TABLE 6.

Mouse models with increased global protein O-GlcNAcylation, including with exogenous expression of a dominant negative OGA, Oga knockout, OGT, and GFAT overexpression. Most of the observed phenotypes are tissue dysfunctions, with a few exceptions of potential benefits in metabolism-related phenotypes (highlighted in bold).

Oga deletion	Mouse model	Phenotype	References
Inducible expression of dnOga in the mammary tissue	Crossing TRE-EGFP-NCOATGK mice with MMTV-rtTA	↑ protein O-GlcNAcylation as measured by immunohistochemistry using RL2, ↓ mammary ductal side-branching morphogenesis	Bowe et al. (2006)
		Blocked estrogen cell signaling	Whisenhunt et al. (2006)
Inducible expression of dnOga in the skeletal muscle	Crossing TRE-EGFP-NCOATGK mice with MCK-rtTA	↑ protein O-GlcNAcylation as measured by western blots using RL2, muscle atrophy, impaired mobility, and 70–80% morbidity in male mice 2–4 weeks after Dox	Huang et al. (2011)
Inducible expression of dnOga in the lens fiber cells	Crossing TRE-EGFP-NCOATGK mice with gamma-F-crystallin-rtTA	↑ Protein O-GlcNAcylation as measured by western blots using RL2, ↓ proteasome activity, ↑ in cataract surface area in the lenses, and inhibition of lens fiber cell denucleation (Wang et al., 2009)	Wang et al. (2009)
Embryonic Oga deletion	Insertion of the gene trap in the first intron	↑ protein O-GlcNAcylation in 20-month-old tissues compared to 4 months, as wells as Oga deletion cells and animals as measured by western blots using the CTD110.6 antibody MEFs exhibited mitotic defects, embryonic developmental delay, and perinatal lethality	Yang et al. (2012)
		↑protein O-GlcNAcylation as measured by western blots using the CTD110.6 antibody Oga+/- are lean with ↓ fat mass, ↑ energy expenditure, and improved glucose tolerance and resistant to HFD-induced deficits in glucose metabolism, obesity, and hepatic steatosis	Yang et al. (2015)
Ubiquitous Oga deletion (exon1 and promoter) starting at oocytes	Crossing Oga floxed mice with MMTV-Cre	3% of KO mice survived at weaning and exhibited ↓ Oga mRNA and protein, ↑ global protein O-GlcNAcylation as measured by western blots with RL2 KO mice exhibited hypoglycemia and low liver glycogen stores Oga+/- also exhibited altered metabolism as assessed using CLAMS. Only female Oga+/- mice exhibited ↑ weight gain compared to wildtype in response to HFD	Keembiyehetty et al. (2015)
Oga deletion (exon1 and promoter) in the nervous system	Crossing Oga floxed mice with Nestin-Cre	↑ protein O-GlcNAcylation as measured by western blots with RL2 KO mice exhibited brain development delay with hypopituitarism, early-onset obesity, and metabolic dysregulation	Olivier-Van Stichelen et al. (2017)
		PET analyses demonstrated that brain uptake of 18F-LSN3316612 (a high-affinity ligand of OGA) was reduced by 82% compared with control	Paul et al. (2019)
Inducible expression of shRNA of Oga	Doxycycline promoter-Oga-shRNA at Rosa26 locus, Dox for 10 days	↓ OGA mRNA was on average of 70–80%, ↓ binding to 3H-Thiamet G in brain homogenates of ∼80% ↑ 1.4 × protein O-GlcNAcylation in brain homogenates as assessed by a quantitative sandwich immunoassay using both wheat germ agglutinin and the RL2 antibody The decrease of OGA did not result in overt phenotypes	Hastings et al. (2017)
MHC-OGT; MHC-OGA		↑OGT in the heart results in adverse cardiac remodeling and premature death ↑OGA in the heart led to resistance to pathological stress induced by pressure overload	Umapathi et al. (2020)
GFAT↑ in skeletal muscle and fat	GLUT4 promoter	Insulin resistance	Hebert et al. (1996), McClain (2002), McClain et al. (2000)
GFAT↑ in liver	PEPCK promoter	Obesity, hyperlipidemia, impaired glucose tolerance, and insulin resistance	McClain, (2002), Veerababu et al., 2000)
GFAT↑ in β cells	RIP promoter	Hyperinsulinemia, obesity, and diabetes phenotypes	McClain, (2002), Tang et al. (2000)
Inducible Gfat1↑ or Gfat1↓ in cardiomyocytes	TRE-Gfat1:: αMHC-tTA; αMHC-MCM::Gfat1 floxed	↑ Gfat1→ ↑ hypertrophic response to pressure overload; ↑ overall cardiac protein O-GlcNAcylation and mTOR activity. Inhibiting mTOR by rapamycin or inhibiting OGT by alloxan attenuated Gfat1 overexpression phenotype ↓ Gfat1→ ↓ hypertrophic response to pressure overload, ↓ overall cardiac protein O-GlcNAcylation, and mTOR activity	Tran et al. (2020)