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

Abstract

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.

Acne and COVID‐19 susceptibility, hospitalization, and severity: A genetic correlation study

“…LYPLAL1, encoding lysophospholipase-like 1, is implicated in obesity and unique adipose tissue distribution patterns. 6 It operates synergistically with PNPLA3, GCKR, and TM6SF2, positioning LYPLAL1 at the nexus of metabolic-associated fatty liver disease predisposition. 7 Given the established associations between these genetic loci and the severity of COVID-19, 7 we postulate that acne might modulate COVID-19 hospitalization risks via the LYPLAL1 pathway.…”