Proteomic and Structural Manifestations of Cardiomyopathy in Rat Models of Obesity and Weight Loss

Abstract

Obesity cardiomyopathy increases the risk of heart failure and death. Obesity is curable, leading to the restoration of the heart phenotype, but it is not clear if there are any after-effects of obesity present after weight loss. We characterize the proteomic landscape of obesity cardiomyopathy with an evaluation of whether the cardiac phenotype is still shaped after weight loss. Cardiomyopathy was validated by cardiac hypertrophy, fibrosis, oversized myocytes, and mTOR upregulation in a rat model of cafeteria diet-induced developmental obesity. By global proteomic techniques (LC-MS/MS) a plethora of molecular changes was observed in the heart and circulation of obese animals, suggesting abnormal utilization of metabolic substrates. This was confirmed by increased levels of cardiac ACSL-1, a key enzyme for fatty acid degradation and decreased GLUT-1, a glucose transporter in obese rats. Calorie restriction and weight loss led to the normalization of the heart’s size, but fibrosis was still excessive. The proteomic compositions of cardiac tissue and plasma were different after weight loss as compared to control. In addition to morphological consequences, obesity cardiomyopathy involves many proteomic changes. Weight loss provides for a partial repair of the heart’s architecture, but the trace of fibrotic deposition and proteomic alterations may occur.

Effect of high-fat diet and empagliflozin on cardiac proteins in mice

“…Empagliflozin did not significantly improve obesity-induced cardiac hypertrophy in our study, which could be due to the short duration of administration and low dose of the drug, but it did reduce myocardial collagen content, and inhibit myocardial remodeling, which is consistent with previous findings [28]. Weight loss greatly alleviates the aberrant protein expression generated by obesity, resulting in cardioprotective effects, according to proteomics studies [16,29]. The current study found that obese mice's body weight reduced dramatically following treatment with empagliflozin, but it's still unclear if the cardioprotective effect of empagliflozin on obesity is mediated by weight loss or by other mechanisms.…”

“…Mice in the WE group had reduced heart walls and enlarged inner chambers compared to the WF group, but the difference was not statistically significant (P > 0.05). This is consistent with previous studies that have seen that cardiac fibrosis acquired during weight gain persists after weight loss [16]. These results suggest that obesity thickens the ventricular wall and reduces the volume of the heart chambers, and that empagliflozin has a protective effect on cardiac function.…”

“…It has been postulated that Sestrin2-mediated AMPK-mTOR signaling is important in empagliflozin's cardioprotective properties [8]. Apoe, Apoc1, Saa2, Apoa2, and Pon1 (all implicated in cholesterol metabolism) were found to change considerably after empagliflozin treatment, but not in the presence of weight loss [16]. In addition, the main mechanism of action of empagliflozin is the inhibition of renal reuptake of glucose, the HFD provided in this study is triacylglycerol rich and it is unclear whether the reduction in body weight in mice is associated with enhanced β-oxidation of fat.…”

“…Its goal is to uncover the inherent relationships between biological genotypes and phenotypes, resulting in innovative and realistic concepts for disease diagnosis and therapy [14]. Proteomic techniques have been used to detect protein expression in animal and human heart tissue studies [15,16]. However, most current research on cardioprotective medicines in obese patients is limited to clinical observational studies, and the drugs' mechanisms of action are unknown.…”

UTP14A, DKC1, DDX10, PinX1, and ESF1 Modulate Cardiac Angiogenesis Leading to Obesity-Induced Cardiac Injury

“…The mechanisms underlying obesity-induced cardiac dysfunction have not been fully elucidated [ 8 ]. Previous studies showed that obesity causes alterations in cardiac energy metabolism in cardiomyocytes, particularly fatty acid metabolism [ 9 , 10 ], and analysis has revealed that acyl-CoA synthetase long-chain family member 1 (ACSL-1) and glucose transporter member 4 (GLUT-4) may be the key proteins responsible for heart damage [ 11 ]. Other studies discovered that obesity contributes to a chronic inflammatory state in the body and interferes with a variety of metabolic processes [ 12 ].…”