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

"exercise mimetics".