Main areas of the CRC 1052

A, Overeating. The molecular basis of the regulation of energy homeostasis has rapidly expanded, primarily focussing on homeostatic signals controlling hypothalamic function. Research focussed to target defined hypothalamic neurons or pathways for the Treatment of obesity has provided only limited success in the treatment of obesity. This is a consequence of the abundant redundancy of pathways in control of energy homeostasis and from the fact that higher brain functions such as reward-seeking behaviour can eventually override hypothalamic control mechanisms. Thus, unraveling the complex neurocircuits in control of energy homeostasis and defining the integrating molecular mechanisms provides an approach to overcome these limitations. The long-term perspective of this major research line is to develop an integrated model for the role of the nervous System in human obesity.

B, Fat Deposition and Inflammation. As a long-term perspective, our CRC proposal carries the potential to define novel treatment targets within adipose tissue or related to unrecognized gene-environment interactions and altered adipokine signalling as underlying defects in obesity-related metabolic and cardiovascular diseases. this represents a novel approach to the urgently needed innovative pharmacological obesity treatment. to accomplish this aim, our CRC initiative integrates translational research projects, in which hypotheses derived from experimental models or specific human phenotypes can be translated into the setting of prospective clinical studies and vice versa compounds targeting adipose tissue dysfunction may be tested in various model systems including transgenic mice.

C, Adipokines. With the expanding number of novel identified adipokines there is an increasing need to define their function, molecular targets and potential clinical relevance as biomarkers or in the treatment obesity and metabolic diseases. We will use the unique setting of this CRC to systematically characterize novel adipokines using a broad spectrum of approaches including the recombinantlarge-scale production and labelling of adipokines and their application to well-defined animal models, definition of the crystal structure, identification of their molecular targets and intracallular signal transduction, validation of theirs relevance in human cohorts of childhood obesity, extreme phenotypes and weight loss intervention studies. As a long-term perspective, we aim to expand our experience gained with the clinical use of leptin in the treatment of human lipodystrophy to a potential application of the most promising adipokine(s) in human studies.