Type 2 diabetes is one of the most common chronic diseases in the world, and the number of those affected has been raising dramatically in recent years. In type 2 diabetes the body fails to use insulin effectively, which leads to the chronic increase in blood glucose that characterises the disease. It is not known why the body becomes resistant to insulin but evidence suggests that an imbalance between energy intake, storage, and expenditure can lead to obesity and insulin resistance. Thus, to understand the origins of diabetes it is fundamental to understand how the organism evaluates and controls its metabolic requirements. The hypothalamus in the base of the brain is essential for orchestrating such functions, aided by specific cell groups which detect changes in extracellular levels of nutrients. I suggest that a disruption in these sensing mechanisms in the hypothalamus can lead to a metabolic imbalance in the body. In this project I will study the properties of hypothalamic nutrient-sensing neurones in a model of obesity and insulin resistance. A novel approach that will combine state-of-the-art cell physiology, biochemistry, cellular and mitochondrial bioenergetics, and molecular imaging methods in a multidisciplinary environment will be key to unravel some of the mechanisms used by nutrient-sensing neurones in health and disease. This project will thus provide a better understanding of the role of these mechanisms in obesity, insulin resistance, and diabetes. That knowledge will potentially open new avenues to the development of novel strategies for treating metabolic diseases.