Knockout of murine Lyplal1 confers sex-specific protection against diet-induced obesity

Human genome-wide association studies found single nucleotide polymorphisms (SNPs) near LYPLAL1 (Lysophospholipase 1) that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering LYPLAL1 affects obesity and metabolic disease we created and characterized a mo...

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Bibliographic Details
Published in:	Journal of molecular endocrinology Vol. 70; no. 3; p. 1
Main Authors:	Vohnoutka#, Rishel B., Kuppa#, Annapurna, Hegde#, Yash, Chen, Yue, Pant, Asmita, Tohme, Maurice E, Choi, Eun-Young (Karen), McCarty, Sean M., Bagchi, Devika P., Du, Xiaomeng, Chen, Yanhua, Chen, Vincent L., Mori, Hiroyuki, Bielak, Lawrence F., Maguire, Lillias H., Handelman, Samuel K., Sexton, Jonathan Z., Saunders, Thomas L., Halligan, Brian D., Speliotes, Elizabeth
Format:	Journal Article
Language:	English
Published:	England Bioscientifica Ltd 01-04-2023 Society for Endocrinology & BioScientifica Ltd
Subjects:	Adipose tissue Alanine transaminase Animal models Animals Body fat Body weight gain CRISPR Diet, High-Fat - adverse effects Evolutionary conservation Fatty liver Female Genome-wide association studies Genome-Wide Association Study Genomes High fat diet Humans Lysophospholipase Lysophospholipase - genetics Male Metabolic disorders Metabolic rate Metabolism Mice Mice, Inbred C57BL Mice, Knockout Obesity Obesity - genetics Obesity - metabolism Sex Single-nucleotide polymorphism Steatosis Sucrose Triglycerides adipose steatosis sex-based phenotype diet-induced obesity
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Summary:	Human genome-wide association studies found single nucleotide polymorphisms (SNPs) near LYPLAL1 (Lysophospholipase 1) that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering LYPLAL1 affects obesity and metabolic disease we created and characterized a mouse knockout of Lyplal1. We fed the experimental group of mice high fat, high sucrose (HFHS) diet for 23 weeks, and the controls were fed regular chow diet. Here we show that CRISPR-Cas9 whole-body Lyplal1 knockout (KO) mice fed a HFHS diet showed sex-specific differences in weight gain and fat accumulation as compared to chow diet. Female, not male, KO mice weighed less than WT mice, had reduced body fat percentage, white fat mass, and adipocyte diameter not accounted for by changes in metabolic rate. Female, but not male, KO mice had increased serum triglycerides, decreased aspartate, and alanine aminotransferase. Lyplal1 KO mice of both sexes have reduced liver triglycerides and steatosis. These diet-specific effects resemble the effects of SNPs near LYPLAL1 in humans, suggesting that LYPLAL1 has an evolutionary conserved sex-specific effect on adiposity. This murine model can be used to study this novel gene-by-sex-by-diet interaction to elucidate the metabolic effects of LYPLAL1 on human obesity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Concept development, EKS; Study design, BDH, DPB, TLS, EKS; Project Administration, RBV, AK, BDH; Animals development and breeding RBV, BDH, YH, AK, EKS; Data generation/acquisition: BDH, YH, RBV, AP, AK, YuC, MET, HM, EKS Data Analysis, RBV, BDH, EC, SMM, JZS, SKH, AK, AP, YH, TLS; Animal tissue collection RBV, AK, BDH, YH, YuC, AP, DPB, XD, YaC, LFB, LHM, SKH, TLS, EKS ; Writing & Editing – Original Draft, RBV, AK, BDH, EKS; Writing – Review & Editing, EKS, BDH, RBV, AK, YH, YuC, AP, EC, VLC, SKH, TLS; Figure generation, RBV, BDH, AK; Supervision and Funding acquisition, EKS. All authors reviewed and approved final manuscript. Author Contributions These authors contributed equally
ISSN:	0952-5041 1479-6813 1479-6813
DOI:	10.1530/JME-22-0131