Obesity of Knockout Mice Suggests That Obesity-Associated Variants Near Human Decrease G2E3 Activity

Purpose: In humans, single nucleotide polymorphisms (SNPs) near the adjacent protein kinase D1 () and G2/M-phase-specific E3 ubiquitin protein ligase () genes on chromosome 14 are associated with obesity. To date, no published evidence links inactivation of either gene to changes in body fat. These two genes are also adjacent on mouse chromosome 12. Because obesity genes are highly conserved between humans and mice, we analyzed body fat in adult and knockout (KO) mice to determine whether inactivating either gene leads to obesity in mice and, by inference, probably in humans.

Methods: The and KO lines were generated by gene trapping and by homologous recombination methodologies, respectively. Body fat was measured by DEXA in adult mice fed chow from weaning and by QMR in a separate cohort of mice fed high-fat diet (HFD) from weaning. Glucose homeostasis was evaluated with oral glucose tolerance tests (OGTTs) performed on adult mice fed HFD from weaning.

Results: Body fat was increased in multiple cohorts of KO mice relative to their wild-type (WT) littermates. When data from all KO (n=32) and WT (n=31) mice were compared, KO mice showed increases of 11% in body weight (<0.01), 65% in body fat (<0.001), 48% in % body fat (<0.001), and an insignificant 3% decrease in lean body mass. KO mice were also glucose intolerant during an OGTT (<0.05). In contrast, KO and WT mice had comparable body fat levels and glucose tolerance.

Conclusion: Significant obesity and glucose intolerance were observed in , but not , KO mice. The conservation of obesity genes between mice and humans strongly suggests that the obesity-associated SNPs located near the human and genes are linked to variants that decrease the amount of functional human G2E3.