Acute reciprocal regulation of adiponectin and leptin

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The project‘s research program focuses on the application of the genetic model organism mouse, to study in vivo the mechanism of an acute reciprocal cross-regulation of adiponectin and leptin. Objective 1 "Determine whether or not and how adiponectin siganling through AdipoR1 and AdipoR2 regulates leptin production" and objective 2 "Determine whether or not and how leptin signaling through LepRb regulates adiponectin production", are subdivided in a discovery and intervention part. Discovery part: The diverse set of outstanding new mouse models will allow me to examine the spacio-temporal elucidation of AdipoR and LepR signaling. Combining an adipocyte specific doxycycline-inducible AdipoR double knockout mouse model and an adipocyte specific doxycycline-inducible LepR knockout mouse model will enable me to reflect both sides of the interaction. Intervention part: the most distinguished targets found to be regulated in adipocytes by the respective receptor signaling, will be manipulated by well established adeno-associated virus (AAV) gene transfer technology. The swift aquisition of mechanistical insights into the cross-regulation of adiponectin and leptin can be expected by my adipocyte selective AAV targeting approach. The alternative approach to use small molecule inhibitors will add to the diversity of methods. With objective 3 ,"Explore the therapeutic potential of manipulating pivotal signaling nodes of adiponectin/leptin cross-regulation in obesity, I will test knowledge gained under the work program’s intervention part in an independent disease mouse model mimicking human overnutrition-caused obesity. This is key to measure the exact effect size, and lays the foundation for drug discovery or clinical research to estimate the therapeutic potential of addressing certain target proteins in regards to obesity and associated diseases.