High‐Saturated Fat High‐Sugar Diet Accelerates Left‐Ventricular Dysfunction Faster than High‐Saturated Fat Diet Alone via Increasing Oxidative Stress and Apoptosis in Obese‐Insulin Resistant Rats

Abstract

Scope It has been hypothesized that a high‐saturated‐fat, high‐sugar diet (HFHS) causes worse cardiometabolic dysfunction than a high‐saturated‐fat diet (HFD) due to severe mitochondrial dysfunction, oxidative stress, and apoptosis in obese insulin‐resistant rats. Methods and Results Rats are divided into three groups to receive normal diet (ND), HFD, or HFHS for 24 weeks. Cardiometabolic parameters are determined at baseline and every 4 weeks until the end of the feeding protocol. At week 24, hearts are removed to determine mitochondrial function and dynamics, apoptosis, and insulin signaling. HFD and HFHS rats develop obese insulin‐resistance at week 8. However, fasting plasma glucose level is increased only in HFHS rats. Myocardial insulin signaling is markedly impaired in HFHS rats compared to other groups. Cardiac autonomic imbalance is observed in both HFD and HFHS rats beginning at week 8. However, cardiac dysfunction is observed earlier (week 8) in HFHS rats, and later at week 12 in HFD rats. Moreover, cardiac and mitochondrial oxidative stress levels, and apoptosis are greater in HFHS rats than HFD rats. Conclusion Both HFD and HFHS cause cardiometabolic dysfunction. HFHS causes more severe metabolic disturbance, oxidative stress, and apoptosis than HFD, which leads to an accelerated LV dysfunction in HFHS rats.

CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

“…Oxidative stress is a very vital contributor to HFD-induced myocardial lipotoxicity. Previous studies show that excessive lipid accumulation triggered by HFD feeding could cause increased oxidative stress and subsequent apoptosis of cardiomyocytes 1,33. Consistent with these observations, we demonstrated that the levels of ROS were higher in palmitate-stimulated NRCMs and DIO heart.…”

The impact of DRP1 on myocardial fibrosis in the obese minipig

“…Prolonged severe obesity may result in left ventricular (LV) dilation, increased LV wall stress, compensatory LV hypertrophy, myocardial fibrosis and LV diastolic dysfunction with progression to systolic dysfunction if wall stress remains high . The high‐fat diet (HFD) is known to be a major cause of obesity, and the HFD is used to induce cardiometabolic dysfunction and for investigation of the mechanisms responsible for metabolic heart disease . The overload of nutrients impairs cardiac mitochondrial function, leading to decreased mitochondrial biogenesis, reduced mitochondrial coupling efficiency and decreased ATP synthesis .…”

“…Mice fed a HFD have increased DRP1‐dependent mitochondrial fission which is linked to increased oxidative stress, decreased ATP production, insulin resistance and cardiac dysfunction . Rats fed a HFD have cardiometabolic dysfunction, myocardial mitochondrial dysfunction and impairment of mitochondrial dynamics; the HFD not only downregulates mitochondrial fusion‐related proteins but also upregulates fission‐related proteins …”

“…9,10 The high-fat diet (HFD) is known to be a major cause of obesity, and the HFD is used to induce cardiometabolic dysfunction and for investigation of the mechanisms responsible for metabolic heart disease. [11][12][13] The overload of nutrients impairs cardiac mitochondrial function, leading to decreased mitochondrial biogenesis, reduced mitochondrial coupling efficiency and decreased ATP synthesis. 14,15 Mice fed a HFD have increased DRP1-dependent mitochondrial fission which is linked to increased oxidative stress, decreased ATP production, insulin resistance and cardiac dysfunction.…”

“…16,17 Rats fed a HFD have cardiometabolic dysfunction, myocardial mitochondrial dysfunction and impairment of mitochondrial dynamics; the HFD not only downregulates mitochondrial fusion-related proteins but also upregulates fission-related proteins. 11,12 In our previous study, we established a myocardial fibrosis minipig model via HFD feeding. This obese minipig exhibits the metabolic syndrome (which includes hypertension, hyperglycaemia, abdominal obesity, and dyslipidaemia) and fatty liver; furthermore, the endoplasmic reticulum stress, autophagy and lipotoxicity participate in the pathological mechanism of cardiomyopathy.…”