Studies On The Roles And Related Mechanisms Of Vitamin D Receptor In Glucose Metabolism And Depression

Diabetes and depression are two major diseases with the high prevalence in modern society,as well as the high risk of comorbidity.About 30%of patients with diabetes have depression symptoms.Depression is strongly linked to increased mortality and aggravated diabetic complications in individuals with type 2 diabetes,which results in poorer treatment outcomes.Type 2 diabetes comorbid with depression(T2DD)has been considered as a huge threat to public health.Therefore,it is significant to carry out research on the pathological mechanism of diabetes combined with depression and expand new ideas for the development of therapeutic drugs.Clinical studies have shown that compared with the normal population,the serum vitamin D levels in patients with type 2 diabetes or depression is low,and its level is negatively correlated with the risk of disease.Moreover,the serum vitamin D level in patients with T2DD is also reduced significantly.Vitamin D binding with vitamin D receptor(VDR)forms the complex to modulate transcriptions of target genes and plays an important role in the bone metabolism and immune regulation.The functions of VDR are deteriorated by vitamin D deficiency.Clinical evidence suggests that VDR dysfunction may be closely related to the occurrence of depression in type 2 diabetes.However,the underlying mechanism is still largely unknown.In the present study,VDR gene knockout mice and wild type(WT)mice were applied to comprehensively investigated changes caused by VDR gene deletion in glucose metabolism and depression-related behavior analysis.Furthermore,signaling transduction and transcriptome sequencing and analysis of hippocampus were explored in mice.Our research aims to clarify the underlying mechanisms in the occurrence and development of abnormal glucose metabolism and depression,and reveal potential targets modulated by VDR.Our findings will provide new ideas for prevention and treatment of T2DD and support the potential application of vitamin D in T2DD.Results:(1)Effects of VDR gene deletion on depression-related behavior analysis and glucose metabolism in micePrimarily,VDR knockout(VDR KO)and wild type(WT)mice were obtained by VDR gene heterozygous mice breeding and PCR identification.The glucose metabolism and behavior analysis of VDR KO mice and WT mice were done respectively.The experimental resultsconfirmed that:? Compared with WT mice,the body weight and fasting blood glucose of VDR KO mice significantly reduced.However,in oral glucose tolerance test(OGTT),after glucose solution taken orally,the blood glucose levels of VDR knockout mice at various time points were higher than those of WT mice,which suggested that the ability of glucose clearing and insulin sensitivity were impaired in VDR KO mice.? The behavior analysis of mice was done using the small animal behavior analysis system.In tail suspension test,an increase in immobility time was observed in VDR knockout mice compared to WT mice.In open field test,a significantly reduced residence time in the center of the open field was found in VDR KO mice.The results of the sucrose preference test showed that the sucrose consumption of VDR KO mice was strongly decreased compared with WT mice.These findings confirm the occurrence of depression in VDR KO mice.? The serum corticosterone levels in VDR KO mice increased hugely compared with WT mice,while serotonin levels decreased.Moreover,levels of IL-1? and IL-6 also increased significantly.All these results suggested that VDR deletion could result in the abnormal glucose metabolism and the occurrence of depression.(2)Impacts of VDR gene deletion on signaling transduction related to depression and glucose metabolismSignaling transduction related to depression and glucose metabolism were analyzed by western blotting assay.? Glucose metabolism-related pathways:Compared with WT mice,levels of p-AKT in liver and muscle of VDR KO mice were significantly reduced,while p-AMPK in liver was unaffected,p-AMPK level in muscle were increased oppositely.Importantly,GLP-1R expression in liver was reduced markedly,suggesting that VDR deletion would inhibit the GLP-1R/AKT pathway to impair insulin sensitivity.Interesting,a decrease in SGLT2 expression and an increase in SGLT1 was observed in kidney tissue of VDR mice compared to WT mice for the first time.? Depression-related pathways:Activations of ERK and CREB in the hippocampus of VDR KO mice are suppressed,together with reduced BDNF expression,while c-casp3 level was increased.In addition,GLP-1R expression and downstream signals such as AKT,?-catenin were strongly inhibited,which indicated the hippocampal neural regeneration was impaired in VDR KO mice.Above all,VDR knockout will cause a significant decrease in GLP-1R expression,and then inhibit the activation of downstream related signaling molecules,resulting in reduced insulin sensitivity in mice and impaired hippocampal neuron regeneration.(3)Transcriptome sequencing and analysis of hippocampus of WT type mice and VDR gene knockout miceSequencing analysis of the transcriptomes of hippocampus in WT mice and VDR knockout mice was performed.The differences between long-chain non-coding RNA(lncRNA),messenger RNA(mRNA),and circular RNA(circRNA)were analyzed.The results showed that VDR gene knockout resulted in significant changes in lncRNA,mRNA and circRNA in hippocampus.Further detailed research will be carried out on in future.ConclusionsClinical reports indicate that vitamin D deficiency is closely related to type 2 diabetes and depression,but the underlying mechanism remains unclear.Vitamin D deficiency will affect the function of vitamin D receptor VDR.This research carried out research on VDR gene knockout mice,and confirmed that VDR gene deletion will cause abnormal glucose metabolism and depression symptoms in mice.Further study on the mechanism revealed that VDR knockout will significantly reduce the expression of GLP-1R and then inhibit GLP-1R activation of important signaling molecules such as AKT,?-catenin,and CREB downstream of the pathway leads to reduced insulin sensitivity and impaired hippocampal neuron regeneration.This study expands existing knowledge of VDR function and confirms that VDR is an important regulatory molecule in the pathological mechanism of abnormal glucose-metabolism and depression,providing new strategies and intervention targets for the prevention and treatment of such diseases.