Identification of novel candidate neural genes for diet-induced obesity in outbred heterogeneous stock rats

We used linear mixed models to detect physiological and expression quantitative trait loci (pQTLs and eQTLs, respectively) in the full dataset and separately by diet and sex. Genes with cis-eQTLs that overlapped pQTLs were assessed as candidate causal genes through mediation analysis. We also identified VMH genes differentially expressed by diet in both sexes, followed by pathway analysis.

We identified 47 pQTLs where seven mapped multiple traits, 11 were diet-specific and 13 were sex-specific. We identified nine candidate causal genes, including Pcare, Rbks, Mpv17 and Gpn1 within a pleiotropic pQTL for multiple adiposity traits on rat chr. 6 and Tnsfs9 within a pQTL for fat pad weight on rat chr. 9. We also identified Ccdc77 as a candidate gene within a LFD-specific pQTL for activity levels and Rtel1 and Polr3k within a male-specific pQTL for fatty liver.

Genes involved in extracellular matrix and inflammation were dysregulated by diet, particularly in females, while males on HFD showed upregulation of several addiction pathways. This work demonstrates the importance of accounting for diet and sex in genetic studies for obesity and identifies novel candidate genes as neural regulators of diet-induced obesity and related traits.