Activity-based Photoacoustic Probes Reveal Elevated Intestinal MGL and FAAH Activity in a Murine Model of Obesity.
Activity-based Photoacoustic Probes Reveal Elevated Intestinal MGL and FAAH Activity in a Murine Model of Obesity.
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DOI：
10.1002/anie.202211774
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发表时间：
2022-11-02
影响因子：
16.6
通讯作者：
Chan, Jefferson
中科院分区：
文献类型：
--
作者：
Lucero, Melissa Y.;Gardner, Sarah H.;Yadav, Anuj K.;Borri, Austin;Zhao, Zhenxiang;Chan, Jefferson
肥胖是一种慢性健康状况，其特征是体内脂肪过多，可通过全身炎症导致并加剧心血管疾病、II型糖尿病、高血压和癌症。不幸的是，由于涉及花生四烯酸(AA)的重叠底物范围，以选择性的方式可视化炎症反应的关键介质，如单酰甘油脂肪酶(MGL)和脂肪酸酰胺水解酶(FAAH)是一个深刻的挑战。具体地说，这些酶协同作用产生AA，在肥胖的背景下，AA被认为与控制食欲和能量代谢有关。在这项研究中，我们开发了第一个选择性的基于活性的传感探针，通过光声成像检测MGL(PA-HD-MGL)和FAAH(PA-HD-FAAH)的活性。PA-HD-MGL和PA-HD-FAAH被其靶酶激活后，信号分别增强了1.74倍和1.59倍。由于它们特殊的选择性分布和深层组织光声成像能力，这些探针被用来测量肥胖小鼠模型中的MGL和FAAH活性。与相互矛盾的报告显示MGL水平可以减弱或升高相反，我们的结果支持后者。事实上，我们发现在胃肠道中这两个靶点都显著增加。这些关键发现为揭示内源性大麻素途径在肥胖介导的炎症中的作用奠定了基础。基于活性的传感探针和全身光声成像已经能够在肥胖和胃肠道炎症的背景下选择性地检测单甘油脂肪酶(MGL)和脂肪酸酰胺水解酶(FAAH)的活性。
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. Activity-based sensing probes and whole-body photoacoustic imaging have enabled the selective detection of monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) activity in the context of obesity and gastrointestinal tract inflammation.
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影响因子：
4.7
作者：
Bearrood, Thomas E.;Aguirre-Figueroa, Guadalupe;Chan, Jefferson
通讯作者：
Chan, Jefferson
影响因子：
3.7
作者：
Chon SH;Douglass JD;Zhou YX;Malik N;Dixon JL;Brinker A;Quadro L;Storch J
通讯作者：
Storch J
影响因子：
18.2
作者：
Anorma C;Hedhli J;Bearrood TE;Pino NW;Gardner SH;Inaba H;Zhang P;Li Y;Feng D;Dibrell SE;Kilian KA;Dobrucki LW;Fan TM;Chan J
通讯作者：
Chan J
DOI：
10.1002/anie.201802143
发表时间：
2018-06-18
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Bruemmer KJ;Green O;Su TA;Shabat D;Chang CJ
通讯作者：
Chang CJ
DOI：
10.1016/j.bpg.2014.07.013
发表时间：
2014-08-01
影响因子：
3.2
作者：
Bonfrate, Leonilde;Wang, David Q-H.;Portincasa, Piero
通讯作者：
Portincasa, Piero