Human epicardial adipose tissue expresses glucose-dependent insulinotropic polypeptide, glucagon, and glucagon-like peptide-1 receptors as potential targets of pleiotropic therapies

• Published in: European journal of preventive cardiology 2023-06, Vol.30 (8), p.680-693
• Main Authors: Malavazos, Alexis Elias, Iacobellis, Gianluca, Dozio, Elena, Basilico, Sara, Di Vincenzo, Angelica, Dubini, Carola, Menicanti, Lorenzo, Vianello, Elena, Meregalli, Chiara, Ruocco, Chiara, Ragni, Maurizio, Secchi, Francesco, Spagnolo, Pietro, Castelvecchio, Serenella, Morricone, Lelio, Buscemi, Silvio, Giordano, Antonio, Goldberger, Jeffrey J, Carruba, Michele, Cinti, Saverio, Corsi Romanelli, Massimiliano Marco, Nisoli, Enzo
• Format: Article
• Language: English
• Subjects: Adipose Tissue - metabolism; Aged; Endothelial Cells - metabolism; Fatty Acids; Female; Gastric Inhibitory Polypeptide - metabolism; Gastric Inhibitory Polypeptide - pharmacology; Glucagon - metabolism; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor - genetics; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose; Humans; Male; Middle Aged; Receptors, G-Protein-Coupled - genetics
• ISSN: 2047-4873; 2047-4881
• 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 fa