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

ABSTRACT: Obesity is in large part a brain disease that is caused by genetics, the environment (e.g., diet) and their interactions. Identifying genes in the brain that interact with diet to influence obesity is not possible in humans. The goal of this study was to use outbred heterogeneous stock (HS) rats to identify genetic loci for diet-induced obesity followed by RNAseq in the ventromedial hypothalamus (VMH) to identify candidate causal genes. We measured multiple metabolic traits (including fat and lean mass, fasting glucose, insulin, and lipids, glucose tolerance, food intake and activity levels) after long-term consumption of a low-fat (LFD) or high-fat diet (HFD) in 2000 HS rats, split equally be sex and diet. Rats were genotyped using low-coverage whole genome sequencing. RNAseq was run in the VMH of a sub-set of 400 HS rats split equally by sex and diet. 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE330152 | GEO | 2026/05/11

REPOSITORIES: GEO

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Project description:The hypothalamus (HYP) underlies basal endocrine, physiological, and behavioral drives which inherently differ across species and sexes—ranging from growth and puberty to appetite and metabolism to social behavior. Especially in the rodent brain, these sex-differentiated functions correspond to differences in the volume, cell types, and gene expression of distinct HYP subareas. Recent studies have elucidated the transcriptional profile of single cells in the rodent ventromedial hypothalamus (VMH) and arcuate (ARC), which influence appetitive/social behaviors and growth/metabolism, respectively. However, there is a paucity of studies examining the molecular architecture of the adult human HYP, and transcriptional sex differences in the human VMH and ARC have not been characterized in single-cell or spatial contexts. Using 10x Genomics Visium and Xenium platforms, we generated a multimodal, spatially-resolved molecular atlas of human postmortem VMH and ARC from male and female adult donors. Sex-differential gene expression analysis within these regions revealed correlated autosomal expression differences, with stronger overall sex effects in the ARC. We then leveraged the single-cell-resolution of Xenium to localize sex-differential expression to cell types, finding most occur in ESR1- and KISS1-expressing neurons of the ARC. Finally, we investigated VMH and ARC gene expression in relation to genes associated with neuropsychiatric diseases, identifying a striking enrichment of genes upregulated in the male VMH for known and candidate risk genes for autism spectrum disorders. This work provides a multisample view of the human VMH and ARC in young/middle adulthood across both sexes, including data at both transcriptome-wide and single-cell resolutions, the first single-cell transcriptional atlas of molecular sex differences in the adult human VMH and ARC, and highlights potential sex-differentiated roles for VMH and ARC in neurobehavioral disorders.

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

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