A Small Contribution to a Large Problem: Leptin-Signaling and the Gut-Brain Axis

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PROJECT SUMMARY - A small contribution to a large problem: Leptin-signaling and the gut-brain axis The proposed research aims to solve the self-assembly of the leptin receptor (LEP-R) complex controlling energy homeostasis and its influence on gut microbiota composition. Leptin and its receptor have been proposed to be the link between nutritional status and the gut microbiome, although whether this hormone and its action is Despite its important role in human health, the molecular details of the human leptin receptor (hLEP-R) complex remain elusive. Our interdisciplinary approach utilizing a combination of molecular dynamic (MD) simulations, in vitro biophysical characterization, in cell assays, and in vivo experiments using Drosophila melanogaster (D. melanogaster) as our genetic model system puts our research in a unique position to build on our previous discoveries in human leptin (hLEP). Thus, conserved across the animal kingdom is poorly studied. taking advantage of the background developed in mammalian research to study the phenotype of D. melanogaster to test our hypothesis if LEP-signaling is a shared character among animals. The aim for year one is to produce transgenic flies, solve the backbone assignments, and find experimental conditions for Cryo- EM experiments for the LEP-R complexes using transfer electron microscopy (TEM) at the MICRO core at UH. The long-term aim is to understand LEP-signaling and the role of the diet and microbiome in driving the signaling behavior. We will define the signaling-complex's molecular details, effects of the gut microbiota’s secreted enzymes on this complex, and, reciprocally, leptin’s impact on microbiome composition. In this project, we will characterize human LEP (hLEP) and hLEP-R’s, elucidating the molecular details of LEP-signaling to set the stage for studies of the links among diet, microbiota, and LEP-R.