Deletion of Ligand Dependent Corepressor-Like (LCoRL) Protects Against Diet-induced Obesity Deletion of Ligand Dependent Corepressor-Like (LCoRL) Protects Against Diet-induced Obesity

ABSTRACT OBJECTIVE: Genome Wide Association Studies (GWAS) in humans, dogs, and livestock have uncovered genes which may play a role in metabolism. However, functional analysis is required to link the metabolic phenotype with the associated gene. Here we identified the Ligand Dependent Corepressor-Like (LCoRL) as a potential metabolic regulator. METHOD: We used CRISPR/Cas9 approaches in mice to generate a Lcorl null allele (Lcorl-/-). We characterized Lcorl-/- mice by assessing body weight, body composition, food intake, and glucose homeostasis as well as assessing transcriptional changes in Lcorl-/- livers by RNA-sequencing. Finally, we challenged mice with a 60% high fat diet (HFD) and a treadmill exercise stress test. RESULTS: Mice homozygous for loss of Lcorl are viable and fertile. However, Lcorl-/- pups show stunted postnatal growth for the first few weeks of life. This is followed by a catchup growth, such that, Lcorl-/- mice are indistinguishable from wildtype littermates by 7-9 weeks of age. Three-week-old mice show reduced circulating insulin like growth factor-1 (IGF-1) levels without a change in pituitary Growth hormone (Gh) mRNA levels. Interestingly, Lcorl-/- mice remain lean compared to wildtype littermates as they age. This is associated with a decrease in daily food intake. Additionally, Lcorl-/- mice show no change in energy expenditure; however, Lcorl-/- mice show a greater amplitude of their respiratory exchange ratio (RER) compared to controls, suggesting differential usage of fat and carbohydrates across the light/dark cycle. This altered RER may result from the reduction in day-time food intake or disrupted mobilization of fat and carbohydrate stores. Consistent with enhanced metabolic health, Lcorl-/- mice also show improved glucose tolerance and insulin sensitivity. Finally, Lcorl-/- mice are protected against a 60% high fat diet challenge and show reduced exercise capacity in a stress test. CONCLUSION: This phenotypic characterization of the Lcorl-/- mouse reveals that LCoRL is a causal gene resulting in the changes in metabolism seen in GWAS in humans and livestock and provides novel mechanistic insights of a gene important in human disease and economically valuable traits in livestock.