Photoacoustic Applications | Selective Detection of Two Obesity-Related Enzyme Activities
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Release time：2023-07-20
Summary： Obesity is a chronic condition characterized by excessive fat accumulation in the body. Prolonged obesity often gives rise to systemic inflammation, which can contribute to and exacerbate cardiovascular diseases, type 2 diabetes, hypertension, and even cancer. As key mediators of inflammatory responses, monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) work together to produce arachidonic acid (AA), which in obese individuals is directly linked to appetite regulation and metabolic rate.
Obesity is a chronic condition characterized by excessive fat accumulation in the body. Prolonged obesity often triggers systemic inflammation, which can contribute to and exacerbate cardiovascular diseases, type 2 diabetes, hypertension, and even certain cancers. As key mediators of inflammatory responses, monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) work together to generate arachidonic acid (AA). In obese individuals, AA is directly linked to appetite regulation and metabolic rate. Consequently, monitoring the levels or concentrations of MGL and FAAH in the body can, to some extent, help predict an individual’s risk of developing the aforementioned conditions. However, conventional methods such as immunohistochemical staining—commonly used to assess the expression levels of these two enzymes—cannot provide a direct measure of enzyme activity, as enzymatic activity can vary significantly in response to changes in substrate concentration, cofactor availability, and local tissue conditions, including pH.
Probe Design
In response to this limitation, Melissa Y. Lucero and colleagues have pioneered the development of enzymatic activity–specific probes that enable selective detection of MGL and FAAH activities via photoacoustic imaging. Photoacoustic imaging was chosen because it offers deep tissue penetration with minimal signal attenuation in vivo, allowing micron‑scale imaging at depths of up to 10 cm. The selectivity arises from the differential degradation of distinct functional groups: although the same contrast agent molecule is employed, the authors covalently attach an amino acid (AA) to the agent via an ester linkage for MGL activity detection, while linking AA through a peptide bond for FAAH activity detection. To ensure the probe’s high efficiency and stability, they incorporated a hemicyanine dye (HD)—a class of dyes that enhance the photosensitivity of imaging agents—into the contrast agent design, thereby boosting signal intensity (Figure 1).
Figure 1. Design strategies for selective, high-efficiency contrast agents: a) MGL-selective contrast agent PA‑HD‑MGL; b) FAAH-selective contrast agent PA‑HD‑FAAH. Here, “1” denotes cyanine dye.
After the reaction, it remains in the developer in the structure of a hemicyanine dye; compounds 2 and 3 are the photoacoustic imaging agent chemical structures targeting MGL and FAAH, respectively.
Test Results
The authors first characterized two types of probes. The developing agents 2 and 3, modified with hemicyanine dyes (see Figure 1), exhibit peak photoacoustic signals at incident wavelengths of 740 nm and 730 nm, respectively, whereas the developing agents PA‑HD‑MGL and PA‑HD‑FAAH, functionalized with arachidonic acid, produce only weak photoacoustic signals across the entire near-infrared spectral range. Consequently, by degrading their respective developing agents, MGL and FAAH can achieve 7.29‑ and 4.15‑fold increases in photoacoustic signal intensity (Figure 2), thereby enabling selective detection.
Figure 2. In vitro assay results: a) Probe signal detection; b, c) Photoacoustic signal intensity of the probe in the near-infrared region; d, e) Specific degradation assays of the probe under different enzymatic conditions.
Finally, the authors also conducted cellular and animal obesity‑model experiments and successfully observed a substantial increase in MGL and FAAH levels in obese mice (Figure 3).
Figure 3. Determination of MGL and FAAH levels in an obese mouse model: The left panel shows a comparison of signal intensity for MGL levels between mice fed a low-fat diet and those fed a high-fat diet.
The right panel shows a comparison of signal intensity for FAAH levels in mice fed a low-fat versus a high-fat diet.
Summary
Through ingenious chemical‑structure design, the authors have enabled the quantitative and selective measurement of MGL and FAAH enzymatic activities, thereby providing empirical support for the hypothesis that individuals with obesity exhibit higher levels of these two enzymes compared to healthy subjects.
References:
[1] M Y Lucero, S H Gardner, A K Yadav, et al., Angewandte Chemie International Edition 2022 (DOI: 10.1002/anie.202211774)
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