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 link specific sensory modalities, to energy balance circuits in the brain. Our long-term goal is to identify the molecula mechanisms that integrate sensory signals in the nervous system with intrinsic cues to regulate body fat, and the defects in this process that lead to obesity. The objective of the proposed research is to determine the role of the G? protein GPA-8 in C. elegans, a powerful and tractable model system for the study of energy balance circuits. GPA-8 is homologous to the mammalian ?-gustducin G? protein, and is expressed in oxygen-sensing neurons in C. elegans. The central hypothesis of the proposed research is that GPA-8 signaling from sensory neurons integrates oxygen sensing with body fat content. We expect that understanding the mechanism of action of GPA-8 in C. elegans will be a critical step toward identifying the neural circuits and conserved molecular mechanisms by which oxygen sensation in the nervous system influences body fat content.
Our Specific Aims are to: I. Identify the GPA-8-expressing neurons that regulate body fat. Using neuron-specific promoters, we will restore GPA-8 expression in subsets of neurons in gpa-8 mutant animals to define the precise anatomical sites of GPA-8 action in regulating body fat. II. Define the intracellular mode of action for GPA-8. GPA-8 is a G? protein suggesting that loss of G protein signaling in oxygen-sensing neurons regulates body fat. We will test the effects of loss of G protein activation cycle genes specifically in oxygen-sensing neurons, to determine the intracellular mode of action of GPA-8. III. Determine the mechanisms of integration of oxygen sensation with fat stores. We will test a candidate genetic pathway involved in cGMP signaling and in oxygen-sensing for changes in body fat under different oxygen concentrations, to delineate the neural mechanisms underlying the integration of oxygen-sensing and body fat content. With respect to expected outcomes, the completion of the proposed work will enable the first insights into the neural circuits and molecular mechanisms that connect oxygen-sensing in the nervous system, with body fat content. Importantly, our findings will allow us to identify signaling paradigms underlying the gut-brain axis that controls energy balance. Because all of the genes under study have clear mammalian orthologs, our contribution here will have a positive impact on rapidly identifying new molecular targets for combating obesity and its associated illnesses. The proposed research is significant because a molecular connection between neural oxygen sensing and body fat content provides a new dimension to our understanding of organismal energy balance and the causes underlying obesity.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Hyde, James F
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Scripps Research Institute
La Jolla
United States
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Hussey, Rosalind; Littlejohn, Nicole K; Witham, Emily et al. (2018) Oxygen-sensing neurons reciprocally regulate peripheral lipid metabolism via neuropeptide signaling in Caenorhabditis elegans. PLoS Genet 14:e1007305
Palamiuc, Lavinia; Noble, Tallie; Witham, Emily et al. (2017) A tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism. Nat Commun 8:14237
Hussey, Rosalind; Stieglitz, Jon; Mesgarzadeh, Jaleh et al. (2017) Pheromone-sensing neurons regulate peripheral lipid metabolism in Caenorhabditis elegans. PLoS Genet 13:e1006806
Witham, Emily; Comunian, Claudio; Ratanpal, Harkaranveer et al. (2016) C. elegans Body Cavity Neurons Are Homeostatic Sensors that Integrate Fluctuations in Oxygen Availability and Internal Nutrient Reserves. Cell Rep 14:1641-1654
Srinivasan, Supriya (2015) Regulation of body fat in Caenorhabditis elegans. Annu Rev Physiol 77:161-78
Noble, Tallie; Stieglitz, Jonathan; Srinivasan, Supriya (2013) An integrated serotonin and octopamine neuronal circuit directs the release of an endocrine signal to control C. elegans body fat. Cell Metab 18:672-84