Adipocyte-Derived Lipid and Mitochondrial Signals in Neuroprotectionand Brain Senescence

The long-term objective is to elucidate the mechanisms of adipocyte-brain communication and their impact on glial function, neuroprotection, and brain aging, with potential implications for preventing dementia and age- related cognitive decline. We will do this my executing two specific Aims: i) Investigate the role of adipocyte- derived lipoproteins in glial phagocytosis, neuroprotection, and senescence. ii) Examine how adipocyte mitochondrial oxidative phosphorylation impacts glial function and senescence. To achieve these aims, using Drosophila as a model organism, we will explore how adipocyte-derived signals influence glial cell function, particularly phagocytic activity. We will focus on two key adipocyte-derived signals: lipoproteins and mitochondrial components. For Aim 1, we will investigate how lipoproteins and their receptors modulate glial phagocytic activity through various molecular and cellular approaches, including knockdown studies, signaling pathway analyses, and lipidomics. For Aim 2, we will examine the impact of adipocyte mitochondrial function on glial cells using similar techniques, as well as targeted proteomics and Translating Ribosome Affinity Purification (TRAP). Our research will employ genetic manipulation, confocal microscopy, biochemical assays, and high-throughput sequencing to analyze glial function, lipid metabolism, and gene expression changes in response to altered adipocyte signaling. We will assess the effects of these signals on glial senescence, lipid accumulation, and neuroprotective capabilities under various metabolic conditions and during aging. This study aims to uncover novel mechanisms of adipocyte-brain communication and their roles in neuroprotection and age-related cognitive decline. The high degree of evolutionary conservation between Drosophila and mammals in adipocyte-brain signaling and glial biology suggests that our findings may have broad translatable implications for human health, potentially leading to new therapeutic strategies for improving age-related conditions impacted by diet-induced obesity. Project Number: 1RF1AG095159-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Akhila Rajan | Institution: FRED HUTCHINSON CANCER CENTER, SEATTLE, WA | Award Amount: $2,586,818 | Activity Code: RF1 | Study Section: Cellular Mechanisms in Aging and Development Study Section[CMAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11210081