Sensory perception plays an important role in maintaining energy balance and normal body fat content.Despite its significance, there is a major gap in our understanding of the molecular mechanisms that linkspecific sensory modalities, to energy balance circuits in the brain. Our long-term goal is to identify themolecular mechanisms that integrate sensory signals in the nervous system with intrinsic cues to regulate bodyfat, and the defects in this process that lead to obesity. The objective the of proposed research is to determinethe role of the G protein GPA-8 in C. elegans, a powerful and tractable model system for the study of energybalance circuits. GPA-8 is homologous to the mammalian -gustducin G protein, and is expressed inoxygen-sensing neurons in C. elegans. The central hypothesis of the proposed research is that GPA-8signaling from sensory neurons integrates oxygen sensing with body fat content. We expect thatunderstanding the mechanism of action of GPA-8 in C. elegans will be a critical step toward identifying theneural circuits and conserved molecular mechanisms by which oxygen sensation in the nervous systeminfluences body fat content.
Our Specific Aims are to: I. Identify the GPA-8-expressing neurons that regulatebody fat. Using neuron-specific promoters, we will restore GPA-8 expression in subsets of neurons in gpa-8mutant animals to define the precise anatomical sites of GPA-8 action in regulating body fat. II. Define theintracellular mode of action for GPA-8. GPA-8 is a G protein suggesting that loss of G protein signaling inoxygen-sensing neurons regulates body fat. We will test the effects of loss of G protein activation cycle genesspecifically in oxygen-sensing neurons, to determine the intracellular mode of action of GPA-8. III. Determinethe mechanisms of integration of oxygen sensation with fat stores. We will test a candidate genetic pathwayinvolved in cGMP signaling and in oxygen-sensing for changes in body fat under different oxygenconcentrations, to delineate the neural mechanisms underlying the integration of oxygen-sensing and body fatcontent. With respect to expected outcomes, the completion of the proposed work will enable the first insightsinto the neural circuits and molecular mechanisms that connect oxygen-sensing in the nervous system, withbody fat content. Importantly, our findings will allow us to identify signaling paradigms underlying the gut-brainaxis that controls energy balance. Because all of the genes under study have clear mammalian orthologs, ourcontribution here will have a positive impact on rapidly identifying new molecular targets for combating obesityand its associated illnesses. The proposed research is significant because a molecular connection betweenneural oxygen sensing and body fat content provides a new dimension to our understanding of organismalenergy balance and the causes underlying obesity.
The importance of this project to human health is to reveal fundamental new insights into the role of the sensory nervous system in controlling body fat content. Our discoveries of the conserved genes and molecular mechanisms that connect a discrete sensory modality, oxygen sensing, to body fat content, and the defects in this process that lead to obesity are expected to be of great relevance in ameliorating this public health crisis.
