Obesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity

Area of Science:

• Genetics
• Metabolic Research
• Obesity Studies

Background:

• Single nucleotide polymorphisms (SNPs) near human PRKD1 and G2E3 genes are linked to obesity.
• No prior studies have demonstrated a direct link between the inactivation of G2E3 or PRKD1 and changes in body fat.
• Obesity-associated genes are often conserved between humans and mice, making mouse models valuable for investigation.

Purpose of the Study:

• To investigate whether the inactivation of G2e3 or Prkd1 genes in mice leads to obesity.
• To determine if G2e3 or Prkd1 gene inactivation causes changes in body fat percentage and glucose homeostasis in mice.
• To infer the potential role of G2E3 gene function in human obesity based on conserved gene function.

Main Methods:

• Generation of G2e3 and Prkd1 knockout (KO) mouse lines using gene trapping and homologous recombination.
• Measurement of body fat in adult KO and wild-type (WT) mice using Dual-energy X-ray absorptiometry (DEXA) and Quantitative Magnetic Resonance (QMR).
• Assessment of glucose homeostasis via oral glucose tolerance tests (OGTTs) in mice fed a high-fat diet (HFD).

Main Results:

• G2e3 KO mice exhibited significantly increased body weight (11%), body fat (65%), and % body fat (48%) compared to WT littermates.
• Lean body mass was not significantly affected in G2e3 KO mice.
• G2e3 KO mice demonstrated impaired glucose tolerance during OGTTs, while Prkd1 KO mice showed no significant differences in body fat or glucose tolerance compared to WT mice.

Conclusions:

• Inactivation of the G2e3 gene in mice results in significant obesity and glucose intolerance.
• The Prkd1 gene knockout did not lead to obesity or glucose intolerance in the studied mice.
• These findings suggest that reduced functional G2E3 is likely responsible for the obesity observed in individuals with specific G2E3/PRKD1 genetic variants.