Sleeve Gastrectomy-Induced AMPK Activation Attenuates Diabetic Cardiomyopathy by Maintaining Mitochondrial Homeostasis via NR4A1 Suppression in Rats

Abstract

Diabetic cardiomyopathy (DCM) is characterized by impaired diastolic and systolic myocardial performance and is a major cause of morbidity and mortality in patients with diabetes. Surgical bariatric procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes (T2DM) and have benefits with myocardial function. Maintaining cardiac mitochondrial homeostasis is a promising therapeutic strategy for DCM. However, whether SG surgery affects mitochondrial function and its underlying mechanism remains unclear. This study aimed to investigate the effect of SG surgery on mitochondrial homeostasis and intracellular oxidative stress in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose and high fat-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a remarkably metabolic benefit of SG, including a reduced body weight, food intake, blood glucose levels, and restored glucose tolerance and insulin sensitivity post-operatively. Also, SG ameliorated the pathological cardiac hypertrophy, myocardial fibrosis and the dysfunction of myocardial contraction and diastole, consequently delayed the progression of DCM. Also, SG restored the mitochondrial dysfunction and fragmentation through the AMPK signaling activation mediated nuclear receptor subfamily 4 group A member 1 (NR4A1)/DRP1 suppression in vivo. H9c2 cardiomyocytes showed that activation of AMPK could reverse the mitochondrial dysfunction somehow. Collectively, our study provided evidence that SG surgery could alleviate mitochondrial dysfunction in DCM. Moreover, AMPK-activated NR4A1/DRP1 repression might act as a significant reason for maintaining mitochondrial homeostasis in the myocardium, thus contributing to morphological and functional alleviation of DCM.

Duodenal‐jejunal bypass surgery activates eNOS and enhances antioxidant system by activating AMPK pathway to improve heart oxidative stress in diabetic cardiomyopathy rats

“…One study showed that sleeve gastrectomy (SG) can increase expression of SOD2 and NRF2/HO‐1 pathway in the heart of T2DM rats, which showed the improvement of antioxidative system. 40 These results suggest that although SG and DJB are different operations, they may share similar pathways associated with the cardiac antioxidative system.…”

The Protective Effect of 11-Keto-β-Boswellic Acid against Diabetic Cardiomyopathy in Rats Entails Activation of AMPK

“…Therefore, these metabolic effects of AKBA can be assumed to be AMPK-dependent. Indeed, hyperglycemia has been consistently associated with reduced levels of cardiac, hepatic, and adipose tissue activities of AMPK [ 17 , 18 , 19 , 61 , 62 ]. On the other hand, the activation of AMPK by direct and indirect activators, as well as plant-derived activators, could alleviate obesity, hyperglycemia, IR, hepatic lipotoxicity, and hyperlipidemia in animal models of obesity and metabolic syndrome [ 61 , 62 , 63 ].…”

“…Studies have also shown a potent protective effect of AMPK against diabetes and cardiovascular health via the regulation of glucose uptake and utilization, lipid synthesis, fatty acid oxidation, autophagy, oxidative stress, inflammation, and apoptosis [ 16 ]. Indeed, the activities of AMPK are significantly depleted in the heart of diabetic animals (i.e., T1/T2DM) and are associated with cardiomyocyte lipotoxicity, oxidative stress, inflammation, reduced contractility, apoptosis, and remodeling [ 17 , 18 , 19 ]. In addition, genetic depletion or pharmacological inhibition of AMPK-induced structural and functional disturbances, remodeling, and dilated cardiomyopathy have been observed in experimental healthy mice [ 20 , 21 ].…”

Bariatric surgery for diabetic comorbidities: A focus on hepatic, cardiac and renal fibrosis

“…Both cellular and tissue mitochondrial respiration were increased in patients receiving RYGB or SG compared to preoperatively (Nijhawan et al, 2013). Evidence suggests that in a rat model of DCM, SG restores mitochondrial dysfunction and fragmentation by activating 5′ adenosine monophosphateactivated protein kinase (AMPK) signaling (Li et al, 2022). Myocardial Ca 2+ transients exhibit significantly higher amplitudes and faster decay after SG and DJB, suggesting that bariatric surgery can promote myocardial Ca 2+ homeostasis in DCM rats (Huang et al, 2018).…”

“…Myocardial Ca 2+ transients exhibit significantly higher amplitudes and faster decay after SG and DJB, suggesting that bariatric surgery can promote myocardial Ca 2+ homeostasis in DCM rats (Huang et al, 2018). The above-mentioned postoperative repair of mitochondrial function and Ca 2+ homeostasis can improve cardiac structure and cardiac function by reducing myocardial collagen deposition and fibrosis (Huang et al, 2018;Li et al, 2022). Despite this, there are currently few clinical studies on specific improvements in postoperative cardiac mitochondrial function and calcium homeostasis in patients undergoing bariatric surgery (Kindel and Strande, 2018).…”