Effects Of Thyroid Hormone Nuclear Receptor α1-conditional Mutation On Fat Metabolism In Mice

Objective: Thyroid hormone(TH)regulates the metabolic processes necessary for normal growth and development,and regulates the metabolism of human.When hyperthyroidism occurs,excess thyroid hormones increase energy expenditure,and fat breakdown is greater than fat synthesis,leading to lower cholesterol levels and weight loss.When hypothyroidism occurs,insufficient thyroid hormones cause a reduction in fat content,resulting in increased cholesterol levels and weight gain.Thyroid hormones mainly regulate the transcription of their downstream target genes by binding to their nuclear receptors.However,the mechanism of thyroid hormone nuclear receptors on fat metabolism is unclear.Therefore,our research group constructed a mouse model of TRα1 conditional mutation in order to explore the mechanism of the effect of thyroid hormone nuclear receptor α1 on mouse fat metabolism.Methods: We used the aP2-Cre / TRα1E403X fat conditional mutation mouse model that has been prepared by our research group.The experimental point was 8 weeks of age.Experimental items: rectal temperature,body weight;white fat,brown fat weight;gear experiment,rotating rod experiment;HE staining of adipose tissue.Result: 1.Mouse DNA gel electrophoresis gene identification and western blot confirmed that the TRα1 E403 X mutation site was specifically knocked out in fat from DNA levels and protein levels;8-week homozygous lethality was 54.55% in male mice and female mice The homozygous lethality was 53.85%.2.Rectal temperature and growth and development: The rectal temperature,length,and weight of homozygous mutant mice were lower than that of heterozygous mutant mice,and that of heterozygous mutant mice were lower than that of control mice.3.Adipose: White fat(including inguinal region fat,omental fat,perirenal fat,gonadal fat,interscapular white fat)of homozygous mutant mice is significantly lower than that of heterozygous mutant mice and control mice.The brown fat of homozygous mutant mice was significantly lower than that of heterozygous mutant mice,and the brown fat of heterozygous mutant mice was significantly lower than that of control mice.4.Gear experiment and rotating rod experiment results: In gear experiments,the exercise circles number of homozygous mutant mice was significantly lower than that of heterozygous mutant mice,and the number of exercise circles of heterozygous mutant mice was significantly lower than that of control mice.In rotating rod experiments,dwell time of homozygous mutant mice was significantly lower than that of heterozygous mutant mice,and that of heterozygous mutant mice was lower than that of control mice.5.Morphological experimental results: Beige structure of fat in inguinal region fat of homozygous mutant mice.Fat in the inguinal region of heterozygous mutant mice has still a large lipid droplet structure,but its lipid droplets were smaller than the control.There was no difference in brown fat morphology among the three groups of mice.Conclusion: TRα1 fat conditional mutant mice(aP2-Cre / TRα1E403X)have stunted growth and development,low rectal temperature and reduced exercise capacity.Homozygous mutant mice have a high lethality phenotype.Considering the widespread expression of aP2 in brain tissues,TRα1 mutations are related to the brain tissue.This study suggests that aP2-Cre mice are not the ideal tool to study the effects of TRα1 on fat metabolism.