Central nervous and metabolic effects of intranasal leptin in diet induced obesity and studies on leptin receptor signal transduction induced by leptin fragments

• Applicant: Dr. Carla Schulz
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2006 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34181278

One of the main features of obesity is a central nervous resistance to leptin, a white adipose tissue feedback hormone. This leptin resistance is mainly located at the blood brain barrier (BBB), leptin applied directly into the brain remains effective. The brain can also be targeted non-invasively by intranasal (i.n.) leptin application; transport is via the olfactory nerve, thus circumventing the BBB. Recently we have shown that in lean rats i.n. leptin effectively enters the brain to affect energy homeostasis. Since i.n. leptin does circumvent the BBB, it is expected to be effective in obesity as well, offering a possible therapeutic approach also in humans. To further elucidate this, we will study the effects of i.n. leptin in rats with diet induced obesity, the animal experimental model best resembling human obesity. We will study the endocrine and metabolic sequelae of this mode of administration and examine the brain expression of neuropeptides downstream of the leptin receptor. Some fragments of the native leptin molecule, which are supposed to penetrate more easily into the brain because of their size, are also effectively stimulating leptin receptors. However only very few data exist on their effects on energy homeostasis and on leptin receptor signal transduction. In an in-vitro model we will study signal transduction effects by leptin fragments. In summary, we will test our hypothesis that i.n. leptin is effective in obesity and we will characterise leptin fragments with respect to their potential feasibility in the i.n. treatment of obesity.

• DFG Programme: Research Grants