I read with great interest the paper by Haberka et al1 published in this issue of Polish Archives of Internal Medicine (Pol Arch Intern Med). In their study, the authors found that epicardial adipose tissue (EAT) expresses glucagon like-1 receptor (GLP-1R) and glucagon like-2 receptor (GLP-2R) and both GLP-Rs correlate with the renin-angiotensin-aldosterone system (RAAS) in patients with coronary artery disease (CAD).
Epicardial adipose tissue is a novel cardiovascular risk factor, with peculiar anatomy, transcriptome, and proteasome.2,3 Its unobstructed contiguity with the adjacent myocardium and coronary arteries makes EAT unique and capable of bidirectional cross-talks with the heart. The fragile equilibrium between the cardioprotective thermogenic properties and the detrimental proinflammatory effects of EAT is often unbalanced.4,5 Hence, EAT easily turns into a pathogenic factor of cardio-metabolic diseases such as CAD, diabetes, and atrial fibrillation. However, there is a more recent feature that makes EAT an appealing therapeutic target and modifiable risk factor. Thanks to its responsiveness and measurability with either ultrasound or more accurate computed tomography, EAT can be a target of pharmaceutical agents modulating adipose tissue.
More specifically, and as confirmed by Haberka et al,1 EAT expresses GLP-1R. Our group discovered for the first time that human EAT expresses GLP-1R.6 Immunofluorescence analysis showed the presence of GLP-1R protein within EAT whereas the signal was absent in the subcutaneous fat. Intriguingly, GLP-1R signal was detected in EAT of both diabetic and nondiabetic patients.6 GLP-1R mRNA was also found in the heart chambers,7 and given the functional proximity of EAT to the heart, this becomes even more exciting.
How can this finding open new avenues and strategies in the prevention and treatment of cardiovascular diseases? GLP-1 receptor agonists (GLP-1A) rapidly emerged as drugs with pleiotropic effects. GLP-1A provides weight loss and cardiovascular protective effects beyond the diabetes control, as several clinical trials have demonstrated.8,9 Subjects on either daily or weekly GLP-1A had better glycemic control, lost weight, and had lower rates of hospitalization or death due to cardiovascular causes.8,9
Can this be related to the presence of GLP-1R with EAT? It is plausible to run some hypotheses. GLP-1 can favor EAT preadipocyte differentiation into mature adipocytes.10 This effect can improve local insulin sensitivity and glucose homeostasis. GLP-1R activation can stimulate EAT thermogenesis and adipocyte browning.11 Interestingly, EAT GLP-1R mRNA expression correlates with genes encoding for beta-oxidation and white-to-brown adipocyte differentiation.12 This could contribute to the weight loss observed in patients taking GLP-1A. Our group showed that EAT thickness dramatically shrinks (between 20% and 30%) when liraglutide, daily GLP-1A or semaglutide or dulaglutide, weekly GLP-1As, are added on metformin.13,14 GLP-1 analogues may target EAT GLP-1R and therefore reduce local adipogenesis, improve fat utilization, induce brown fat differentiation and ultimately reduce EAT mass. The relation of EAT GLP-1R with the RAAS components, well reported by Haberka et al,1 suggests an additional pathway. Particularly, the modulation of EAT angiotensin-converting enzyme (ACE) plays a role in the myocardial and perivascular inflammation, also in COVID-19 cardiac syndrome.15 Down-regulation of ACE2 increases EAT M1 macrophages whereas angiotensin (1-7) reduces EAT proinflammatory macrophages. GLP-1 agonistic effects may upregulate EAT ACE2 expression and then lower local inflammation, oxidative stress and endothelial damage. Findings of Haberka et al1 certainly warrant future studies to evaluate whether and to what extent GLP-1As can modulate ACE-2 and overall the RAAS.
As previously observed by our group,6 Haberka et al1 found that GLP-2R is also expressed in EAT.1 The clinical significance of this finding is still unclear. However, GLP-2R analogues, teduglutide and glepaglutide, have been recently associated with an improvement of obesity-related inflammation. The therapeutic potential of these novel GLP-2R analogues deserves future investigations.
