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  1. Numerous fatty acid receptors have proven to play critical roles in normal physiology. Interactions among these receptor types and their subsequent membrane trafficking has not been fully elucidated, due in part to the lack of efficient tools to track these cellular events. In this study, we fabricated the surface-enhanced Raman scattering (SERS)-based molecular sensors for detection of two putative fatty acid receptors, G protein-coupled receptor 120 (GPR120) and cluster of differentiation 36 (CD36), in a spatiotemporal manner in single cells. These SERS probes allowed multiplex detection of GPR120 and CD36, as well as a peak that represented the cell. This multiplexed sensing system enabled the real-time monitoring of fatty acid-induced receptor activation and dynamic distributions on the cell surface, as well as tracking of the receptors’ internalization processes on the addition of fatty acid. Increased SERS signals were seen in engineered HEK293 cells with higher fatty acid concentrations, while decreased responses were found in cell line TBDc1, suggesting that the endocytic process requires innate cellular components. SERS mapping results confirm that GPR120 is the primary receptor and may work synergistically with CD36 in sensing polyunsaturated fatty acids and promoting Ca2+mobilization, further activating the process of fatty acid uptake. The abilitymore »to detect receptors’ locations and monitor fatty acid-induced receptor redistribution demonstrates the specificity and potential of our multiplexed SERS imaging platform in the study of fatty acid–receptor interactions and might provide functional information for better understanding their roles in fat intake and development of fat-induced obesity.

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