Substrate Report for: PA-HD-MGL

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 is 1.88-fold and 1.50-fold higher, 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 reports suggesting levels of MGL should be attenuated, our results revealed a marked increase of both targets in the gastrointestinal tract. These key finding sets the stage to uncover the role of the endocannabinoid pathway in obesity-mediated inflammation.