| Obesity is a global epidemic mainly caused by the imbalance of long-term energy intake and energy consumption.With the rapid development of economy and the continuous improvement of people's living standard,the dietary structure of our residents is changing,there is a trend of high energy food intake increasing and close to the western dietary pattern,and the "westernization" of dietary structure makes the obesity population increase rapidly in our country.thyroid hormone,as an endocrine hormone,can promote lipid catabolism and is of great significance in regulating lipid metabolism and energy balance.therefore,from the perspective of thyroid hormone homeostasis,this study investigated whether the lipid-lowering effect of 1-deoxynojirimycin(DNJ)on obese mice induced by high-fat diet was related to its improved effect on thyroid hormone homeostasis and further improved the lipid-lowering mechanism of DNJ.A model of obese mice was established by feeding high-fat diets,then continue feeding high-fat diets at the same time intragastric administrate 2.0,4.0,8.0 mg/(kg.d)of DNJ for 45 d.The main results were as follows:(1)Study the effects of DNJ on body weight and blood lipid levels in obese mice.at the end of gavage,the body weight of female and male rats with high-dose DNJ intervention decreased by10.9% and 10.19%(P <0.05),the TC levels decreased by 16.77% and 15.44%(P <0.05),the TG levels decreased by 28.23% and 40.35%(P <0.05),the serum LDL-c decreased by 30.86% and33.33%(P <0.05),and the serum HDL-c levels increased by 58.75% and 42.80%(P <0.05),respectively.(2)Study the effect of DNJ on serum cytokines in obese mice,the results showed that female and male obese mice had improved leptin resistance after 45 days of high dose DNJ administration compared with obese controls,and serum leptin decreased by 24.74%,21.27%(P<0.05);adiponectin increased by 43.19%,29.58%(P<0.05);female mice FGF21 increased by37.03%(P<0.05);male mice FGF21 decreased by 21.07%(P<0.05);the serum TNF-?,IL-6 and INOS of female mice decreased by 29.06%,25.72%,28.32%(P <0.05),and male mice serum TNF-?,IL-6,and INOS decreased by 30.84%,37.80%,29.01%(P<0.05),respectively.Indicating that DNJ can reduce the long-term high-fat diet-induced inflammatory response with anti-inflammatory effects.(3)Study the effect of DNJ on thyroid hormone homeostasis in obese mice,the results showed that compared with the obese control group,after 45 days of high dose DNJ administration,the TSH levels of female and male rats were reduced by 9.65% and 9.73%(P<0.05),respectively,and TT4 of female and male rats increased by 22.03% and 15.99%(P<0.05),respectively.The levels of TT3 increased by 66.86% and 47.79%(P<0.05),respectively.DIO1 activity in liver of female and male rats increased by 40.99% and 24.40% respectively(P <0.05),liver DIO1 protein levels increased by 35.68% and 29.50% compared with obese controls(P<0.05).the relative expression of DIO1 m RNA was significantly upregulated(P<0.05),while TR? Protein levels in female and male mice increased by 37.53% and 27.81%(P<0.05),respectively;the relative expression of TR? m RNA was significantly upregulated(P<0.05).Suggesting that DNJ can improve thyroid hormone homeostasis in obese mice,enhance liver thyroid hormone receptor signaling,and enable thyroid hormone to fully exert its regulatory effect on lipid metabolism.Because inflammatory factors can inhibit thyroid hormone synthesis and DIO1 activity and gene expression,the improved effect of DNJ on thyroid hormone homeostasis may be related to its anti-inflammatory effect.(4)To study the effect of DNJ on hepatic lipase metabolism in obese mice,the results showed that high dose DNJ could significantly inhibit the activity of ACC1 and HMGCR in female and male mice,improve the activity of ATGL,CPT1?,CYP7A1 and promote lipid catabolism.High-dose DNJ was able to upregulate ATGL m RNA expression by 44.70%,25.61%(P<0.05),CPT1? m RNA expression by 106.84%,192.24%(P<0.05),CYP7A1 m RNA expression by 60.70%,233.55%(P<0.05).ATGL,CPT1?,CYP7A1 genes are transcriptionally regulated by thyroid hormone,indicating that DNJ can inhibit synthetic enzyme activity and improve the activity of metabolic enzyme,and upregulate metabolic enzyme m RNA expression by improving the thyroid hormone homeostasis to improve lipid metabolism.(5)The effects of DNJ on mitochondrial biosynthesis and autophagy in mice liver were studied.Compared with the obese control group,high-dose DNJ was able to upregulate the relative expression of PGC-1? m RNA in female and male rats by 33.37%,108.76%(P <0.05)and increase PGC-1? protein level by 28.27%,43.99%(P <0.05)respectively;upregulate the relative expression of NRF1 m RNA in female and male rats by 70.00%,67.91%(P <0.05)and increase NRF1 protein level by 50.25% and 40.26%(P <0.05)respectively;the relative expression of female and male ULK1 m RNA was upregulated by 27.71%,47.59%(P <0.05),and the protein level increased by19.24%,22.76%(P <0.05);the expression of AMPK?1 m RNA in female and male mice was upregulated by 60.33%,50.68%(P <0.05),respectively.Thyroid hormones are able to promote PGC-1? and NRF1 expression to promote mitochondrial synthesis,while also promoting damage mitochondrial autophagy by enhancing AMPK signaling.Therefore,DNJ may promote liver mitochondrial biosynthesis and autophagy by improving thyroid hormone homeostasis.The above results indicate that DNJ restores the response to TSH,upregulates liver DIO1 gene expression,improves liver DIO1 enzyme activity,and promotes the expression of liver thyroid hormone receptor TR?,improves thyroid hormone homeostasis and its metabolism,upregulated the expression of thyroid hormone responsive lipid metabolism gene,promotes mitochondrial synthesis and autophagy,decreases blood lipid levels,and improves weight gain caused by high-fat diet. |
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