Endocrinology Unit, Clinical Nutrition and Cardiovascular Prevention Service, IRCCS Policlinico San Donato, San Donato Milanese, Italy.
Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy.
Eur J Prev Cardiol. 2023 Jun 1;30(8):680-693. doi: 10.1093/eurjpc/zwad050.
Human epicardial adipose tissue (EAT) plays a crucial role in the development and progression of coronary artery disease, atrial fibrillation, and heart failure. Microscopically, EAT is composed of adipocytes, nerve tissues, inflammatory, stromovascular, and immune cells. Epicardial adipose tissue is a white adipose tissue, albeit it also has brown fat-like or beige fat-like features. No muscle fascia divides EAT and myocardium; this allows a direct interaction and crosstalk between the epicardial fat and the myocardium. Thus, it might be a therapeutic target for pharmaceutical compounds acting on G-protein-coupled receptors, such as those for glucose-dependent insulinotropic polypeptide (GIP), glucagon (GCG), and glucagon-like peptide-1 (GLP-1), whose selective stimulation with innovative drugs has demonstrated beneficial cardiovascular effects. The precise mechanism of these novel drugs and their tissue and cellular target(s) need to be better understood. We evaluate whether human EAT expresses GIP, GCG, and GLP-1 receptors and whether their presence is related to EAT transcriptome. We also investigated protein expression and cell-type localization specifically for GIP receptor (GIPR) and glucagon receptor (GCGR).
Epicardial adipose tissue samples were collected from 33 patients affected by cardiovascular diseases undergoing open heart surgery (90.9% males, age 67.2 ± 10.5 years mean ± SD). Microarray and immunohistochemistry analyses were performed. Microarray analysis showed that GIPR and GCGR messenger ribonucleic acids (mRNAs) are expressed in EAT, beyond confirming the previously found GLP-1 [3776 ± 1377 arbitrary unit (A.U.), 17.77 ± 14.91 A.U., and 3.41 ± 2.27 A.U., respectively]. The immunohistochemical analysis consistently indicates that GIPR and GCGR are expressed in EAT, mainly in macrophages, isolated, and in crown-like structures. In contrast, only some mature adipocytes of different sizes showed cytoplasmic immunostaining, similar to endothelial cells and pericytes in the capillaries and pre-capillary vascular structures. Notably, EAT GIPR is statistically associated with the low expression of genes involved in free fatty acid (FFA) oxidation and transport and those promoting FFA biosynthesis and adipogenesis (P < 0.01). Epicardial adipose tissue GCGR, in turn, is related to genes involved in FFA transport, mitochondrial fatty acid oxidation, and white-to-brown adipocyte differentiation, in addition to genes involved in the reduction of fatty acid biosynthesis and adipogenesis (P < 0.01).
Having reported the expression of the GLP-1 receptor previously, here, we showed that GIPR and GCGR similarly present at mRNA and protein levels in human EAT, particularly in macrophages and partially adipocytes, suggesting these G-protein-coupled receptors as pharmacological targets on the ongoing innovative drugs, which seem cardiometabolically healthy well beyond their effects on glucose and body weight.
人类的心外膜脂肪组织（EAT）在冠状动脉疾病、心房颤动和心力衰竭的发展和进展中起着至关重要的作用。在显微镜下，EAT 由脂肪细胞、神经组织、炎症、基质血管和免疫细胞组成。心外膜脂肪组织是一种白色脂肪组织，尽管它也具有棕色脂肪样或米色脂肪样特征。没有肌肉筋膜将 EAT 和心肌分开; 这允许心外膜脂肪和心肌之间的直接相互作用和串扰。因此，它可能是作用于 G 蛋白偶联受体的药物化合物的治疗靶点，例如葡萄糖依赖性胰岛素促分泌多肽（GIP）、胰高血糖素（GCG）和胰高血糖素样肽-1（GLP-1）的受体，这些受体的选择性刺激用创新药物已经证明了有益的心血管作用。这些新型药物的确切机制及其组织和细胞靶标需要更好地理解。我们评估人类 EAT 是否表达 GIP、GCG 和 GLP-1 受体，以及它们的存在是否与 EAT 转录组有关。我们还专门研究了 GIP 受体（GIPR）和胰高血糖素受体（GCGR）的蛋白表达和细胞类型定位。
从 33 名接受心脏直视手术的心血管疾病患者（90.9%为男性，年龄 67.2 ± 10.5 岁）中收集心外膜脂肪组织样本。进行了微阵列和免疫组织化学分析。微阵列分析显示，GIPR 和 GCGR 信使核糖核酸（mRNA）在 EAT 中表达，此外还证实了先前发现的 GLP-1[3776 ± 1377 任意单位（A.U.），17.77 ± 14.91 A.U.和 3.41 ± 2.27 A.U.]。免疫组织化学分析一致表明，GIPR 和 GCGR 在心外膜脂肪组织中表达，主要在巨噬细胞、分离的和冠状样结构中表达。相比之下，只有不同大小的一些成熟脂肪细胞显示细胞质免疫染色，类似于毛细血管和前毛细血管血管结构中的内皮细胞和周细胞。值得注意的是，EAT GIPR 与涉及游离脂肪酸（FFA）氧化和转运以及促进 FFA 生物合成和脂肪生成的基因的低表达呈统计学相关（P < 0.01）。反过来，EAT GCGR 与涉及 FFA 转运、线粒体脂肪酸氧化和白色到棕色脂肪细胞分化的基因以及涉及减少 FFA 生物合成和脂肪生成的基因相关（P < 0.01）。
在先前报道 GLP-1 受体表达的基础上，我们在这里表明，GIPR 和 GCGR 同样在人类 EAT 的 mRNA 和蛋白质水平上表达，特别是在巨噬细胞和部分脂肪细胞中，表明这些 G 蛋白偶联受体作为正在进行的创新药物的药理学靶点，这些药物似乎在代谢健康方面表现良好，远远超出了它们对葡萄糖和体重的影响。
