SUN-697 Profiling Hepatokine Gene Expression in a Nonhuman Primate Model at Single Nucleus Resolution for Application to in Vivo Mosaic Screening in Other Species to Gain Insights Into Obesity Phenotypes

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Abstract Disclosure: J. Hsieh: Gordian Biotechnology. V. Kartha: Gordian Biotechnology. J. Chen: Gordian Biotechnology. S. Wang: Gordian Biotechnology. D. Popov: Gordian Biotechnology. A. Gupta: Gordian Biotechnology. G. Donepudi: Gordian Biotechnology. D. Fuentes: Gordian Biotechnology. L. Fung: Gordian Biotechnology. L. Chio: Gordian Biotechnology. C. Carrico: Gordian Biotechnology. F. LePort: Gordian Biotechnology. M. Borch Jensen: Gordian Biotechnology, Siren Biotechnology. Background: Hepatokines are hormones secreted by the liver that can play an important role in energy homeostasis by acting on organs such as the adipose tissue and skeletal muscle. Interspecies differences in hepatokine action can complicate the translation of preclinical observations to clinical efficacy and safety. In-depth, longitudinal characterization of gene expression profiles at single-cell resolution in NHP liver is lacking, and can enable nomination of rodent screen targets based on cell state-specific, and physiologically-relevant transcriptomic changes. Methods: 11 African Green Monkeys ranging in age from 6 to 17 years were fed a diet high in fat, cholesterol, and sucrose along with supplementation of high fructose treats. Body weight was recorded monthly throughout the duration of the study. After 20 and 54 weeks of diet-feeding, the liver was sampled by biopsy and analyzed by single nucleus RNA-sequencing (snRNA-Seq). In vivo mosaic screening was performed in mice fed an obesogenic high fat, cholesterol, and fructose diet for 62 weeks by administering a low dose of a cocktail of AAV therapies directed to hepatocytes. The transcriptomic perturbations induced by individual interventions were examined by snRNA-Seq. Results: The NHP with the fastest rate of weight gain had the highest number of uniquely upregulated genes in hepatocytes amongst the 11 animals studied. Significantly affected reactome pathways include Membrane Trafficking, Epigenetic Regulation of Gene Expression, Macroautophagy, and Transcriptional Regulation by RUNX1. Downregulated reactome pathways in the hepatocytes included Immune System, Interferon Gamma Signaling, and Toll Like Receptor 4 (TLR4) Cascade. Despite both having anorexigenic effects, high expression of GDF15 and LEAP2 mapped to different hepatocyte subsets in the NHP liver. Hepatocyte LEAP2 expression increased between the 20-week and 54-week liver biopsies in all animals regardless of weight gain, whereas GDF15 expression was affected in only one animal. Hepatocyte TSKU, LECT2, and AHSG expression increased in the animal with rapid weight gain between the 20-week and 54-week liver biopsies. In contrast, in the similarly-aged weight gain-resistant NHP, there was a lowering of hepatocyte TSKU, LECT2, and AHSG expression. NHP hepatocyte signatures associated with various hepatokines were then applied to analyze a murine liver screen. In mice, Gcgr knockdown depressed the hepatocyte population associated with high Fst, suggesting that the inverse approach of glucagon receptor agonism could increase follistatin and help contribute to weight loss. Conclusion: Basic characterization of metabolic dysfunction in a translatable model such as NHPs can provide valuable tools to analyze rodent studies. Presentation: Sunday, July 13, 2025

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