| Obese mice induced by high-fat diet (HFD) for26weeks were used to explore periodicchanges in central redox state and the level of thyroid hormone, and the association toglucose metabolism. Through the intervention of antioxidants, the preventive and protectiveeffects of lipoic acid, resveratrol and quercetin on central oxidative damage, imbalance inthe secretion of thyroid hormone and disorder in glucose metabolism was researched andcompared in order to provide a theoretical basis for the mechanism and means of preventionand treatment of some chronic diseases.Three hundred female C57BL/6mice (4week old) were randomly and averagely dividedinto five groups according to their body weight after feeding normal diet for a week: Controlgroup (normal diet); High-fat diet group (HFD); Lipoic acid group (HFD+0.1%LA);Resveratrol group (HFD+0.06%R); Quercetin group (HFD+0.01%Q). The animals weresacrificed in batches at the3th,6th,13thand26thweek, then blood glucose (FPG), glycosylatedplasma protein (GSP), plasma insulin (FINS), thyroid hormone (T3and T4) were measured.What’s more, markers of oxidative stress in cortex and hippocampi (GSH/GSSG, TAOC,MDA, AOPP,3-NT,4-HNE and DiTyr) were examined; in addition, Morris water mazeexperiments were conducted at the8th,18thand26thweek; at last, the expression of somerelated genes’ mRNA in liver, muscle, cortex, hippocampi and hypothalamus weredetermined by RT-PCR.Results:1) HFD group presented a significant (P<0.05) higher level of plasma TH fromthe3thto13thweek, but a significant lower level at the26thweek (P<0.05), the antioxidantsrecovered the TH level significantly (P<0.05), and resveratrol is best at increasing the level ofT3and FT3at the26thweek.2) The level of FPG, FINS, GSP and Insulin Resistance Index(IRI) increased significantly (P<0.05) in HFD group from the6thto26thweek, meanwhile,Insulin sensitivity index (ISI) decreased significantly (P<0.05), the antioxidants alleviatedhyperglycemia and hyperinsulinemia significantly (P<0.05), the effect: lipoic acid>resveratrol> quercetin.3) Feeding high-fat diet for26weeks resulted in a significantdecrease in the expression of glucose metabolism-related genes’ mRNA (HIF-1α and GLUT4)in muscle (P<0.05).4) The expression of key gluconeogenic enzyme genes’ mRNA (PEPCKand G6pase) in liver was up-regulated significantly from the6thto26thweek (P<0.05).5)Oxidative stress emerged in hippocampi and cortex of HFD group at the6thand13thweekrespectively; after26weeks, cortex and hippocampi exhibited a significant (P<0.05) higherlevel of AOPP,3-NT and4-HNE, DiTry as compared to the control group. The antioxidantfactors improved central oxidative damage significantly (P<0.05), and quercetin is the best.The expression of GSK-3β and InsR mRNA increased, but antioxidant genes (Nrf2, NQO1and HO-1), GLUT4and BDNF mRNA decreased significantly (P<0.05). HFD group showed a significant increase in the expression of GSK-3β mRNA, but decrease in the expression ofantioxidant genes’ mRNA (Nrf2, NQO1, HO-1, GST and GCLC) in hypothalamus (P<0.05).6) High-fat diet induced a significant increase in the expression of TRH mRNA from the3thto13thweek (P<0.05), but a significant decrease at the26thweek in hypothalamus (P<0.05).7) The results of Morris water maze trial showed a significant impairment (P<0.05) inlearning and memory ability of HFD group at the18thweek, and the situation exacerbated atthe26thweek, the antioxidants enhanced learning and memory ability significantly (P<0.05),and the quercetin was the best.Conclusion:1) Feeding HFD for3-13weeks activated the Hypothalamic-Pituitary-Thyroid axis (HPT axis), leading to a higher level of expression of TRH and TH;but after26weeks, the normal function of HPT axis was damaged, resulting in a lower levelof TH, which may be related to hypothalamic oxidative damage-induced lower level of theexpression of TRH.2) Hyperglycemia and hyperinsulinemia between the6thand13thweekcan be related to higher level of TH, which promoted the expression of PEPCK and G6pasein liver; nevertheless, the imbalance in glucose metabolism at the26thweek can be ascribedto the abnormal expression of PEPCK, G6pase, HIF-1α and GLUT4, which gave rise toglucose metabolism disorders in liver and muscle, and the abnormal expression of thosegenes was closely associated with lower TH level and insulin resistance.3) Consuminghigh-fat diet for a long time resulted in central oxidative damage which can be attributed tothe overexpression of GSK-3β that impairs the antioxidant ability of Nrf2passway;HFD-induced central oxidative damage, impaired glucose metabolism and the lowerexpression of BDNF lead to impaired learning and memory ability.4) Three kinds ofantioxidant factors alleviated the adverse effects induced by HFD and protected the normalfunction of HPT axis. Lipoic acid is the most beneficial to body weight and blood glucose;but quercetin is best at improving central oxidative damage and learning and memory ability;nevertheless, resveratrol has the strongest regulatory capacity on TH system.To sum up, oxidative stress in the brain induced by high-fat diet, resulting in the declineof central normal function and dysfunction of HPT axis, which can be considered as theimportant contribution to the HFD-induced disorder of glucose metabolism. |
