Novel genes on rat chromosome 10 are linked to body fat mass, preadipocyte number and adipocyte size

We have previously identified a quantitative trait locus (QTL) on rat chromosome 10 in a F2 cross of WOKW and Dark Agouti rats responsible for obesity and cholesterol metabolism. To pinpoint the region carrying causal genes, we established two new sub-congenic lines, L1 and L2, with refined segments of chromosome10. All lines were extensively characterized under different diet conditions. We employed transcriptome analysis in visceral adipose tissue (AT) by RNA-Seq technology to identify potential underlying genes in the segregating regions. Three candidate genes were measured in paired samples of visceral and subcutaneous AT from 232 individuals with a wide range of body weight and parameters of glucose homeostasis.

Under standard chow diet, body weight as well as fat mass measurements showed that male sub-congenic strains remained obese compared to parental strain whereas under high fat diet (HFD) conditions L1 rats were protected from diet induced obesity. Interestingly, adipocyte size distribution in subcutaneous and epigonadal AT of L1 rats did not undergo typically ballooning under HFD conditions and the number of preadipocytes in AT was significantly elevated in L2 compared to L1 and parental rats. Transcriptome analysis identified 3 candidate genes in visceral AT. In humans, candidate genes were differentially expressed between SC and visceral AT and one gene was strongly correlated with age, waist, cholesterol and parameters of glucose homeostasis.

Our data provide novel candidate genes for obesity which map on rat chromosome 10, strongly associated with body fat mass regulation, preadipocyte number and adipocyte size in rats and humans.