Abstract
Human genome-wide association studies found SNPs near LYPLAL1 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. Here we show that CRISPR-Cas9 whole-body Lyplal1 knockout (KO) mice fed a high fat, high sucrose (HFHS) diet showed sex-specific differences in weight gain and fat accumulation. 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.
Competing Interest Statement
The authors have declared no competing interest.
- Abbreviations
- LYPLAL1
- WT lysophospholipase like 1
- KO
- knockout
- HFD
- high fat diet
- HFHS
- high fat, high sucrose
- GWAS
- genome-wide association studies
- WAT
- white adipose tissue
- iWAT
- inguinal white adipose tissue
- pWAT
- perirenal white adipose tissue
- gWAT
- gonadal white adipose tissue
- BAT
- brown adipose tissue
- AST
- aspartate aminotransferase
- ALT
- alanine aminotransferase
- ALP
- alkaline phosphatase
- GTT
- glucose tolerance test
- ITT
- insulin tolerance test
- CLAMS
- comprehensive lab animal monitoring system
- NMR
- nuclear magnetic resonance
- H&E
- hematoxylin and eosin
- RER
- respiratory exchange ratio
- PAS
- periodic acid Schiff
- PAS-D
- periodic acid Schiff - diastase
- Nnt
- Nicotinamide nucleotide transhydrogenase
- UCP1
- uncoupling protein 1
- BK
- big potassium channel
- gRNA
- guide RNA
- AUC
- area under the curve
- PAM
- protospacer adjacent motif
- PFA
- paraformaldehyde
- PBS
- phosphate buffered saline
- RIPA
- radioimmunoprecipitation assay
- BSA
- bovine serum albumin
- BCA
- bicinchoninic acid
- TBST
- tris buffered saline
- PMSF
- phenylmethylsulfonyl fluoride
- FFPE
- formalin-fixed, paraffin embedded
- (RT)
- room temperature