. Previous studies have shown that abnormal regulation of such genes by epigenetic mechanisms is linked with the development of cancer. Epigenetic mechanisms involve chemical processes that change chromatin structure and gene expression without changing the genetic code. Accordingly, epigenetic modifications of gene structure through nutritional and physiological stress provide mechanisms for inducing obesity that are independent of new mutations to the genome. Experimental models based upon genetically identical mice provide powerful tools for identifying epigenetic and environmental mechanisms causing obesity and other chronic diseases.