Role of new lipids FAHFAs in the brain and their involvement in pathological conditions.

• Applicant: Dr. Maria Fernandez Rubin de Celis, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Endocrinology, Diabetology, Metabolism ; Cell Biology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 337847048

Several lipids species such as omega-3 fatty acids, phospholipids, sphingolipids and cholesterol play major roles on brain homeostasis and function. A novel class of signaling lipids constituted by a fatty-acid bound to a hydroxy-fatty acid (FAHFAs) was recently discovered by the hosting group. A subfamily of this lipid class, palmitic acid hydroxy-stearic acids (PAHSAs), was shown to exert antidiabetic and anti-inflammatory actions by promoting insulin-stimulated glucose uptake and insulin secretion and preventing dendritic cell and adipose tissue macrophage activations. These lipids are found in the major metabolic tissues such as the liver and white and brown adipose tissues and in the serum, where their levels strongly correlate with insulin sensitivity. Interestingly, preliminary data from the hosting group indicate that FAHFAs are also present in the brain, where they seem to be synthesized in situ and promote anti-inflammatory effects on astrocytes. In this project proposal, we aim to investigate the potential role of FAHFAs in brain function, cellular metabolism as well as potential implications of these lipids in brain inflammation and cognitive performance. We propose a comprehensive and sequential plan in order to address these questions. First to all, a detailed analysis of the brain distribution of the different FAHFA families will be performed in order to identify those subfamilies with highest concentrations, indicative of potential important functions. Secondly, we will characterize the effects of those FAHFAs on the activity of microglia, astrocytes and neurons. Thirdly, given previous reports suggesting alterations in cognitive performance and anxiety associated to states of insulin resistance in humans, we will analyse potential FAHFA-mediated effects on these brain disorders by using several behavior tests in lean and obesity-induced insulin resistant mice subjected to direct brain administration of FAHFAs. Findings derived from this project may shed light on novel lipid molecules participating in brain function and homeostasis and serve as potential therapeutic targets for brain-related disorders.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Barbara Kahn