Effect And Mechanism Of Seabuckthorn Flavonoids On Glucolipid Metabolism Disorder And Cognitive Impairment Induced By High Calorie Diet In Mice

In recent years,with the continuous improvement of people’s living standards,people have more and more dietary patterns.Among them,high-fat and high-fructose diet(HFFD)has become the most common dietary pattern in the world,leading to the increased risk of multiple metabolic diseases.such as obesity,type II diabetes,cardiovascular disease.Sea-buckthorn is a berry plant,which is rich in vitamins,flavonoids and other active substances beneficial to human health.Sea-buckthorn flavonoids are the main flavonoids in Sea-buckthorn.Sea-buckthorn flavonoids and its active components have multiple biological functions including anti-oxidation,anti-inflammatory,improving immunity and reducing blood lipid.Based on the above,the current study took sea-buckthorn flavone and isorhamnetin as the research objects,and explored the improvement effects and potential mechanisms of sea-buckthorn flavone and isorhamnetin on hepatic glucose and lipid metabolism disorder,and cognitive impairment induced by HFFD in vivo.The main research contents and results are as follows:(1)Intervention effect of sea-buckthorn flavone on HFFD induced obesity in mice:9-week-old C57 BL / 6J mice were fed with HFFD diet for 14 weeks.At the same time,they were fed with dietary supplement of sea-buckthorn flavone diet mode:(1)low-dose Sea-buckthorn flavone diet(0.06% w/w);(2)High dose Sea-buckthorn flavone diet(0.31%,w/w).The results showed that dietary supplementation with Sea-buckthorn flavonoids inhibited the weight gain in HFFD induced obese mice.Moreover,Sea-buckthorn flavonoids decreased HOMA-IR value and fasting blood glucose levels in HFFD induced obese mice.At the same time,Sea-buckthorn flavonoids can effectively balance the serum lipid contents in HFFD induced obese mice.(2)Ameliorative effects and mechanisms of sea-buckthorn flavonoids on hepatic glucolipid metabolism disorders induced by HFFD in obese mice.The disorders of hepatic glycolipid metabolism in obese mice were assessed by histological staining and molecular biological methods.The results showed that sea-buckthorn flavonoids could significantly inhibit HFFD-induced liver weight gain and improve liver histomorphological damage in obese mice.Meanwhile,dietary supplementation with sea-buckthorn flavonoids improved hepatic lipid accumulation by regulating the expression of hepatic lipid metabolism genes PPARα and PPARγ.In addition,dietary supplementation with sea-buckthorn flavonoids effectively inhibited hepatic insulin resistance and activation of NFκB inflammatory pathway,reduced the expression of pro-inflammatory factors such as i NOS and COX-2,and suppressed HFFD-induced liver inflammation in obese mice.(3)Effect and mechanism of sea-buckthorn flavonoids on cognitive impairment in HFFD induced obese mice: behavioral experiments showed that sea-buckthorn flavonoids improved the impairment of working memory and spatial memory in HFFD induced obese mice.H & E staining and synaptic ultrastructural images showed that sea-buckthorn flavonoids improved the damage of synaptic structure in hippocampus of obese mice induced by HFFD.In addition,sea-buckthorn flavonoids increased the expression of PSD-95 synaptic functional protein in obese mice;Moreover,sea-buckthorn flavonoids increased the expression of neurotrophic factor BDNF by activating ERK / CREB / BDNF signaling pathway in the brain of obese mice,and inhibited insulin resistance.In addition,sea-buckthorn flavonoids decreased the neuroinflammatory factors COX-2,IL-1 β and i NOS levels.(4)The primary active components of sea-buckthorn flavonoids and their absorption and tissue distribution in rats were investigated: the contents of isorhamnetin,kaempferol and quercetin were measured by high performance liquid chromatography(HPLC).Moreover,the absorption and distribution in rats were studied by using seabuckthorn flavone solution as the experimental drug.The HPLC method for the determination in biological samples of sea-buckthorn flavonoids was successfully established and verified.At the same time,in the pharmacokinetic experiment,it was found that the blood concentrations of the above main components in rats increased with time and reached the peak at 3 h;In the detection of tissue samples,the results showed that the main components of sea-buckthorn flavonoids,were enriched in various tissues of rats during 1 ～ 5 hours after intragastric administration.(5)To explore the ameliorating effect of isorhamnetin on body weight gain and cognitive impairment in HFFD-induced obese mice.9-week-old C57 BL / 6J mice were fed with HFFD diet for 14 weeks.At the same time,they were fed with dietary supplement of isorhamnetin diet mode:(1)low-dose isorhamnetin diet(0.03% w/w);(2)High dose isorhamnetin diet(0.06%,w/w).The results showed that dietary supplementation with isorhamnetin inhibited HFFD-induced bodyweight gain and serum lipid content,isorhamnetin supplementation also improved the work and spatial memory of obese mice.Moreover,dietary supplementation with isorhamnetin activated the ERK/CREB/BDNF signaling pathway and increased the m RNA and protein expression of neurotrophic factors.Meanwhile,dietary supplementation with isorhamnetin ameliorated HFFD-induced neuronal damage and synaptic structural damage in the hippocampus of obese mice,and increased the expression of synaptic functional protein PSD-95.In addition,isorhamnetin inhibited the activation of microglia,decreased the levels of inflammatory factors in the brain,and improved neuroinflammatory responses in the brain of mice.In conclusion,dietary supplementation of sea-buckthorn flavonoids and its main component isorhamnetin can inhibit HFFD-induced weight gain in obese mice,reduce serum lipid levels,inhibit systemic insulin resistance and inflammatory response,increase the expression of neurotrophic factors,improve Cognitive impairment.This study provides a theoretical basis for the functional food development of sea-buckthorn,a characteristic berry,and provides new research ideas for other food functional components to interfere with HFFD-induced glucolipid metabolism disorder and cognitive impairment.