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

Authors Powell DR, Doree DD, DaCosta CM, Platt KA, Hansen GM, van Sligtenhorst I, Ding ZM, Revelli JP, Brommage R

Received 23 April 2020

Accepted for publication 2 July 2020

Published 27 July 2020 Volume 2020:13 Pages 2641—2652

DOI https://doi.org/10.2147/DMSO.S259546

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Juei-Tang Cheng


David R Powell, Deon D Doree, Christopher M DaCosta, Kenneth A Platt, Gwenn M Hansen, Isaac van Sligtenhorst, Zhi-Ming Ding, Jean-Pierre Revelli, Robert Brommage

Lexicon Pharmaceuticals Inc, The Woodlands, TX, 77381, USA

Correspondence: David R Powell
Lexicon Pharmaceuticals Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA
Tel +1 281 863 3060
Fax +1 281 863 8115
Email dpowell@lexpharma.com

Purpose: In humans, single nucleotide polymorphisms (SNPs) near the adjacent protein kinase D1 (PRKD1) and G2/M-phase-specific E3 ubiquitin protein ligase (G2E3) 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 G2e3 and Prkd1 knockout (KO) mice to determine whether inactivating either gene leads to obesity in mice and, by inference, probably in humans.
Methods: The G2e3 and Prkd1 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 G2e3 KO mice relative to their wild-type (WT) littermates. When data from all G2e3 KO (n=32) and WT (n=31) mice were compared, KO mice showed increases of 11% in body weight (P< 0.01), 65% in body fat (P< 0.001), 48% in % body fat (P< 0.001), and an insignificant 3% decrease in lean body mass. G2e3 KO mice were also glucose intolerant during an OGTT (P< 0.05). In contrast, Prkd1 KO and WT mice had comparable body fat levels and glucose tolerance.
Conclusion: Significant obesity and glucose intolerance were observed in G2e3, but not Prkd1, KO mice. The conservation of obesity genes between mice and humans strongly suggests that the obesity-associated SNPs located near the human G2E3 and PRKD1 genes are linked to variants that decrease the amount of functional human G2E3.

Keywords: glucose tolerance, gene trap, homologous recombination, Prkd1, PRKD1, SNP

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