Investigating the Role of Genetic Variants and Aging on Eicosanoid Metabolism in Adipose Tissue

1 Background. This research project leverages humans as a model system to investigate how 2 specific genetic variants and aging jointly influence polyunsaturated fatty acid (PUFA) 3 metabolism in white adipose tissue (WAT). WAT plays a crucial role in maintaining energy 4 homeostasis, serving both as an energy storage reservoir and a regulator of lipolysis and 5 lipogenesis. WAT is also the primary repository for PUFAs, governing their systemic 6 bioavailability. Disruptions in WAT PUFA metabolism can lead to altered production of WAT- 7 derived eicosanoids, contributing to metabolic disorders and neurodegenerative diseases. 8 Aging significantly alters WAT function and is associated with increased production of pro- 9 inflammatory eicosanoids. Concurrently, genetic variants influence eicosanoid metabolism, as 10 demonstrated by recent genome-wide association studies identifying 41 genetic loci 11 associated with plasma eicosanoid levels, including PNPLA3. Preliminary data. Our 12 preliminary data show i) that PNPLA3-I148M carriers accumulate PUFA-rich triglycerides in 13 WAT and ii) a strong positive correlation between age and PUFA content in PNPLA3-I148M 14 carriers, suggesting a gene-by-age interaction. Knowledge Gap. Despite established 15 associations between WAT dysfunction and disease, the mechanisms by which genetic 16 variants and aging synergistically affect PUFA metabolism and WAT eicosanoid production 17 are poorly understood. Hypotheses: We hypothesize that a) the presence of PNPLA3-I148M 18 in adipocytes induces the release of arachidonic acid from adipocytes membrane, leading to 19 WAT eicosanoid production, and metabolic dysfunction; and b) there is a synergy between 20 genetic variants and aging, leading to altered WAT eicosanoid production and metabolic 21 dysfunction. Aim 1: Using human-derived iPSCs differentiated into white adipocyte-like cells, 22 we will elucidate the mechanistic role of PNPLA3-I148M in adipocyte function and PUFA- 23 derived eicosanoid production. Aim 2: We will analyze WAT from bariatric surgery patients, 24 focusing on previously identified eicosanoid-associated loci, to identify genetic variants that 25 synergistically interact with aging to influence WAT eicosanoid production. Significance. This 26 research will advance our understanding of how genetic variants and aging jointly influence 27 WAT dysfunction and eicosanoid production. Our findings could lead to precision medicine 28 approaches that tailor interventions (such as NSAIDs or omega-3 supplementation) based on 29 an individual's genetic profile and age, creating more effective strategies for mitigating age- 30 related metabolic and neurodegenerative diseases. Project Number: 1R21AG093405-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Eleonora Scorletti | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $446,875 | Activity Code: R21 | Study Section: Basic Mechanisms of Diabetes and Metabolism Study Section[BMDM] View on NIH RePORTER: https://reporter.nih.gov/project-details/11304795