| Background Obesity is a common metabolic disease that is mainly caused by long-term exceeding energy intake,resulting in excessive energy accumulation.Relevant epidemiological reports show that the problem of obesity facing by human society is becoming increasingly serious.A number of studies have shown that obesity will increase the potential risk of many diseases including hypertension,diabetes,cardiovascular disease and other metabolic diseases,and may raise the incidence of cardiovascular disease complications.Obesity has become a rigorous health problem that has attracted worldwide attention and needs to be solved urgently.Adipose tissue serves as an energy storage organ and an endocrine organ at the same time.It plays an important role in maintaining the metabolism of glucose and lipids in human body.It can be divided into two types,namely white fat which is widely distributed and brown fat which has a very important effect although the total amount is small.As an important structure for energy storage,white fat constitutes most of the adipose tissue,and is common in typical obesity and metabolic syndrome models.There are large lipid droplets located in the cells of white fat tissue.While brown fat tissue can convert the ingested chemical energy into released heat energy instead of store it in the form of lipid droplets,and the lipid droplets of the contained fat cells are relatively small.The activation of brown fat tissue is beneficial to alleviate the body’s hyperlipidemia and improve the metabolic status.Therefore,promoting the browning of white adipose tissue is the key to alleviating obesity and other related diseases.Studies have confirmed that peroxisome proliferator receptor co-activator γ-1(PGC-1α)is a transcriptional activator protein of the nuclear receptor family that is widely involved in multiple metabolic pathways such as mitochondrial biosynthesis,which can bind with multiple transcription factors and is able to regulate downstream factors,PGC-1α plays an important role in brown fat metabolism regulation,its activation can promote brown fat metabolism activity.Epicardial adipose tissue(EAT)is a type of unique accumulation of fat around the heart,located between the myocardium and the visceral pericardium(generally preferentially distributed at the bottom of the heart,the apex of the left ventricle,the atrioventricular sulcus and the periventricular sulcus.It distributed along the coronary arteries and veins).Under normal physiological conditions,EAT plays a variety of local and systemic roles in the human body,including metabolism,heat production,secretion,and mechanical properties,and will affect the dynamic balance of glucose and lipid metabolism,which will affect the structure of the heart.However,the above-mentioned equilibrium state is destroyed in obese patients,and the pathophysiological changes act on the epicardial adipose tissue,leading to the pathological thickening or volume enlargement of the later,losing its normal function,and then promoting coronary heart disease,atrial fibrillation and a variety of cardiovascular diseases.At present,most studies on epicardial fat are focused on its own physiological functions,characteristics and the pathophysiological changes that occur in related diseases.However,the mechanism of cardiac function damage that triggered by obesity-mediated epicardial fat tissue imbalance still remains inconclusive.Our previous research found that epoxyeicosatrienoic acids(EETs)which are a class of lipid mediator that is beneficial to energy metabolism and cardiovascular health,play an important role in the occurrence and development of obesity-related cardiovascular diseases.administration of s EH inhibitor(s EHi)can reduce the decomposition of EET in the body,stabilize the concentration of EET,and further improve the cardiac function after myocardial infarction through anti-inflammatory and antioxidant effects.Based on the above-mentioned background,we constructed a high-fat-induced obesity mouse model,and applied s EH inhibitors to increase EET levels,aiming to screen a new possible mechanism for up-regulating browning epicardial adipose tissue to improve heart function(EET-PGC-1α-EAT browning),and making efforts to further supplement the important factors that may play a role in this pathway,finally provide new targets for the prevention and treatment of obesity and related heart damage.Aims1.Clarify the effect of obesity on epicardial adipose tissue and heart function;2.To find out the effect of regulating EET levels on the browning of epicardial adipose tissue and the influence of cardiac function damage;3.Try to explore and reveal the new mechanism of EET level