3-(2-4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3h)-quinazolinone and Obesity

Topics: Animals; Cardiomyopathies; Mice; Mice, Obese; Mitophagy; Myocytes, Cardiac; Obesity; Protein Kinases; Ubiquitin-Protein Ligases

An imbalance of brain mitochondrial dynamics, increases in brain inflammation and apoptosis, and increasing cognitive dysfunction, have been reported as being associated with prediabetes and myocardial ischemia-reperfusion (IR) injury. Since inhibiting mitochondrial fission with Mdivi-1 or promoting fusion with M1 had cardioprotective effects in myocardial IR injury and obesity, the neuroprotective roles of Mdivi-1 and M1 when administered at different time points of myocardial IR injury in obese prediabetes have never been determined. Ninety-six male Wistar rats were fed with either a normal (ND: n = 8) or a high-fat diet to induce prediabetes (HFD: n = 88) for 12 weeks. At week 13, all rats were subjected to left anterior descending coronary artery ligation for 30 min, followed by reperfusion for 120 min. HFD rats were randomly divided into 10 groups and assigned into either a pre-ischemic group treated with vehicle (HFV), pre-ischemic, during-ischemic, or onset of reperfusion groups treated with either Mdivi-1 (MDV), M1, or combined (COM). Heart function was examined invasively, with the heart being terminated to investigate myocardial infarction. Brains were collected to determine mitochondrial functions, inflammation, apoptosis, and pathological markers. Mdivi-1, M1, and COM treatment at different periods exerted cardioprotection against myocardial IR injury in HFD-fed rats by reducing infarct size and left ventricular dysfunction. All interventions also improved all brain pathologies against myocardial IR injury in prediabetic rats. These findings suggest that differential temporal modulation of mitochondrial dynamics may be appropriate regimens for preventing heart and brain complications after myocardial IR injury in obese prediabetes.

Topics: Animals; Apoptosis; Brain; Cardiotonic Agents; Inflammation; Male; Mitochondrial Dynamics; Myocardial Reperfusion Injury; Obesity; Prediabetic State; Rats; Rats, Wistar

Dynamin-related protein-1 (Drp1) is a key regulator in mitochondrial fission. Excessive Drp1-mediated mitochondrial fission in skeletal muscle under the obese condition is associated with impaired insulin action. However, it remains unknown whether pharmacological inhibition of Drp1, using the Drp1-specific inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), is effective in alleviating skeletal muscle insulin resistance and improving whole-body metabolic health under the obese and insulin-resistant condition. We subjected C57BL/6J mice to a high-fat diet (HFD) or low-fat diet (LFD) for 5-weeks. HFD-fed mice received Mdivi-1 or saline injections for the last week of the diet intervention. Additionally, myotubes derived from obese insulin-resistant humans were treated with Mdivi-1 or saline for 12 h. We measured glucose area under the curve (AUC) from a glucose tolerance test (GTT), skeletal muscle insulin action, mitochondrial dynamics, respiration, and H

Topics: Animals; Anti-Obesity Agents; Cells, Cultured; Diet, High-Fat; Dynamins; Glucose; Humans; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mitochondria, Muscle; Muscle, Skeletal; Obesity; Quinazolinones

Obese insulin resistance impairs cardiac mitochondrial dynamics by increasing mitochondrial fission and decreasing mitochondrial fusion, leading to mitochondrial damage, myocardial cell death and cardiac dysfunction. Therefore, inhibiting fission and promoting fusion could provide cardioprotection in this pre-diabetic condition. We investigated the combined effects of the mitochondrial fission inhibitor (Mdivi1) and fusion promoter (M1) on cardiac function in obese insulin-resistant rats. We hypothesized that Mdivi1 and M1 protect heart against obese insulin-resistant condition, but also there will be greater improvement using Mdivi1 and M1 as a combined treatment. Wistar rats (n=56, male) were randomly assigned to a high-fat diet (HFD) and normal diet (ND) fed groups. After feeding with either ND or HFD for 12 weeks, rats in each dietary group were divided into groups to receive either the vehicle, Mdivi1 (1.2 mg/kg, i.p.), M1 (2 mg/kg, i.p.) or combined treatment for 14 days. The cardiac function, cardiac mitochondrial function, metabolic and biochemical parameters were monitored before and after the treatment. HFD rats developed obese insulin resistance which led to impaired dynamics balance and function of mitochondria, increased cardiac cell apoptosis and dysfunction. Although Mdivi1, M1 and combined treatment exerted similar cardiometabolic benefits in HFD rats, the combined therapy showed a greater reduction in mitochondrial reactive oxygen species (ROS). Mitochondrial fission inhibitor and fusion promoter exerted similar levels of cardioprotection in a pre-diabetic condition.

Topics: Animals; Apoptosis; Cardiotonic Agents; Diet, High-Fat; Insulin Resistance; Male; Mitochondria, Heart; Mitochondrial Dynamics; Obesity; Quinazolinones; Rats, Wistar; Reactive Oxygen Species