In conclusion, it seems plausible that pharmacologically targeting EAT GLP-1R may induce previously unexpected beneficial cardio-metabolic effects. The potential of modulating EAT transcriptome and resume some of its physiological function (ie, thermogenic) with targeted pharmacological agents (ie, GLP-1As) can open new avenues in the pharmacotherapy of cardiometabolic diseases.
Prof. Gianluca Iacobellis, MD, PhD, Division of Diabetes, Endocrinology and Metabolism, University of Miami, Miller School of Medicine, 1400 NW 10th Ave, Dominion Tower suite 805-807, Miami, FL 33 136, United States, phone: +1 305 243 3636, email: giacobellis@med.miami.edu
February 15, 2021.
February 16, 2021.
March 30, 2021.
The opinions expressed by the author(s) are not necessarily those of the journal editors, Polish Society of Internal Medicine, or publisher.
None declared.
Iacobellis G. Can epicardial fat glucagon-like peptide-1 receptor open up to the cardiovascular benefits of glucagon-like peptide-1 analogues? Pol Arch Intern Med. 2021; 131: 224-225. doi:10.20452/pamw.15904
- 1.
- Haberka M, Siniarski A, Gajos G, et al. Epicardial, pericardial fat and glucagon-like peptide-1 and -2 receptors expression in stable patients with multivessel coronary artery disease: an association with the renin-angiotensin-aldosterone system. Pol Arch Intern Med. 2021; 131: 233-240.Crossref
- 2.
- Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol. 2015; 11: 363-371.Crossref
- 3.
- Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med. 2005; 2: 536-543.Crossref
- 4.
- Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation. 2003; 108: 2460-2466.Crossref
- 5.
- McAninch EA, Fonseca TL, Poggioli R, et al. Epicardial adipose tissue has a unique transcriptome modified in severe coronary artery disease. Obesity (Silver Spring). 2015; 23: 1267-1278.Crossref
- 6.
- Iacobellis G, Camarena V, Sant DW, Wang G. Human epicardial fat expresses glucagon-like peptide 1 and 2 receptors genes. Horm Metab Res. 2017; 49: 625-630.Crossref
- 7.
- Baggio LL, Yusta B, Mulvihill EE, et al. GLP-1 receptor expression within the human heart. Endocrinology. 2018; 159: 1570-1584.Crossref
- 8.
- Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375: 1834-1184.Crossref
- 9.
- Gerstein HC, Colhoun HM, Dagenais GR, et al; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019; 394: 121-130.
- 10.
- Yang J, Ren J, Song J, et al. Glucagon-like peptide 1 regulates adipogenesis in 3T3-L1 preadipocytes. Int J Mol Med. 2013; 31: 1429-1435.Crossref
- 11.
- Beiroa D, Imbernon M, Gallego R, et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes. 2014; 63: 3346-3358.Crossref
- 12.
- Dozio E, Vianello E, Malavazos AE, et al. Epicardial adipose tissue GLP-1 receptor is associated with genes involved in fatty acid oxidation and white-to-brown fat differentiation: a target to modulate cardiovascular risk? Int J Cardiol. 2019; 292: 218-224.Crossref
- 13.
- Iacobellis G, Mohseni M, Bianco S, Banga PK. Liraglutide causes large and rapid epicardial fat reduction. Obesity (Silver Spring). 2017; 25: 311-316.Crossref
- 14.
- Iacobellis G, Villasante Fricke AC. Effects of semaglutide versus dulaglutide on epicardial fat thickness in subjects with type 2 diabetes and obesity. J Endocr Soc. 2020; 4: bvz042.Crossref
- 15.
- Couselo-Seijas M, Almengló C, Agra-Bermejo RM, et al. Higher ACE2 expression levels in epicardial cells than subcutaneous stromal cells from patients with cardiovascular disease: diabetes and obesity as possible enhancer. Eur J Clin Invest. 2020 Nov 29. [Epub ahead of print]Crossref