The Mechanism Underlying The Dysregulation Of Gestational Glucose And Lipid Metabolism Induced By Hypothyroidism

Objective Hypothyroidism is a metabolic disease which is characterized by low level of thyroid hormone(TH)and high level of thyroid-stimulating hormone in serum [1].TH is crucial for regulating lipid and glucose metabolism,and insulin signaling,which plays essential role in maintaining the health of pregnant women and their offspring.However,the current literature is just focusing on the development of offspring born to the untreated mothers with hypothyroidism,rather than mothers themselves.Additionally,the interaction between hypothyroidism and pregnancy,and its impact on the women’s health are still elusive.Therefore,this study was designed to compare the metabolic differences in dams with hypothyroidism starting before pregnancy and after pregnancy.Methods At age of 5 weeks,female mice(16.8±0.8g)were randomly divided into pre-pregnant hypothyroidism group(PH),gestational hypothyroidism group(GH)and normal control group(NC).The mice in PH group received iodine-deficient diet containing 0.15% propylthiouracil(IDP diet)and normal drinking water for 4 weeks before pregnancy,while standard irradiated diet and water were available ad libitum to the mice in GH and NC groups,simultaneously.The murine body weight,fasting plasma glucose(FPG)levels and food intake were measured each week.Serum samples were obtained(n=6/group)after four weeks of treatment for detecting free triiodothyronine(FT3),free thyroxine(FT4)and thyroid-stimulating hormone(TSH).At age of 10 weeks,female mice were mated with males at a ratio of 2:1.The presence of a vaginal mucous plug in next morning after mating was considered as an index of pregnancy.The mice in PH and NC groups during pregnancy continued to receive the diet and water identical to pre-pregnancy,but the mice in GH group received the IDP diet from the start of pregnancy.Pregnant mice’s body weights,FPG levels and food intake were detected at every three days in three groups,respectively.Mice were performed glucose tolerance test(GTT)after delivery.After 8h fasting,dams(n=10/group)were euthanized with 10% chloral hydrate and then killed by cervical dislocation.Serum samples were obtained to detect FT3,FT4,TSH,TC,TG,HDL-C,LDL-C and Insulin.Thyroid,pancreas and liver tissues were harvested from the sacrificed mice for histological analyses.The expression of proteins related to glucose and lipid metabolism was analyzed by Western blotting.Results Compared with normal control,gestational hypothyroidism exhibited more prominent increase than pre-pregnant hypothyroidism in plasma TC and LDL-c,and caused hepatic TG accumulation.Similarly,more significant elevations of protein expressions of SREBP1 c and p-ACL,while more dramatic inhibition of CPT1 A and LDL-R levels were also observed in murine livers from mice with gestational hypothyroidism than those with pre-pregnant hypothyroidism.Meanwhile,by H&E staining,the murine liver in GH group manifested numerous spherical vacuoles of fat droplets at the periphery of the hepatic lobule.In comparison with GH group,the PH group displayed fat droplets that decreased in size and number.Moreover,the murine hepatic levels of TC,HMGCS1 as well as gluconeogenesis were dramatically and equally enhanced in two hypothyroid groups,while plasma TG and protein expressions of p-AKT,p-Fox O1,p-GSK3β and APOC3 were reduced substantially in two hypothyroid groups.Conclusion Taken together,our current study illuminated that mild hypothyroidism may have an impact on insulin resistance and result in metabolic dysfunction of glucose and lipid in dams.More importantly,our present results revealed that gestational hypothyroidism may elicit much more significant lipid dysregulation in dams than pre-pregnant hypothyroidism.These findings may shed a new light on future clinical practice.