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.

Obesity and related consequences to ageing

“…Studies on rodents and humans showed that the body of a healthy, lean individual is composed of approximately 15-28 % fat mass (Avram et al 2005a) with low variance; however, a high-fat diet (HFD) induces obesity with a wide variability of fat mass accumulation as seen in some mouse genotypes (Moitra et al 1998;Hausman et al 2001;Koza et al 2006). Similarly, a wide range of phenotypes occur at the metabolic and functional levels in obese individuals, where excessive AT accumulation may lead to the metabolic syndrome (Kirkland 2013).…”

“…Recent microarray studies on subcutaneous WAT comparing mice exposed to different nutritional conditions during early post-natal development and then in adult mice exposed to HFD identified a set of genes highly associated with ATE, including mesoderm specific transcript (Mest), caveolin1 (Cav1), caveolin2 (Cav2), and secreted frizzled-related protein 5 (Sfrp5) (Koza et al 2006;Voigt et al 2013). The absence of MEST protein in the interscapular BAT in adult obese mice (Nikonova et al 2008) indicates that Mest is one of the few genes known to be expressed at high levels only in WAT.…”

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

“…However, there are large interindividual differences in this compensatory response to increased fat intake. A recent study has evidenced that major changes in the genome of individual animals may be established prior to the introduction of a high-fat diet (19).…”

Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights

“…Indeed, even in genetically identical C57BL/6J mice there are subsets of high-and low-weight gaining mice during high-fat feeding, suggesting there have to be strong epigenetic effects. (67) Similarly, human studies are confounded by nutrient and environmental factors as well as genetic heterogeneity, which may explain the different impact of obesity on skeleton, as discussed in "Clinical Insight" section.…”

“…Indeed, even in genetically identical C57BL/6J mice there are subsets of high-and low-weight gaining mice during high-fat feeding, suggesting there have to be strong epigenetic effects. (67) Similarly, human studies are confounded by nutrient and environmental factors as well as genetic heterogeneity, which may explain the different impact of obesity on skeleton, as discussed in "Clinical Insight" section.Animal models provide insights into the molecular and cellular mechanisms of bone remodeling related to obesity and T2D, and have served to illuminate this complex interaction of tissues. L-SACC mice, with impaired insulin clearance in the liver, serve as a model of hyperinsulinemia with normal nonfasting glucose levels.…”