regulation that affects epicardial fat browning and heart function,and supplement the possible crucial factors and signal pathways in the EET-PGC-1α-EAT browning pathway;4.Provide feasible new targets for the prevention and treatment of obesity and related heart damage.Methods1.Construct obese mouse models induced by high-fat diet,apply corresponding AUDA intervention,and make use of methods such as echocardiography,RT-PCR,hemodynamic testing,and morphological staining to monitor and analyze mouse models’ signs,blood test indicators(blood sugar,blood lipids,etc.),hemodynamics,cardiac structure and function conditions,the m RNA level of inflammatory factors in EAT,the pathological changes in myocardium and epicardial adipose tissue,and the changes in EAT Brown fat metabolism activity,etc.The aim is to observe the effect of obesity on epicardial adipose tissue and cardiac function,and to explore the effect of regulating EET levels on the browning process of epicardial adipose tissue and obesity-related cardiac function damage,and find out the mechanism of these effects;2.Isolate and culture primary human bone marrow mesenchymal stem cells(BM-MSCs)and further induce their adipogenic differentiation to construct an in vitro model,combined with corresponding AUDA intervention,detecting by flow cytometry,morphological staining,si RNA intervention,Western Blot,RT-PCR,etc.to explore the new mechanism of EET level regulation affecting epicardial fat browning and heart function,and finally verify the new mechanism in obese mouse models.Results1.Obesity has a negative effect on epicardial adipose tissue and heart function.Construct a High-Fat-Diet-induced obesity mouse model and compare its basic physical signs,blood indicators,hemodynamics,heart structure and function,epicardial fat inflammatory factor m RNA levels,myocardial and epicardial fat with mice in negative control group.The pathological changes of tissues and the difference in the metabolic activity of brown fat in epicardial adipose tissue prove that obesity worsens metabolic status of the body,intensifies the inflammatory response of epicardial adipose tissue,decreases the metabolic activation of brown adipose tissue,and induces pathological changes in heart structure which damage the heart function.2.Increasing the level of EET can promote the browning of the EAT and partly reverse the deterioration of heart function caused by obesity.By administering s EHi to murine models to increase their EET levels and testing related indicators,the results showed that upregulating EET can alleviate the damage of basic physical signs,blood indicators,hemodynamics,heart structure and function,m RNA level of EAT’s inflammatory factor,pathological changes in myocardium and epicardial adipose tissue,and brown fat metabolic activity in epicardial adipose tissue.EETs can improve the browning of EAT,antagonize the damage effect of obesity on cardiac functions.3.Up-regulating EET levels can antagonize obesity-related cardiac function damage through the EET-AMPK-PGC-1α-EAT browning pathway.On the basis of in vivo experiments,we constructed a cell model and found that administration of s EHi can increase the expression of fat metabolism-related factor PGC-1α,and si RNA intervention in the expression of PGC-1αcan inhibit browning of adipocyte.In addition,s EHi intervention can induce the activation of AMPK signaling pathway,and the administration of Compound C to inhibit AMPK activation can attenuate the effect of EET on PGC-1α.After discovering the above pathways in cell models,experimental animal models were used again to apply corresponding interventions to verify that the above pathway plays an important role in the process of epicardial fat browning and the progress of obesity-related heart damage.Conclusions1.Obesity worsens metabolic status of the body,increases the level of oxidative stress in epicardial adipose tissue,decreases the metabolic activation of brown adipose tissue,and causes pathological changes in heart structure and decreased heart function;2.Increasing the EET level can improve browning of the epicardial adipose tissue and alleviate the deterioration of heart function caused by obesity;3.The EET-AMPK-PGC-1α pathway is an important pathway for epicardial adipose tissue browning,and the reduce of AMPK and PGC-1α may affect the structure and function of the heart by inhibiting epicardial fat browning.4.PGC-1α is an important target for intervention in the metabolic disorder of epicardial adipose tissue,and it is expected to provide feasible new ideas for the prevention and treatment of obesity and obesity related heart damage. |
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