Characterizing hypothalamic damage patterns in pigs with metabolic disorders by transcriptome analysis.

PURPOSE: The hypothalamus serves as a crucial regulator of energy homeostasis, and accumulating research shows that defects in the hypothalamus are implicated in the link between type 2 diabetes mellitus (T2DM) and obesity. This study was designed to explore the patterns of hypothalamic damage under conditions of metabolic disorders through transcriptome sequencing. METHODS: Five wild-type pigs (WT) and five transgenic pigs (PIGinH11) of comparable ages and body weights were selected for this study. Both groups were fed a high-fat, high-sucrose diet (HFHSD) for 12 weeks. Subsequently, serological parameters were evaluated, and RNA sequencing was carried out on hypothalamic tissues. The transcriptome sequencing results were verified by RT‒PCR and immunofluorescence experiments. RESULTS: A total of 561 differentially expressed genes were identified in the PIGinH11 pigs, with 176 genes being upregulated and 381 genes being downregulated. Protein‒protein interaction (PPI) analysis revealed that the top differentially expressed genes could be grouped into three clusters, namely, vasoconstriction and dilation, inflammation, and metabolism. The genes CD8A, HDG, and NOS1 might be the core genes of each cluster. The KEGG pathway enriched by Gene Set Enrichment Analysis (GSEA) results revealed that pathways related to protein synthesis-related inflammation were upregulated in PIGinH11 pigs, whereas those associated with calcium homeostasis were downregulated. CONCLUSION: The results of the present study demonstrated that in PIGinH11 pigs, which are sensitive to energy alterations, the hypothalamus exhibited inflammation, calcium dysregulation, and activated protein synthesis at the transcriptomic level under metabolic disorders. The NO-sGC-cGMP pathway may play a critical role in hypothalamic inflammation, warranting further in-depth investigation.