According to alarming reports of the World Health Organization, worldwide more people die
from the consequences of overfeeding than from hunger. Sedentary lifestyle and excess food
consumption have indeed provoked a worldwide obesity epidemic. Importantly, obesity is not
just a cosmetic problem, but predisposes to the development of chronic metabolic diseases,
including Type 2 diabetes (T2D) and cardiovascular disease, which are imposing increasing
pressure on healthcare. Whereas preventive actions are the cornerstone of sustainable
curtailing of the obesity epidemic, the required lifestyle changes are not easily adhered to.
Therefore, there is an urgent need for pharmacological therapeutic strategies to complement
treatments based on dietary and/or exercise regimens.
The polypeptide hormone leptin is an anorexigenic hormone that is produced by the white
adipose tissue and acts on hypothalamic neurons that regulate satiety and feeding behaviour.
Remarkably, most cases of diet-induced obesity, the so called "garden-variety obesity", are
characterized by high levels of circulating leptin. This leptin, however, fails to elucidate its
anorexigenic action, which is reminiscent of a leptin-resistant state, similar to the insulin
resistance apparent in T2D. In this study, we will therefore focus on the identification and
mode of action of modulators of hypothalamic leptin receptor function. Because recent
studies indicate exercise enhances central leptin sensitivity, we will here use exercise as an
experimental paradigm to identify hypothalamic proteins involved in leptin receptor function.
Using an unbiased approach, combining state-of-the-art mass spectrometry and mammaliantwo-
hybrid technologies, we hope to reveal novel targets for the development of leptinsensitizing