Abstract
Olfactory and metabolic dysfunctions are intertwined phenomena associated with obesity and neurodegenerative diseases; yet how mechanistically olfaction regulates metabolic homeostasis remains unclear. Specificity of olfactory perception integrates diverse environmental odors and olfactory neurons expressing different receptors. Here, we report that specific but not all olfactory neurons actively regulate fat metabolism without affecting eating behaviors in Caenorhabditis elegans, and identified specific odors that reduce fat mobilization via inhibiting these neurons. Optogenetic activation or inhibition of the responsible olfactory neural circuit promotes the loss or gain of fat storage, respectively. Furthermore, we discovered that FLP-1 neuropeptide released from this olfactory neural circuit signals through peripheral NPR-4/neuropeptide receptor, SGK-1/serum- and glucocorticoid-inducible kinase, and specific isoforms of DAF-16/FOXO transcription factor to regulate fat storage. Our work reveals molecular mechanisms underlying olfactory regulation of fat metabolism, and suggests the association between olfactory perception specificity of each individual and his/her susceptibility to the development of obesity.
Highlights
Olfactory and metabolic dysfunctions are intertwined phenomena associated with obesity and neurodegenerative diseases; yet how mechanistically olfaction regulates metabolic homeostasis remains unclear
Among the 30 mutants that we screened, we identified that the mutants of daf-11, which encodes a conserved transmembrane guanylyl cyclase, show a fat storage increase (Supplementary Fig. 1a)
Transmembrane guanylyl cyclases catalyze the conversion of GTP to cGMP, a secondary messenger that is widely used in sensory signal transduction across different species17. daf-11(m47) carries a nonsense mutation leading to deletion of the entire guanylyl cyclase catalytic domain, which is likely a null mutation[18]; while daf-11(ks67) carries a missense mutation targeting a key residue in the catalytic domain, which is likely a hypomorph[18]
Summary
Olfactory and metabolic dysfunctions are intertwined phenomena associated with obesity and neurodegenerative diseases; yet how mechanistically olfaction regulates metabolic homeostasis remains unclear. These studies imply a bi-directional association between obesity and olfactory distortion, but the results from these studies are contradictory, given that the gross removal of olfactory systems[3] and the enhancement of olfactory sensitivity[4] can both prevent high-fat induced obesity These conflicting findings under obese conditions raise the questions, how the sense of smell regulates fat metabolism under physiological conditions, and how the specificity of olfactory perception plays a role in this regulation. In bilaterally asymmetric AWC neurons that express different receptors, the specificity of olfactory sensation is observed even between the right and left pair, where one AWC neuron responds to the odor 2-butanone, and 2,3-pentanedione targets the other[14] This mechanism of neuronal asymmetry expands the diversity of olfactory neurons with distinct specificity, and creates a circuit suited for signal integration via a diverse set of inputs to different downstream interneurons[15]. Through genetic and optogenetic approaches, we demonstrated that only one of asymmetric AWC neurons is crucial for this regulation, supporting the high selectivity of the olfactory sense in fine-tuning metabolic physiology
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