Unravelling a unifying network for leptin and insulin interaction in the hypothalamus as a potential link between obesity and associated diseases. Genetherapeutic, pharmacological and nutritive interventions of crucial signalling pathways.

• Applicant: Dr. Alexander Tups
• Subject Area: Nutritional Sciences
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 243471766

Central resistance to the adiposity signals leptin and insulin has deleterious effects on whole body energy homeostasis and glucose metabolism. It has been comprehensively characterized by us and others that this resistance is largely mediated by altered signalling events distal to the leptin and insulin receptors in neurons of the hypothalamus. Subsequently, different pathways involved in mediating leptin and insulin signal transduction in the hypothalamus have been identified; however, their interplay is only poorly understood. We identified an evolutionary highly conserved signalling pathway, the WNT/GSK3 pathway as a novel and essential integrator of both leptin and insulin signalling in the hypothalamus. We could furthermore demonstrate that not hyperleptinemia per se appears to trigger central resistance to the hormone rather inflammation induced by high fat feeding contributes to the manifestation of this phenomenon. This proposal aims at characterizing a unifying signalling network of leptin and insulin interaction in the hypothalamus. The exact role of GSK3 and prominent pro-inflammatory kinases such as JNK and IKKbeta in the network of leptin and insulin signalling in the hypothalamus will be assessed. Using state of the art genetherapeutic and pharmacological methodologies hypothalamic inflammation shall be reversed and impaired leptin and insulin signalling restored. Delineating the complex interaction of both hormones has the potential to significantly improve our knowledge about the pathogenesis of obesity and associated severe diseases.

• DFG Programme: Research Grants
• International Connection: New Zealand
• Participating Persons: Professor Dr. Dave Grattan; Professor Peter Shepherd, Ph.D.