Rhythm Regulation Of Lipid Absorption And Intervention Technology

The prevalence of obesity has become a major health problem in the worldwideincluding China.According to the latest global health observatory data from WHO,more than 1.9 billion adults are overweight and of these over 600 million adults are obese.Many studies indicate that obesity is closely associated with increased risk of multiple metabolic diseases,such as Type 2 diabetes,cardiovascular disease,sleep disorders,cancer and so on.Althougha large number ofepidemiological studies have investigated that the development of obesity is related to the changes in meal timing and the disruption of the circadian systemwhich caused by shift work,night-eating syndrome,and social stress,the molecular interactionsbetween timing of food consumption,obesity risk,and the circadian clock system is still unclear,and there also lack effective strategyused to the prevention of obesity.Thus,the study of the relationship between meal time,circadian clock and obesity not only has an important fundamental significance,but also has a guiding significance in the development of new biological and chemical preparationsfor preventing obesity and the metabolic syndrome.In this study,employing a nuclear magnetic resonance technology we found that lipid absorption has a daily rhythimic patternin mouse enterocyte,which showed a higher efficiency at night time than at daytime.Our result indicated that the circadiangene Period 1(Per1)specifically control circadian patterns of behavior in the temporal intestinal lipid absorption.Whilecompared Per1-deficient mice to wild-type mice fed a high-fat diet,the result demonstrated that Per1 deletion exhibited a less fat uptake and accumulation,with a significant decrease in body weight and body fat content.Lipid profiles of plasma and liver were also significantly decreased in Per1/-/mice.Liver tissue and epididymal fat pathological sections also showed a significant decline in fat accumulation compared to WT mice.Per1 mediates ATP-dependent diurnal FAs absorption.Per1 deficiency caused a decrease in the efficiency of reactive oxygen species(ROS)clearance,leading to a higher ROS accumulation produced by lipid oxidation,the morphological deformation of mitochondrial cristae,and a lower mitochondrial ATP production.ROS clearance form lipid oxidation is mainly accomplished by GPX.Further analysis indicated that Per1 collaborates with C/EBP δ to inhibit the transcription of ubiquitination factor Fbxw7,and then mediated the circadian rhythm of P-mTOR protein level.P-mTOR could directly bind to GPX1 and enhance GPX enzyme activity.Per1 changes the mitochondrial function involved in lipid uptake in circadian rhythms by affecting the morphological changes of the mitochondrial ridge.The results suggest that Per1,which could influence daily variations of ultrastructure of mitochondria cristae and its respiratory efficiency,participate in the diurnal control of intestinal lipid absorption.Stress induced the enhancement of Perl expression and improved the ability to clear the mitochondria ROS produced by lipid oxidation.Thereby it could enhance the transport of FFA,leading to excessive lipids absorption and accumulation and increase the risk of obesity.On the other hand,we found that dietary salecan(a water-soluble β-glucan)effectively prevents high-fat diet induced obesity in rat.Dietary 3%salecan markedly decreased in body weight,body fat,liver,adipose weight and lipid contents of serum and livein rat feed on high-fat diet.Through a 1H NMR based metabolomics analysis,salecan can significantly improve the metabolic changes caused by high-fat diet and shift toward that of the low-fat diet groupin the serum and liver extracts.Quantitative Real-time PCR(QRT-PCR)showed that salecan significantly inhibited the expression of Srebpl-c,Fasn,Scdl,Accl involved in de novo lipogenesis and Gpatl,Dgatl,Dgat2 related to triglyceride(TG)synthesis.Salecan could activate Ppara and its target gene Cpt1aexpression leading to an enhanced fatty acidβ-oxidation.Salecan also significantly increased Cyp7al expression,indicating that salecan may increase the decomposition of cholesterol in liver.Thus,dietary salecan could be an effective strategy for preventing obesity and the metabolic syndrome.