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

Rishel B Vohnoutka Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
Abcam, Waltham, Massachusetts, USA

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Annapurna Kuppa Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Yash Hegde Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
College of Human Medicine, Michigan State University, East Lansing, Michigan, USA

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Yue Chen Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Asmita Pant Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Maurice E Tohme Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Eun-Young (Karen) Choi Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

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Sean M McCarty Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA

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Devika P Bagchi Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA

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Xiaomeng Du Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Yanhua Chen Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Vincent L Chen Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA

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Hiroyuki Mori Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA

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Lawrence F Bielak Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA

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Lillias H Maguire Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Corporal Michael Crescenz VAMC, Philadelphia, Pennsylvania, USA

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Samuel K Handelman Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA

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Jonathan Z Sexton Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA

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Thomas L Saunders University of Michigan Transgenic Animal Model Core, Biomedical Research Core Facilities, Ann Arbor, Michigan, USA
Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Brian D Halligan Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

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Elizabeth K Speliotes Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA

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Human genome-wide association studies found single-nucleotide polymorphisms (SNPs) near LYPLAL1 (Lysophospholipase-like protein 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 (KO) of Lyplal1. We fed the experimental group of mice a 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 KO mice fed an 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, had white fat mass, and had adipocyte diameter not accounted for by changes in the metabolic rate. Female, but not male, KO mice had increased serum triglycerides, decreased aspartate, and decreased 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.

Article Type:
Research Article
DOI:
https://doi.org/10.1530/JME-22-0131
Volume/Issue:
Volume 70: Issue 3
Open access