Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and prolif...Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and proliferation of adipose tissues.It has two major isoforms,PPARγ1 and PPARγ2,encoded from a single gene using two separate promoters and alternative splicing.Among them,PPARγ2 is most abundantly expressed in adipocytes and plays major adipogenic and lipogenic roles in the tissue.Furthermore,it has been shown that PPARγ2 is also expressed in the liver,specifically in hepatocytes,and its expression level positively correlates with fat accumulation induced by pathological conditions such as obesity and diabetes.Knockout of the hepatic Pparg gene ameliorates hepatic steatosis induced by diet or genetic manipulations.Transcriptional activation of Pparg in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes.Understanding how the hepatic Pparg gene expression is regulated will help develop preventative and therapeutic treatments for non-alcoholic fatty liver disease(NAFLD).Due to the potential adverse effect of hepatic Pparg gene deletion on peripheral tissue functions,therapeutic interventions that target PPAR g for fatty liver diseases require fine-tuning of this gene's expression and transcriptional activity。展开更多
Background:Gestational diabetes mellitus(GDM)is a common complication during pregnancy.Obesity and overweight are closely related to metabolic diseases and diabetes.However,the role of adipose tissue in the pathogenes...Background:Gestational diabetes mellitus(GDM)is a common complication during pregnancy.Obesity and overweight are closely related to metabolic diseases and diabetes.However,the role of adipose tissue in the pathogenesis of GDM remains to be studied.The aim of this study was to investigate the correlation of vitamin D(VD)levels,VD receptor(VDR),and peroxisome proliferatoractivated receptor g(PPARg)expression with GDM in overweight or obese women.Methods:One hundred and forty pregnant women with full-term single-birth cesarean-section were selected as the study subjects and grouped(70 GDM women,including 35 non-overweight/non-obese women[group G1]and 35 women with overweight or obesity[group G2];70 pregnant women with normal glucose tolerance,including 35 non-overweight/non-obese women[group N1]and 35 overweight/obese women[group N2]).The levels of serum VD,blood biochemistry,and adiponectin were compared in these women.Subcutaneous adipose tissue was isolated from the abdominal wall incision.VDR and PPARg messenger RNA(mRNA)transcript levels in these adipose tissues were quantified by real-time polymerase chain reaction.The differences between the levels of PPARg protein and phosphorylated PPARg Ser273 were detected by Western blotting.Results:The serum VD level ofGDM women was lower in comparison to that of women with normal glucose tolerance(G1 vs.N1:20.62±7.87 ng/mL vs.25.85±7.29 ng/mL,G2 vs.N2:17.06±6.74 ng/mL vs.21.62±7.18 ng/mL,P<0.05),and the lowest in overweight/obese GDM women.VDR and PPARg mRNA expression was higher in the adipose tissues of GDM women in comparison to that of women with normal glucose tolerance(VDR mRNA:G1 vs.N1:210.00[90.58–311.46]vs.89.34[63.74–159.92],G2 vs.N2:298.67[170.84–451.25]vs.198.28[119.46–261.23],PPARg mRNA:G1 vs.N1:100.72[88.61–123.87]vs.87.52[66.37–100.04],G2 vs.N2:117.33[100.08–149.00]vs.89.90[76.95–109.09],P<0.05),and their expression was the highest in GDM+overweight/obese women.VDR mRNA levels positively correlated with the pre-pregnancy body mass index(BMI),pre-delivery BMI,fasting blood glucose(FBG),homeostasis model assessment of insulin resistance(HOMA-IR),and PPARg mRNA while it negatively correlated with the VD and the adiponectin levels(r=0.395,0.336,0.240,0.190,0.235,–0.350,–0.294,respectively,P<0.05).The degree of PPARg Ser273 phosphorylation increased in obese and GDM pregnant women.PPARg mRNA levels positively correlated with pre-pregnancy BMI,pre-delivery BMI,FBG,HOMA-IR,serum total cholesterol,triglyceride,free fatty acid,and VDR mRNA,while it negatively correlated with the VD and adiponectin levels(r=0.276,0.199,0.210,0.230,0.182,0.214,0.270,0.235,–0.232,–0.199,respectively,P<0.05).Conclusions:Both GDM and overweight/obese women had decreased serum VD levels and up-regulated VDR and PPARg mRNA expression in adipose tissue,which was further higher in the overweight or obese women with GDM.VDmay regulate the formation and differentiation of adipocytes through the VDR and PPARg pathways and participate in the occurrence of GDM.展开更多
