TY - JOUR
T1 - Activity-based Photoacoustic Probes Reveal Elevated Intestinal MGL and FAAH Activity in a Murine Model of Obesity
AU - Lucero, Melissa Y.
AU - Gardner, Sarah H.
AU - Yadav, Anuj K.
AU - Borri, Austin
AU - Zhao, Zhenxiang
AU - Chan, Jefferson
N1 - This work was supported the National Institutes of Health (R35 GM133581 to JC). MYL acknowledges the Pines Graduate Fellowship for support. SHG thanks the Cancer Center at Illinois for a Graduate Student Cancer Scholarship. AB was supported by a School of MCB Summer Undergraduate Research Fellowship. JC thanks the Helen Corley Petit Scholar Program and the Camille and Henry Dreyfus Foundation for support. Major funding for the 500 MHz Bruker CryoProbe was provided by the Roy J. Carver Charitable Trust (Muscatine, Iowa; Grant No. 15‐4521) to the School of Chemical Sciences NMR Lab. The Q‐Tof Ultima mass spectrometer was purchased in part with a grant from the National Science Foundation, Division of Biological Infrastructure (DBI‐0100085). The authors thank Mr. Cameron Keeton for preliminary spectroscopic analysis of the first‐generation probes and Dr. Sandra McMasters and the Cell Media Facility for assistance preparing cell culture media.
PY - 2022/11/2
Y1 - 2022/11/2
N2 - Obesity is a chronic health condition characterized by the accumulation of excessive body fat which can lead to and exacerbate cardiovascular disease, type-II diabetes, high blood pressure, and cancer through systemic inflammation. Unfortunately, visualizing key mediators of the inflammatory response, such as monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), in a selective manner is a profound challenge owing to an overlapping substrate scope that involves arachidonic acid (AA). Specifically, these enzymes work in concert to generate AA, which in the context of obesity, has been implicated to control appetite and energy metabolism. In this study, we developed the first selective activity-based sensing probes to detect MGL (PA-HD-MGL) and FAAH (PA-HD-FAAH) activity via photoacoustic imaging. Activation of PA-HD-MGL and PA-HD-FAAH by their target enzymes resulted in 1.74-fold and 1.59-fold signal enhancements, respectively. Due to their exceptional selectivity profiles and deep-tissue photoacoustic imaging capabilities, these probes were employed to measure MGL and FAAH activity in a murine model of obesity. Contrary to conflicting reports suggesting levels of MGL can be attenuated or elevated, our results support the latter. Indeed, we discovered a marked increase of both targets in the gastrointestinal tract. These key findings set the stage to uncover the role of the endocannabinoid pathway in obesity-mediated inflammation.
AB - Obesity is a chronic health condition characterized by the accumulation of excessive body fat which can lead to and exacerbate cardiovascular disease, type-II diabetes, high blood pressure, and cancer through systemic inflammation. Unfortunately, visualizing key mediators of the inflammatory response, such as monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), in a selective manner is a profound challenge owing to an overlapping substrate scope that involves arachidonic acid (AA). Specifically, these enzymes work in concert to generate AA, which in the context of obesity, has been implicated to control appetite and energy metabolism. In this study, we developed the first selective activity-based sensing probes to detect MGL (PA-HD-MGL) and FAAH (PA-HD-FAAH) activity via photoacoustic imaging. Activation of PA-HD-MGL and PA-HD-FAAH by their target enzymes resulted in 1.74-fold and 1.59-fold signal enhancements, respectively. Due to their exceptional selectivity profiles and deep-tissue photoacoustic imaging capabilities, these probes were employed to measure MGL and FAAH activity in a murine model of obesity. Contrary to conflicting reports suggesting levels of MGL can be attenuated or elevated, our results support the latter. Indeed, we discovered a marked increase of both targets in the gastrointestinal tract. These key findings set the stage to uncover the role of the endocannabinoid pathway in obesity-mediated inflammation.
KW - Activity-Based Sensing
KW - Endocannabinoid System
KW - Inflammation
KW - Obesity
KW - Photoacoustic Imaging
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U2 - 10.1002/anie.202211774
DO - 10.1002/anie.202211774
M3 - Article
C2 - 36083191
AN - SCOPUS:85139451366
SN - 1433-7851
VL - 61
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 44
M1 - e202211774
ER -