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

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, USACorrespondence: David R PowellLexicon Pharmaceuticals Inc., 8800 Technology Fore...

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Autores principales:	Powell DR, Doree DD, DaCosta CM, Platt KA, Hansen GM, van Sligtenhorst I, Ding ZM, Revelli JP, Brommage R
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	glucose tolerance gene trap homologous recombination prkd1 snp Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/9c22197c8b1f4fdfb373f4502ee1558e
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spelling	oai:doaj.org-article:9c22197c8b1f4fdfb373f4502ee1558e2021-12-02T11:14:38ZObesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity1178-7007https://doaj.org/article/9c22197c8b1f4fdfb373f4502ee1558e2020-07-01T00:00:00Zhttps://www.dovepress.com/obesity-of-g2e3-knockout-mice-suggests-that-obesity-associated-variant-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007David 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, USACorrespondence: David R PowellLexicon Pharmaceuticals Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USATel +1 281 863 3060Fax +1 281 863 8115Email dpowell@lexpharma.comPurpose: 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, SNPPowell DRDoree DDDaCosta CMPlatt KAHansen GMvan Sligtenhorst IDing ZMRevelli JPBrommage RDove Medical Pressarticleglucose tolerancegene traphomologous recombinationprkd1prkd1snpSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 13, Pp 2641-2652 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	glucose tolerance gene trap homologous recombination prkd1 prkd1 snp Specialties of internal medicine RC581-951
spellingShingle	glucose tolerance gene trap homologous recombination prkd1 prkd1 snp Specialties of internal medicine RC581-951 Powell DR Doree DD DaCosta CM Platt KA Hansen GM van Sligtenhorst I Ding ZM Revelli JP Brommage R Obesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity
description	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, USACorrespondence: David R PowellLexicon Pharmaceuticals Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USATel +1 281 863 3060Fax +1 281 863 8115Email dpowell@lexpharma.comPurpose: 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
format	article
author	Powell DR Doree DD DaCosta CM Platt KA Hansen GM van Sligtenhorst I Ding ZM Revelli JP Brommage R
author_facet	Powell DR Doree DD DaCosta CM Platt KA Hansen GM van Sligtenhorst I Ding ZM Revelli JP Brommage R
author_sort	Powell DR
title	Obesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity
title_short	Obesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity
title_full	Obesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity
title_fullStr	Obesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity
title_full_unstemmed	Obesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity
title_sort	obesity of g2e3 knockout mice suggests that obesity-associated variants near human g2e3 decrease g2e3 activity
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/9c22197c8b1f4fdfb373f4502ee1558e
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Obesity of G2e3 Knockout Mice Suggests That Obesity-Associated Variants Near Human G2E3 Decrease G2E3 Activity

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