THU051 GH Resistance And Adipose Tissue: Multispecies Measurement Of Morphology And Transcriptome

Abstract

Abstract Disclosure: J.A. Young: None. A. Hinrichs: None. S.R. Bell: None. M. Soneson: None. D.K. Geitgey: None. E. Wolf: None. E.O. List: None. J.J. Kopchick: None. D.E. Berryman: None. Laron Syndrome (LS) is a condition caused by mutations in the growth hormone (GH) receptor gene that renders the individual GH resistant. LS was first described in humans in the 1960’s, and since then, animal models of LS have been developed, including pigs (GHR-KO pigs). One of the notable characteristics of LS, in both humans and animals, is obesity without some of its comorbidities, such as increased cancer and diabetes. The aim of this study was to examine the subcutaneous and visceral adipose tissue of GH resistant pigs and a human with LS using histology and transcriptomics and make cross-species and cross-depot comparisons where possible. Adipocyte sizing analysis showed that GH resistance resulted in a trend towards increased cell sizes in human subcutaneous (SubQ) and visceral (Visc) depots, and a significant increase in pig Visc. Interestingly, the human adipocyte size histogram was similar to that of the pig across genotypes and depots. When examining the adipose transcriptome, PCA analysis showed a strong species clustering, but not a strong depot or genotype clustering. Differentially expressed gene (DEG) analysis comparing GHRKO pigs to their respective wild type controls showed that IGF1 expression was decreased in both depots, as expected, and 38 other genes were also significantly altered in GHR-KO pigs compared to controls, in both depots. Enrichment analysis showed a decrease in an extracellular matrix term in the GHR-KO SubQ compared to controls, while terms associated with fatty acid and carbohydrate metabolism were increased in GHR-KO SubQ. When comparing GHR-KO visceral to WT, terms associated with IGF signaling and longevity regulation had decreased expression, while immune activation and cell motility were increased. Pathway analysis generally agreed with these results, but also showed a decrease in multiple signaling pathways including AMPK and PI3K-Akt in both depots. Paradoxically, the JAK-STAT signaling pathway was increased in GHR-KO Visc compared to controls. Depot differences were also explored using this dataset. Within each genotype, the gene expression of the SubQ and Visc depots resulted in no significant DEGs between depots in the WT pigs, while GHRKO pigs had 24 DEGs between SubQ and Visc. Enrichment analysis and pathway analysis showed no significant results in either depot, presumably due to the low number of DEGs. In conclusion, GHR-KO pigs had expected changes in adipocyte size and expression of metabolic and extracellular matrix genes, but other unexpected changes were also present, including changes to cell motility-related genes. There were few differences between depots within each genotype, indicating that depots are equally affected by GH. Further studies are required to understand the functional changes to adipose tissue caused by LS and the effectiveness of pigs as an LS model. Presentation: Thursday, June 15, 2023