The Mechanism By Which Nutritional L-lactate Supplementation Ameliorates Diet-induced Obesity And Related Metabolic Dysfunction In Mice

Obesity is a chronic metabolic disease that is related to the imbalance of body energy metabolism.Long-term excessive energy accumulation caused by a high-calorie diet will induce obesity and its related metabolic dysfunctions.At present,it is an important research direction to reduce body weight by promoting energy metabolism and consuming excess lipids in adipose tissue to protect against obesity.Lactate,as the main product of glycolysis,has been considered as a metabolic waste produced by anaerobic respiration for a long time.However,recent studies have found that even under aerobic conditions,organisms need to maintain redox balance,acid-base balance,and energy metabolic balance by generating a large amount of lactate in the circulatory system.Lactate shuttles among organs,cells,and organelles in the form of L-lactate in mammals.On the one hand,it acts as an energy carrier to participate in biosynthesis,on the other hand,it acts as a signal molecule to regulate hormone release and various enzyme activities.Dietary fermented foods,such as yogurt,are reported to promote intestinal digestion and absorption,protect intestinal probiotics,reduce blood lipids and prevent atherosclerosis.Therefore,it is of great scientific significance and application prospect to increase plasma lactate levels through lactate nutritional supplementation,including intraperitoneal injection and dietary supplementation,and to explore the regulatory role and mechanism of lactate nutritional supplementation in improving obesity and related metabolic dysfunctions.Here,this study carries out the works from the following three aspects.1)The effects of L-lactate nutritional supplementation on HFD-induced obesity and related metabolic dysfunction.In this study,a gradient dose of sodium L-lactate supplementation was performed in wild-type HFD mice to confirm that 800 mg/kg/d intraperitoneal injection and 4% dietary supplementation were appropriate supplemental doses.After the supplementation dose was determined,the effects of Llactate nutritional supplementation on obesity were investigated by adding L-lactate in HFD-fed mice.The results showed that L-lactate nutritional supplementation reduced body weight,fat mass,insulin resistance,fatty liver,and hyperlipidemia in HFD-fed mice.Investigations on adipose tissue indicated that L-lactate nutritional supplementation not only improved HFD-induced adipose tissue inflammation,but also promoted thermogenesis and lipolysis in white adipose tissue in HFD-fed mice.However,the monitoring of basal energy metabolism showed that only dietary L-lactate significantly increased energy metabolism in HFD-fed mice when energy expenditure was normalized to individuals.This suggests that dietary L-lactate may have other mechanisms to promote energy expenditure compared with L-lactate injection.In addition,although L-lactate injection did not promote individual energy metabolism,it improved systemic insulin resistance in HFD-fed mice,suggesting that L-lactate injection has other cellular and molecular mechanisms for improving insulin resistance independent of energy metabolism.2)The mechanism of L-lactate injection inhibiting macrophage M1 polarization to improve obesity-related insulin resistance.The study found that L-lactate injection significantly inhibited adipose tissue macrophage(ATM)infiltration and proinflammatory M1 polarization in HFD-fed mice.By utilizing PKA and AMPK inhibitors and si RNA of GPR132,the results showed that L-lactate can bind to the macrophage surface receptor GPR132,drive downstream c AMP-PKA signaling,and further promote the phosphorylation of AMPKα1,thereby inhibiting macrophage M1 polarization and the secretion of related inflammatory factors to improve the insulin resistance of adipocytes.These results illustrated the mechanism by which L-lactate injection suppresses ATM pro-inflammatory M1 polarization by activating the GPR132-PKA-AMPKα1 signaling pathway,thereby improving adipose tissue and systemic insulin resistance in HFD-fed mice.3)The mechanism of dietary L-lactate regulating energy metabolism through bile acid signaling.Given the important effects of dietary changes on gut microbiota and its metabolites,and the key role of bile acids in the development of obesity.This study further investigated the mechanism of dietary L-lactate promoting energy metabolism in HFD-fed mice based on bile acid,a metabolite of gut microbiota.The results showed that dietary L-lactate increased total bile acid content and the proportion of secondary bile acid in the circulation in HFD-fed mice,and increased the contents of Cholic acid(CA)and Deoxycholic acid(DCA),which could promote energy metabolism.The alterations of bile acid are due to dietary L-lactate increased the abundance of intestinal bacteria which could transform primary bile acid to secondary bile acid,and increased liver bile acid synthesis enzyme CYP7A1 in HFD-fed mice.In addition,by adding Farnesoid X receptor(FXR)agonist GW4064,the mechanism study showed that dietary L-lactate inhibited the ileum FXR signaling cascade and reduced intestinal secretion of FGF15 to blood in HFD-fed mice,which further promoted the expression of CYP7A1 in the liver and increased the circulatory bile acid level,and then activated the G protein conjugated bile acid receptor TGR5 in adipose tissue,accelerating adipose tissue thermogenesis and energy expenditure in HFD-fed mice.In conclusion,this study indicated that L-lactate supplementation improves dietinduced obesity and related metabolic disorders in mice.This study also elucidated the mechanism by which L-lactate injection inhibits M1 polarization of adipose tissue macrophages and improves obesity-related insulin resistance through the GPR132-PKA-AMPKα1 pathway.Further,this study revealed the mechanism of dietary Llactate accelerating energy metabolism by inhibiting intestinal FXR signal,promoting liver CYP7A1 expression,and activating adipose tissue TGR5 in HFD-fed mice.This study not only enriches the scientific theory of L-lactate regulating body metabolic health,but also provides a new idea and means for using L-lactate nutritional supplement to intervene in diet-induced obesity and its related metabolic diseases.