Effects Of GABAon Oxidative Stress And Thyroid Function And Its Mechanism

In recent years, with diet structure changing in China from main plant foods to animalfoods (high fat) along with social pressure, an increasing trend of obesity emerged. Soexploring the endocrine mechanism of obesity had an important significance for preventingobesity. It was indicated in epidemiological data that hypothyroidism was closely associatedwith obesity, but whether the decreasing of thyroid function in obese occurrence plays a vitalrole and what is the mechanism so far were not reported. Oxidative stress is also related toobesity occurrence and could reduce thyroid function, which may be a possible mechanismfor obesity occurring. This paper mainly pay attention to status of thyroid function in courseof obesity occurring; whether functional component gamma-aminobutyric acid (GABA) couldprevent obesity through improving thyroid function; effects of GABA on thyroid functionunder propylthiouracil（PTU）-induced hypothyroidism were also investigated; in addition,effects of GABA treatment on fatty liver, oxidative stress and protein metabolism in muscle aswell as plasma free amino acid levels (including GABA) under HFD were studied.Plasma lipids status, fasting blood glucose(FBG) and thyroid stimulating hormone (TSH)levels in DIO mice under HFD were significantly increased as well as disordered redox state(elevatory levels of ROS and MDA; reduced SOD, CAT, Gpx activities and TAC level)(P<0.05) compared with those of contral mice; thyroid hormone levels(FT3) weresignificantly decreased and thyroid exhibited significant lesion; expressions of THssynthesis-related genes (tshr, nis, tgb and tpo) and antioxidant-related genes (nrf2, prdx5andgpx3) in thyroid were significant downregulated, accompanied by significantly up-regulatedgenes (mainly duox2) generating H2O2and downregulated expressions of thr β anddeiodinases (d1and d2) in liver and hypothalamus(P<0.05). Normal plasma lipid （except ofTG and HDL-C）, plasma redox state(lowered SOD activity) and TSH levels in DIO-R micewere demonstrated, but plasma THs levels (TT4and FT3) and expressions of thr anddeiodinases were significantly increased(P<0.05), indicating improvements of thyroid andTHs functions providing a mechanism of lower body weights. Three GABA treatmentsresulted in restored FBG and TSH levels(P<0.05).0.2%and0.12%GABA treatmentssignificantly resisted body weight gain, retored redox status, improved expressions ofredox-balanced gene, increased thyroid function (upregulated THs synthesis related geneexpressions and increased TT4, FT4levels) and THs function(P<0.05). GABA could preventobesity occurrence through enhancing thyroid and THs function.Body weight, food intake, TH levels, oxygen consumption, carbon dioxide generation,heat production and ambulatory activity were significantly decreased together withunbalanced plasma redox state (elevated ROS and MDA levels; reduced SOD, CAT, Gpxactivities and TAC level) in hypothyroid rats induced by PTU (P<0.05). Meanwhile, thyroidlesion was observed and THs synthesis-related gene expressions (tshr, nis, tgb and tpo) weresignificantly downregulated (P<0.05). Again, endoplasmic reticulum stress (upregulatedexpressions of chop, erp57and grp78) and apoptosis (upregulated bax and caspase-3expressions; downregulated bcl-2expression） were observed. Following giving0.002 mg/day/kg bw LT4to hypothyroid rats, food intake, body weight gain, THs levels, oxygenconsumption, carbon dioxide genetation, heat production and ambulatory activity weresignificantly increased (P<0.05); plasma redox state was restored (P<0.05). Although statesendoplasmic reticulum stress and apoptosis were restored (P<0.05), thyroid lesion andexpressions of THs synthesis related genes (except tshr) were not improved by LT4.100and200mg/day/kg bw GABA treatments on hypothyroid rats significantly increased food intake,body weight, antioxidant ability, total oxygen consumption, total heat production andimproved thyroid structure injury. THs synthesis-related gene transcriptions, THs levels,endoplasmic reticulum stress and apoptosis by PTU treatment were improved by two doses ofGABA treatments which exhibited better effect than that of LT4treatment (only betteredcaspase-3and bcl-2expressions). Two doses of GABA treatments did not affect body weights,plasma redox state, thyroid hormone levels, thyroid microstructure and function (onlyupregulated expressions of tgb and tpo) as well as expressions of endoplasmic reticulumstress genes and apoptosis-related genes in contral rats. Food intake and ambulatory activitywere increased by high dose of GABA treatment (P<0.05).Liver weight, liver index, liver TG and liver TC contents by HFD treatments weresignificantly increased compared with those in contral group(P<0.05); HFD treatmentreduced liver glycogen (P<0.05) and increased activities of plasma aminotransferases(GPTand GOT), THs, TNF-α and IL-6levels; significantly elevated ROS and MDA contents inliver appeared and that decreased antioxidase activities(SOD, CAT and Gpx) as well asdecreased TAC level in liver took place (P<0.05); transcriptions of liver fatty degradationrelated genes (ppar α, cpt1a and pgc-1α) were significantly inhibited, while transcriptions ofliver fatty synthesis related genes (srebp-1c, fas and acc1) were significantlypromoted(P<0.05). Significantly redressed liver weight and liver index, lowered hepatic fataccumulation, raised liver function and THs levels, restored liver glycogen content, reducedliver oxidative stress and plasma cytokine levels (TNF-α�'�IL-6), increased expressions offat degradation-related genes (ppar α, cpt1a and pgc-1α) and reduced expressions of fatsynthesis-related genes srebp-1c、fas and acc1) by0.2%and0.12%GABA treatment wereobserved(P<0.05). Advidable doses of GABA supplement could prevent the occurrence offatty liver, partly through improving thyroid function and elevating THs levels.HFD treatment cut muscles (whether gastrocnemius or soleus): body weight ratio,sparked oxidative stress on gastrocnemius, elevated protein oxidation levels (AOPP, carbonylconcerntrations) in plasma and gastrocnemius, increased transaminase（GPT and GOT）activities, pFAA imbalance at different degrees (increased glycogenic amino acid levels:serine, glycine, alanine, lysine, glutamic acid and GABA level; decreased arginine level);levels of protein synthesis-and degredation-genes rnRNA were unbalanced(elevatedatrogin-1expression; reduced mTOR and p70S6k expressions) in gastrocnemius. Three dosesof GABA treatments could increase muscle: body weight ratio, relieve oxidative stress, reducelevels of protein oxidation in plasma and gastrocnemius and improve HFD-inducedunbalances of protein synthesis-and degradation-ralated genes expressions (P<0.05).0.12%and0.06%GABA treatments partly retored HFD-induced pFAA levels (restored levels of arginine, serine and alanine) and restored plasma transaminase activities, but0.2%GABAtreatment decreased pFAA levels (except restored glycine and glutamic acid levels)(P<0.05).0.12%GABA treatments made plasma GABA level higher than that of HFD group, but0.2%GABA treatment reduced plasma GABA level lower than that of contral group and alsoincreased succinic semialdehyde dehydrogenase (SSADH) activity(P<0.05) in the liverhinting enhanced GABAdegradation metabolism in high dose of GABAtreatment.