A combination of genetic and environmental factors likely underlies most neurodegenerative diseases. Among environmental factors, metabolic disease is an emerging risk factor, but the mechanisms that confer risk are still poorly understood. We hypothesise that diet-induced obesity dysregulates lipid metabolism and promotes glial activation in a mouse model of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In particular, we aim to study the role of altered lipid metabolism and neuroinflammation in response to short (12 weeks) and prolonged (14-16 months) high-fat diet (HFD) exposure in wildtype and TDP-43Q331-low transgenic mice using a multi-omics approach. Specifically, we have performed lipidomics and mRNA transcriptomic analyses (bulk RNAseq, Nanostring neuroinflammatory panel, and RT-PCR) using the cortex and spinal cords from mice across the different experimental groups. We have found that in both the cortex and spinal cords there were a significant accumulation of triglycerides following HFD treatment. Transcriptomic analyses have indicated upregulation of specific neuroinflammatory markers including myeloperoxidase following HFD treatment. Interestingly, Lrg1, an emerging player in the pathogenesis of several inflammatory and neurodegenerative diseases with links to diabetes, was upregulated in the TDP-43Q331-low transgenic following prolonged HFD. By identifying lipidomic/transcriptomic changes specific to ALS/FTD and metabolic stress across time and regions, we can learn about how the disease process unfolds and gain insights into regional specificity. Moreover, understanding the contributions of specific cell types to inflammatory processes and the role of lipid metabolism following metabolic stress will allow us to perform targeted follow-up of identified candidate genes and pathways.