Effect And Mechanism Of Antioxidant Factors On Lipid Metabolism In High-fat Diet-fed Mice

Objectives: The development of Metabolic syndrome (MS) induced by high fat diet(HFD) is accompanyed with various metabolism changes, and lipid metabolism disorder isone of important aspects of MS. Thyroid hormones are of crucial importance for regulatingenergy metabolism, including lipid metabolism. The objective of this study was to examineeffects of antioxidant factors on the changes of lipid, thyroid hormones metabolism and redoxstate in obese mice. The mechanism of dyslipidemia induced by HFD was investigated, whichcould provide the theoretical basis for preventing obesity.Methods: C57BL/6female mice were fed on normal diet, HFD and HFD plus0.1%LA,0.06%Resveratrol and0.01%Quercetin respectively. Plasma lipid profiles, thyroidstimulating hormone (TSH), free hyroxine (FT4), free triiodothyronine (FT3) and oxidativestress markers: total antioxidants (T-AOC), reduced and oxidized glutathione (GSH/GSSG),malonyladehyde (MDA), reactive oxygen species (ROS) were measured at1-,3-,6-,13-, and26th week. The accumulation of fat in hepatocytes was examined by staining with Oil-Red.Adipose genes of lipid metabolism and hepatic crucial genes of antioxidant signaling pathwaywere analyzed by RT-PCR. Hepatic type1deiodinase (DIO1) activity and mRNA thyroidhormone receptors (TRs) gene expression were also examined.Results: Compared with control group, hepatic GSH/GSSG and T-AOC in mice fedHFD were significantly (P<0.05) reduced by the3rdweek, ROS and MDA were elevated by3rdand6thweek respectively. Adipose GSH/GSSG and T-AOC in HFD group weresignificantly reduced by the6thweek, MDA was elevated by13thweek, which happened laterthan liver. Mice on HFD showed significant (P<0.05) higher weight and plasma lipids thanthe control group after13weeks. High fat feeding induced significant (P<0.05) increase inplasma FT3and FT4up to the13thweek but declined thereafter, while TSH levels increasedthroughout the feeding period. As compared to controls, hepatic deiodinase activity wassignificantly (P<0.05) up-regulated at3rdweek but was decreased by26thweek in HFD group,however, the mRNA of TRs gene expression was elevated at26thweek. The results ofcorrelation analysis indicated that thyroid hormones was significantly associated with lipidmetabolism and redox state. Nuclear factor E2-related factor2(Nrf2) and its target genesNAD(P)H:quinone oxidoreductase1(NQO1), hemeoxygenase-1(HO1), γ-glutamylcysteinesynthetase regulatory subunit (GCLC) were significantly (P<0.05) higher in HFD groupcompared to control after13thweek. However, glycogen synthase kinase3β (GSK-3β), whichmight be a negative regulator of Nrf2activity was low at6thweek but was significantlyup-regulated by26thweek in HFD group. Antioxidants treatment significantly (P<0.05)reduced oxidative stress and plasma lipid level, elevated the activity of deiodinase andrecovered thyroid hormone levels. Resveratrol showed slight advantage.Conclusion: Thyroid hormones and lipid metabolism disorder, oxidative stress wereoccurred in mice fed HFD. The antioxidant factors reduced oxidative stress, elevated thyroid hormones level by up-regulation of deiodinase expression, which might be one mechanism ofameliorating dyslipidemia.