Most of the diseases accompanying fast life rhythm in developed countries are connected with deregulated lipid and glucose metabolism. Diabetes and Alzheimer’s disease (AD) are considered among top threats to human health and they both have in common insulin resistance and common inflammatory signaling pathways. Human and preclinical studies have provided convincing evidence that AD is a degenerative metabolic disease, mediated by impaired insulin responsiveness in the brain, glucose utilization and energy metabolism leading to increased oxidative stress, inflammation and worsening of insulin resistance. The connection between diabetes/obesity and AD, may shed light how sporadic AD develops. Biomarker search in cerebrospinal fluid of AD patients identified TFF3 protein as a new possible candidate for this crosstalk. Novel research showed that non-alcoholic fatty liver disease provoked by High fat diet is able to induce hallmarks of AD and even neuronal death in wild type mice. Diminishment of liver Tff3 gene expression was noticed in early stage of diabetes in Tally Ho mouse model of Type 2 diabetes. Tff3 protein is present in neurons and liver produced Tff3 can act neuroprotective and concentrate in brain upon injury. In this project proposal we will investigate impact of Tff3 protein in liver/brain axis using Tff3 -/-mouse strain and modeling Type 1 and Type 2 diabesity conditions. We will correlate the effect of Tff3 deficiency on liver as major metabolic organ, and hippocampus/cortex as affected brain regions is AD, monitoring neurodegenerative hallmarks and endoplasmatic reticulum stress markers. Using novel technology (XFe96 Extracellular Flux Analyzer) we will estimate impact of Tff3 on mitochondrial respiration and glycolysis in living primary hepatocytes. This systemic approach will help us understand common pathways in diabesity and neurodegeneration and possibly reveal novel therapeutic targets.