Investigations into a new gene in the brain that regulates appetite and body weight

Diabetes and obesity are the leading causes of death in the developed world. In Australia, almost two-thirds of adults are overweight or obese. A large proportion of this obesity can be attributed to over consumption of food well beyond our homeostatic needs. Most of the genetic alterations that contribute to obesity in humans appear to disrupt a network of neurons within a region in the brain named hypothalamus, which plays a pivotal role in regulating eating behaviour and energy expenditure. Thus, defining and understanding this hypothalamic network will provide critical insights into the management of obesity and its subsequent complications. Using discovery based approaches we have identified a novel protein called T28, which is enriched in hypothalamic nuclei that regulate energy and glucose homeostasis. In this project, we will determine whether and how T28 plays a role in the hypothalamic network to control appetite and energy expenditure, by using state of the art neuro-genetic approaches to engineer the mice to have a deletion of T28 specifically in the hypothalamic neurons. More importantly, we will utilize a cutting-edge genetic technology named "CRISPR-mediated activation" to upregulate the expression of T28 in the hypothalamus. We expect to see the "CRISPR-mediated activation"-treated mice become leaner with reduced fat mass, and therefore become metabolically healthier. This project will bring us more knowledge about how to prevent and treat obesity, and provide a novel therapeutic strategy for individuals who have obesity-related metabolic diseases.