Understanding the complexity of polygenic obesity includes the aspect of the hormonal adaptation during the process of selection for high body weight. Therefore we focussed on the analysis of hormones regulating energy homeostasis, growth and insulin sensitivity in the Berlin Fat Mouse Inbred 860 (BFMI860) line which we use as a model for polygenic obesity. The mouse line had been selected for low protein and high fat content before it was inbred. Under a standard maintenance diet the endocrine profile of BFMI860 males is typical for the obesity status with highly increased leptin and insulin and reduced adiponectin levels compared to C57BL/6 (B6) males. In response to a high fat diet, BFMI860 males showed marked hyperleptinemia and hyperinsulinemia with high variability in glucose levels. Their adiponectin levels continued to decline under high fat diet.
To identify the genetic reasons underlying the BFMI860 phenotype a crossbred population of BFMI860×B6 was generated. All F2 animals were fed a high fat diet and analysed regarding the endocrine profile. Mapping quantitative trait loci by linkage analysis has identified a chromosomal region that contributes to high body weight and fat mass, but not lean mass. Homozygous BFMI860 animals had higher leptin and insulin serum levels corresponding to increased body and fat mass. Interestingly, males of the BFMI860 phenotype had reduced adiponectin levels, as expected, while females did not show a reduction in adiponectin levels. The BFMI860 males had also higher average levels of insulin and glucose. In contrast, homozygous BFMI860 females seemed to be more insulin-sensitive and glucose-tolerant likely due to their higher adiponectin levels. We concluded that homozygous BFMI860 males could have a higher risk to become insulin-resistant. Further linkage analysis between the hormone concentrations and segregation of genotypes is in process to find the genetic factors influencing these hormones.
03 - 07 May 2008
European Society of Endocrinology