Lycopene Attenuates The Impairment Of Cognitive Function Via Improving Glycolipid Metabolism Dysfunction In Gut-Liver-Brain Axis

High-fat and high-fructose diet(HFFD)has become more and more popular and HFFD-induced obesity,diabetes,gastrointestinal dysfunction and cognitive impairments seriously affect human health.The underlying molecular mechanisms by which HFFD-induced memory loss were complicated and the glycolipid metabolism in gut-liver-brain axis were closely related to cognitive function.In recent years,the exploration of food functional components that may improve glycolipid metabolism and cognitive function has become an important research direction in food nutrition field.Lycopene(LYC),a major carotenoid present in tomato,has been demonstrated to possess health-beneficial functions,such as anti-inflammatory and anti-oxidant effects and blood-brain barrier permeability.With this background,the aim of the current study was to investigate the inhibitory effect of LYC on HFFD-induced cognitive impairments and the protective effects on HFFD-elicited insulin resistance,lipid metabolism dysfunction in gut-liver-brain axis.The main investigations and results are as follows:(1)To investigate the effect of dietary LYC on HFFD-induced obesity,C57BL/6J mice were treated with HFFD and LYC.The present work revealed that LYC treatment suppressed mice body weight gain compared with the HFFD group;LYC improved lipid contents in plasma of obesity mice;LYC supplementation reversed HFFD-eilicited insulin resistance and glucose intolerance.Moreover,LYC supplementation inhibited systemic inflammation through decreasing circulating IL-1?,TNF? and IL6 levels.(2)Mice brain tissues and SH-SY5 Y cells were selected to investigated the protective effects of LYC on HFFD-induced cognitive deficits,neuronal cells damages,decreased synaptic plasticity,insulin resistance and neuroinflammation in mice brain.Results of animal behavior tests indicated that the supplementation of LYC improved HFFD-induced memory impairments.LYC significantly improved the contents of postsynaptic density in the hippocampus and increased the expressions of synaptosomal functional proteins compared to the HFFD group.Moreover,LYC attenuated HFFD-induced insulin resistance and neuroinflammation in mice brain.Furthermore,LYC supplementation improved glucose-induced insulin resistance through mediating neuroinflammation and oxidative stress in SH-SY5 Y cells.(3)Liver tissues and HepG2 cells were selected to examined the effects of LYC on HFFD-induced hepatic lipid accumulation and insulin resistance.Results showed that LYC decreased liver weight and improved hepatic insulin resistance compared with HFFD group.LYC suppressed hepatic lipid accumulation by increasing lipidolysis and blocking lipogenesis.LYC also alleviated hepatic mitochondrial dysfunction through increasing the expressions of mitochondrial respiration complexs I-IV and mitochondrial functional genes.Moreover,LYC alleviated hepatic inflammatory response via suppressing the activation of MAPKs/NF?B pathways and down-regulating the expressions of proinflammatory cytokine iNOS and COX-2.In addition,LYC treatments effectively reduced triglyceride and total cholesterol concentrations in palmitate-treated HepG2 cells in a PPAR?-dependent manner and LYC improved insulin resistance via mediating IRS-1/AKT pathway and enhancing mitochondrial function in palmitate-treated HepG2 cells.(4)Gut tissues were selected to examined the effects of LYC on HFFD-induced intestinal lipid accumulation and inflammatory responses.Results indicated that LYC supplementation down-regulated intestinal triglyceride levels through improving fatty acid oxidation.Meanwhile,LYC treatment also increased the expressions of Occludin,Zo-1 and Claudin-1 compared to HFFD group,improved intestinal integrity.LYC alleviated HFFD-triggered gut inflammation,decreased circulating LPS level and increased short-chain fatty acid acetic acid contents.(5)Adipose tissues and 3T3-L1 adipocytes were selected to examined the effects of LYC on HFFD-induced lipid accumulation in adipose tissue.Results indicated that LYC blocked HFFD-induced adipocyte hypertrophy and lipid accumulation in adipose tissue by decreasing the expressions of lipogenesis genes and increasing the expressions of lipidolysis genes,including thermogenic and mitochondrial functional genes.Moreover,LYC enhanced autophagy in WATs and improved HFFD-induced inflammation responses in WATs.Furthermore,LYC inhibited lipid accumulation in 3T3-L1 adipocytes by regulating lipid metabolism gene expression.In conclusions,the supplementation of LYC might regulate intestinal barrier function and intestinal microbial products,improved glucose and lipid metabolism in liver and reduced systemic insulin resistance and inflammatory responses induced by high-calorie diets,and ultimately improve synaptic plasticity and cognitive function.The present study could provide a theoretical basis for the development of healthy foods with LYC as a major functional ingredient and could provide new strategies for nutritional intervention studies of other natural functional food components on high-calorie diets induced cognitive impairments.