Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Abstract

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

High-Fat Diets Modify the Proteolytic Activities of Dipeptidyl-Peptidase IV and the Regulatory Enzymes of the Renin–Angiotensin System in Cardiovascular Tissues of Adult Wistar Rats

“…In summary, our data showed higher values of RAS regulatory activities together with lower values of DPP-IV with the Bch diet; these data coincide with investigations that reveal that Ang II stimulates collagen synthesis and inhibits collagenase activity in cardiac fibroblasts [ 78 , 82 , 83 ]. In a contradictory way, other researchers confirm that HFD with a high content of SAFA increases the expression and activity of DPP-IV in the aorta and atrium, playing a role in the development of aortic stiffness, vascular oxidative stress, endothelial dysfunction, and vascular remodeling by promoting increased deposition of collagen fibers [ 84 , 85 , 86 ]. The grouped correlation between DPP-IV and angiotensinases activities in cardiovascular tissues ( Table 1 ) manifested a strong association with collagenase DPP-IV activity when the classical and non-classical pathways of RAS were activated.…”

Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

“…Furthermore, an excessive body weight causes LV remodeling leading to both systolic and, particularly diastolic dysfunctions. In addition, obesity leads to enlargement of the left atrium, from both increased blood volume and diastolic ventricular dysfunction, which increases the risk of HF [ 4 , 41 , 48 , 49 ]. It is important to indicate that heart diseases, stroke, and chronic kidney diseases are all closely related to the pathophysiological mechanisms of high blood pressure.…”

“…Hyperlipidemia and hyperinsulinemia both stimulate FFA transport into cardiomyocytes, and an excess of lipids’ accumulation causes cardiac dysfunction via several mechanisms, including the generation of ROS and the production of lipid metabolites such as diacylglycerols, ceramides, or acylcarnitines. These metabolites further impair insulin signaling, as well as depress contractility by influencing sarcoplasmic reticular Ca 2+ stores and promoting mitochondrial dysfunction, ER stress, or apoptosis [ 49 , 88 , 91 , 95 ]. In addition, ceramides and diacylglycerols activate different protein kinase C isoforms, such as PKCβ, PKCδ, or PKCθ.…”

“…The accumulation of lipids within cardiomyocytes as well as visceral adiposity are associated with the expansion of epicardial and pericardial fat. These lipid depots may provide fatty acid substrates to the myocardium, but they also play a role in the elaboration of pro-inflammatory cytokines and adipokines that impact coronary and myocardial function [ 49 , 96 ]. It is well-known that FFAs are important adipocyte-derived mediators of macrophage-related inflammation, and macrophages may be important mediators of saturated FFAs’ effects on cardiac electrical remodeling [ 94 ].…”

Histone Deacetylases in the Pathogenesis of Diabetic Cardiomyopathy

“…Recent studies have highlighted that a complex interplay between genes and environment may significantly contribute to pathogenesis of microvascular complications associated with diabetes (12). Several potential mechanisms that may contribute to the pathogenesis of the DCM have been proposed, including cardiac structural abnormalities, metabolic disturbances, mitochondrial damage, oxidative stress, autophagy/mitophagy defect, apoptosis, systemic inflammation, epigenetic modification, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment (5,(13)(14)(15)(16)(17).…”