(P18-019-25) Disruption of Nutrient-Related Pathways in the Hypothalamus by Pro-inflammatory Stimuli

Objectives: The hypothalamus regulates nutrient homeostasis, modulates hunger signals, energy balance, and inflammatory response. Functional dysregulation is linked to obesity and metabolic disorders. Pro- and anti-inflammatory conditions elicited by some diets and drug use can disrupt the hypothalamus molecular mechanisms. Brain inflammation, linked to morphine use, can be lessened with anti-inflammatory diets (e.g., rich in omega-3 fatty acids). The objective of the study is to explore the interplay between pro-inflammatory morphine exposure and anti-inflammatory diets in hypothalamic metabolic pathways. The supporting objective is to assess opioid and sex effects on metabolic and nutrient-related gene pathways.

Methods: Using a biomedical model, the hypothalamus of 16 three-week old female and male pigs, chronically exposed to morphine or saline and receiving a nutritionally adequate diet, were studied. RNA sequencing produced 2.1 billion reads that permitted testing for differential gene expression between groups using the edgeR software. Gene Set Enrichment Analysis identified enriched KEGG pathways and Gene Ontology categories.

Results: In total, 923 genes were differentially expressed (FDR p-value < 0.05) between groups. Sex-dependent effects included enrichment of the adipocytokine signaling pathway, including neuropeptide genes AGRP, NPY, and POMC that were under-expressed in morphine- relative to saline-treated females (fold change > 7.6). Dietary supplementation can address deficits in feeding behavior and metabolism associated with adipocytokine level changes. Likewise, ubiquitin hydrolase activity participates in nutrient-sensing pathways, and the ubiquitin carboxyl-terminal hydrolase FAF-X gene (LOC100625207) was over-expressed in males relative to females (fold change > 10).

Conclusions: These results reveal the effect of morphine exposure in the hypothalamus and nutritional strategies for mitigating gene pathway disruptions. Subsequent analyses will focus on evaluating the use of omega-3 fatty acid supplementation to ameliorate the changes in the hypothalamic transcriptome.

Funding Sources: United States Department of Agriculture NIFA Grants 2022-38420-38610 and 2018-67015-27413 and National Institutes of Health Grant P30DA018310.