Adipocytes Initiates An Adipose-cerebral-peripheral Sympathetic Reflex To Induce Insulin Resistance During High-fat Feeding

BackgroudObesity is ascribed to imbalance in energy intake and expenditure,and characterized by excessive accumulation of white adipose tissue,and it is the major reason of Insulin resistance(IR).Obese individuals are often accompanied by sympathetic nervous system(SNS)overactivation.Nonetheless,it is not entirely understood how the accumulation of white asipose tissue affects peripheral SNS activation in other tissue responsible for glucose disposal(e.g.,adipose tissue,and skeletal muscle),and then leading to IR.Salt sensitive hypertension is often found in obese individuals with IR,and hypertension and IR in obese individuals can be improved by resrticting dietary salt intake,but the mechanism by which high salt intake involves in obesity IR is still unclear.Our previous research showed that in animal models of Chronic Kidney Disease(CKD),high salt enhances the renal reflex in the Kidney,and then activates the renin-cerebral renin-angiotensin system(RAS)axis,which promotes renal fibrosis.Thus,we speculate that a high-fat diet(HF)can increase the afferent impulse from white adipose tissue,that reflectively activates muscle and adipose tissue efferent nerve activity to enhance the production of Reactive Oxygen Species(ROS)and Angiotensin Ⅱ(AngⅡ),impaire glucose uptake in local tissue,thus promotes the development of IR Moreover,the process would be exacerbated by high salt intake.MethodsProtocal 1:Male SD rats(180-220g)were fed with a HF feeding(60%fat-derived calories,5.0Kcal/g,HF group)or normal fat feeding(17%fat-derived calories,3.7Kcal/g,Control group)for 9 weeks,and then control or HF rats were assigned randomly to two groups receiving their allocated diets but with normal(0.4%NaCl)or high salt contents(4%NaCl)for 3 weeks..Protocol 2:Male SD rats(180-220g)were fed with a HF feeding(60%fat-derived calories,5.0Kcal/g,HF group)for 9 weeks,then diets turn into high fat high salt(60%fat-derived calories,5.0Kcal/g,4%NaCl)for 3 weeks,and rats were assigned randomly to 11 groups,for the following treatments:intragastric(IG)losartan at 0 or 1 or 500 mg/kg/d,Intracerebrventricular(ICV)administration artificial cerebrospinal fluid as a ICV control,ICV losartan,ICV clonidine,denervation of epidydimal fat pads,Selective deafferentation of epididymal fat pads by injection of Resiniferatoxin into epididymal fat pads,IG tempol,IG hydralazine.ResultsMetabolic dysfunction,local RAS/ROS activation,and increased afferent SNS impulses were observed in adipose tissue of HF rats.Central RAS/ROS activation,and increased central SNS output were discovered in HF rats.It is the increase of SNS efferent impulses to skeletal muscle and adipose tissue and local RAS/ROS activation that decreased blood perfusion in skeletal muscle,impaired insulin signaling pathway and glucose uptake in skeletal muscle and adipose tissue,and then lead to IR.High dietary salt reduced peripheral glucose uptake via activation of adipose-cerebral-muscle RAS/ROS/SNS axis,and then aggravates IR.Denervation of epidydimal fat pads or selective blockade of afferent signals from epidydimal fat pads by local deafferentation downregulated central SNS outflow,corrected the increased skeletal muscle SNS activity,and restored the impaired glucose uptake and perfusion in skeletal muscle,then improve whole body insulin srnsitivity.Central blockade of the RAS/SNS with ICV losartan and ICV clonidine suppressed the activation of the local RAS/ROS/SNS systems,upregulated related insulin signals,enhanced peripheral glucose uptake and improved whole body insulin sensitivity.ConclusionA HF diet engages a sympathetic reflex from the white adipose tissue that activates adipose-cerebral-muscle RAS/ROS/SNS axes and coordinates a reduction in peripheral glucose uptake.These are all enhanced by salt-loading.