(P21-012-25) Effects of Calorie Restriction on Gene Expression Profiles and Associations With Longevity

Objectives: Fasting results in a phased response of metabolic adaptation of our body to increase survival. The adipose tissue, a primary energy depot, plays a critical role in the adaptive response by releasing free fatty acids and glycerol along with a reduced uptake and storage of circulating triglycerides. This metabolic adaptation to fasting is primarily due to the changes in regulation and expression of genes in the adipose tissue. The objective of this study was to understand the role of gene regulation by identifying differentially expressed key genes and the pathways involved in the metabolic adaptation to fasting.

Methods: A secondary analysis was conducted using a gene expression dataset GSE154610 from NCBI. In the original study subcutaneous adipose tissue biopsies were collected from 11 volunteers 2hrs and 26 hrs after consumption of a standardized meal with the timing of sampling roughly corresponding with the near depletion of liver glycogen. Using different analytic methods, we performed differential gene expression and pathway analysis using Bioconductor packages in the R statistical framework. The pre(Fed state) and the post(Fasting state) gene expressions of the subjects were compared by pairwise T-Tests and p-values adjusted for false discovery rate. Genes that had an adjusted p-value < 0.05 or a fold-change greater or lesser than 1.5 were deemed “differentially expressed”. The dysregulated expression of these marker genes and their networks were investigated for their role in different metabolic pathways.

Results: Many genes involved in fatty acid oxidation (DEPP1, PDK4, SLC27A2, IRS2, PFKFB3 etc.) were upregulated. Genes involved in lipid metabolism and tri-glyceride synthesis (ANGPTL8, SREBF1, FADS1, DGAT2 etc.) were downregulated.

Conclusions: Our study identified key genes involved in this metabolic adaptation as potential diagnostic biomarkers and therapeutic targets. Our findings on upregulation of fatty acid oxidation and downregulation of triglyceride and fatty acid synthesis pathways supports studies that show protective effects to neurological disorders and cardiovascular health due to the metabolic adaptation to fasting.

Funding Sources: This material is based upon work supported by NSF HBCU-UP Targeted Infusion Project.