Grant: CIHR Fellowship

Obesity and high-fat regimen lead to brain functions impairment such as altered feeding behavior and development of anxiety- and depressive-like behavior. There is a strong link between obesity and depression in humans and animals alike and high-fat diet-induced brain inflammation is suspected to be that missing link. A novel drug has been generated in the lab of Dr Tschöp to correct obesity and brain inflammation. This compound is a combination of a GLP-1-like molecule, mimicking drugs already on the market to treat type 2 diabetes, and dexamethasone, a well-known anti-inflammatory molecule. Diet-induced obese mice treated with this novel compound exhibit massive weight loss, better insulin sensitivity and reduced neuroinflammation. Our aim is to understand if this novel compound can further improve feeding behavior, anxiety- and depressive-like behaviors, and to better understand the role of specific brain cells -known as astrocytes- in mediating these beneficial effects. This project has a strong translational potential and will also help understand the role of non-neuronal cells in the brain with respect to obesity and high-fat regimen-induced brain inflammation. We will use mouse models and treat them with this novel drug or a control solution and then assess their responses using state-of-the-art behavioral testing. We will also explore the role of astrocytes in their response using various genetically engineered mouse models allowing us to discriminate the effects linked with astrocytes direct or indirect actions and allowing us to artificially activate or repress astrocytes activation in a context of drug treatment. We believe this study will further solidify the potential of this new GLP-1-dexamethasone compound as a anti-obesity & anti-brain inflammation therapy, in addition to shedding light on the cellular mechanisms behind its actions.