Mice lacking sialyltransferase ST3Gal-II develop late-onset obesity and insulin resistance

López, Pablo H.H.; Aja, Susan; Aoki, Kazuhiro; Seldin, Marcus M.; Lei, Xia; Ronnett, Gabriele V.; Wong, G. William; Schnaar, Ronald L.

doi:10.1093/glycob/cww098

Cited by 27 publications

(14 citation statements)

References 53 publications

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“…For the 7 enzymes in this category, obesity of KO mice from published St3gal2, Glrx2, Hdac6 and Prdx6 KO lines agrees with our data. 153–157 Obesity of KO mice from published Gpx7 and Adamts18 KO lines 158 , 159 is consistent with our data and with GWAS data linking obesity to GPX7 158 and to ADAMTS18 which is closely associated with a BMI cluster ( Table 6 ), but not with the absence of obesity in independent Gpx7 and Adamts18 KO lines studied in the IMPC HTS. Our HTS data for Usp13 KO mice are consistent with the obesity of female mice from an independent IMPC Usp13 KO line.…”

Section: Resultssupporting

confidence: 90%

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Powell¹,

Revelli²,

Doree³

et al. 2021

DMSO

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Purpose Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000 TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat. Materials and Methods KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC). Results Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 ( Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1 ) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only. Conclusion These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.

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Section: Resultssupporting

confidence: 90%

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Powell¹,

Revelli²,

Doree³

et al. 2021

DMSO

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show abstract

“…Knockout of ST3Gal-II ( 9 ) reduces GD1and GT1b levels in the brain by 50%, whereas brain-protein sialylation is unchanged [ 35 ]. A loss of ST3Gal-II also leads to late-onset obesity and insulin resistance [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Simulating the enzymes of ganglioside biosynthesis with Glycologue

McDonald¹,

Davey²

2021

Beilstein J. Org. Chem.

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Gangliosides are an important class of sialylated glycosphingolipids linked to ceramide that are a component of the mammalian cell surface, especially those of the central nervous system, where they function in intercellular recognition and communication. We describe an in silico method for determining the metabolic pathways leading to the most common gangliosides, based on the known enzymes of their biosynthesis. A network of 41 glycolipids is produced by the actions of the 10 enzymes included in the model. The different ganglioside nomenclature systems in common use are compared and a systematic variant of the widely used Svennerholm nomenclature is described. Knockouts of specific enzyme activities are used to simulate congenital defects in ganglioside biosynthesis, and altered ganglioside status in cancer, and the effects on network structure are predicted. The simulator is available at the Glycologue website, https://glycologue.org/.

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“…Deletions in ZPLD1 were proven to contribute to the genetic susceptibility of common childhood obesity [ 44 ]. Mice lacking ST3GAL2 (ST3 beta-galactoside alpha-2,3-sialytransferase 2) have 50 % more fat mass and 9 % more lean body mass than the control [ 45 ]. ZGRF1 (Zinc finger GRF-type containing 1) encodes a protein that contains GRF zinc finger (zf-GRF) and transmembrane domains, and a recent genome-wide and exome chip association study revealed that the gene is associated with adiposity [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Genomic insights into body size evolution in Carnivora support Peto’s paradox

Huang

Sun

et al. 2021

BMC Genomics

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Background The range of body sizes in Carnivora is unparalleled in any other mammalian order—the heaviest species is 130,000 times heavier than the lightest and the longest species is 50 times longer than the shortest. However, the molecular mechanisms underlying these huge differences in body size have not been explored. Results Herein, we performed a comparative genomics analysis of 20 carnivores to explore the evolutionary basis of the order’s great variations in body size. Phylogenetic generalized least squares (PGLS) revealed that 337 genes were significantly related to both head body length and body mass; these genes were defined as body size associated genes (BSAGs). Fourteen positively-related BSAGs were found to be associated with obesity, and three of these were under rapid evolution in the extremely large carnivores, suggesting that these obesity-related BSAGs might have driven the body size expansion in carnivores. Interestingly, 100 BSAGs were statistically significantly enriched in cancer control in carnivores, and 15 of which were found to be under rapid evolution in extremely large carnivores. These results suggested that large carnivores might have evolved an effective mechanism to resist cancer, which could be regarded as molecular evidence to support Peto’s paradox. For small carnivores, we identified 15 rapidly evolving genes and found six genes with fixed amino acid changes that were reported to reduce body size. Conclusions This study brings new insights into the molecular mechanisms that drove the diversifying evolution of body size in carnivores, and provides new target genes for exploring the mysteries of body size evolution in mammals.

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Mice lacking sialyltransferase ST3Gal-II develop late-onset obesity and insulin resistance

Cited by 27 publications

References 53 publications

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Simulating the enzymes of ganglioside biosynthesis with Glycologue

Genomic insights into body size evolution in Carnivora support Peto’s paradox

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