Uncontrolled microglial activation is decisively involved in the neuroinflammatory pathogenesis of brain diseases. Consequently, suppression of microglial overactivation appears to be a strategy for the prevention of ...Uncontrolled microglial activation is decisively involved in the neuroinflammatory pathogenesis of brain diseases. Consequently, suppression of microglial overactivation appears to be a strategy for the prevention of nerve injury. In this paper, a novel vanadium complex, vanadyl N-(p-N,Ndimethylaminophenylcarbamoylmethyl)iminodiacetate(VO(p-dmada)), was synthesized from vanadyl sulfate and N,N-dimethyl-p-phenylenediamine, which was structurally characterized by Fourier transform infrared spectrum and ESI-MS analysis. The effect of VO(p-dmada) on neuroinflammation was investigated by using the models of lipopolysaccharide(LPS)-induced BV2 microglial cells and BALB/c mice.Our data demonstrated that VO(p-dmada) significantly suppressed microglial activation by downregulating inflammatory mediators and associated proteins, and inactivating nuclear factor-κ B(NF-κ B) signaling pathway. VO(p-dmada) also upregulated peroxisome proliferator activated receptor gamma(PPARγ) by reducing transglutaminase 2 and heat shock protein 60 expression. Co-treatment with PPARγ antagonist GW9662 significantly impeded the inhibitory effect of VO(p-dmada) on LPS-induced neuroinflammation.These cumulative findings demonstrated that VO(p-dmada) is a potential new drug for the treatment of neuroinflammation-related neurodegenerative diseases.展开更多
Background:Non-alcoholic liver disease is of increased concern and contributing to economic burdens not only in developing countries but in developed countries as well.Identifying the biomarker of early diagnosis and ...Background:Non-alcoholic liver disease is of increased concern and contributing to economic burdens not only in developing countries but in developed countries as well.Identifying the biomarker of early diagnosis and early intervention approaches for non-alcoholic liver disease is unmet and required further investigation.Although the alpha-ketoglutarate(a-KG)is recently proposed to be a potential biomarker in differentiating patients with obesity from those with non-alcoholic liver disease,how a-ketoglutatate is involved in the fatty liver progression is not clear.Methods:A high-fat diet(HFD)feeding animal model,liver functional assays,and molecular approaches were adopted to clarify the impact of a-KG in fatty liver progression.Results:In the current study,it was found that dietary a-KG would inhibit weight gain in male and female mice fed with a normal chew or HFD.HFD feeding caused fatty liver in male mice,but a-KG treatment could substantially inhibit hepatic steatosis progression.Biochemical studies revealed the possible linkage of a-KG protective functions to lipid metabolism.Further analysis identified the important role of peroxisome proliferator-activated receptors in beneficial a-KG-mediated effects on fatty liver progression.Conclusions:The current study demonstrates the therapeutic potential of a-KG and how it may be used,via dietary supplementation,as a preventive intervention for non-alcoholic liver disease in obese patients.展开更多
基金This work was supported by USA National Institutes of Health(NIH)grant,R01DK093774 to Y.K.Lee.
文摘Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and proliferation of adipose tissues.It has two major isoforms,PPARγ1 and PPARγ2,encoded from a single gene using two separate promoters and alternative splicing.Among them,PPARγ2 is most abundantly expressed in adipocytes and plays major adipogenic and lipogenic roles in the tissue.Furthermore,it has been shown that PPARγ2 is also expressed in the liver,specifically in hepatocytes,and its expression level positively correlates with fat accumulation induced by pathological conditions such as obesity and diabetes.Knockout of the hepatic Pparg gene ameliorates hepatic steatosis induced by diet or genetic manipulations.Transcriptional activation of Pparg in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes.Understanding how the hepatic Pparg gene expression is regulated will help develop preventative and therapeutic treatments for non-alcoholic fatty liver disease(NAFLD).Due to the potential adverse effect of hepatic Pparg gene deletion on peripheral tissue functions,therapeutic interventions that target PPAR g for fatty liver diseases require fine-tuning of this gene's expression and transcriptional activity。
文摘Background:Gestational diabetes mellitus(GDM)is a common complication during pregnancy.Obesity and overweight are closely related to metabolic diseases and diabetes.However,the role of adipose tissue in the pathogenesis of GDM remains to be studied.The aim of this study was to investigate the correlation of vitamin D(VD)levels,VD receptor(VDR),and peroxisome proliferatoractivated receptor g(PPARg)expression with GDM in overweight or obese women.Methods:One hundred and forty pregnant women with full-term single-birth cesarean-section were selected as the study subjects and grouped(70 GDM women,including 35 non-overweight/non-obese women[group G1]and 35 women with overweight or obesity[group G2];70 pregnant women with normal glucose tolerance,including 35 non-overweight/non-obese women[group N1]and 35 overweight/obese women[group N2]).The levels of serum VD,blood biochemistry,and adiponectin were compared in these women.Subcutaneous adipose tissue was isolated from the abdominal wall incision.VDR and PPARg messenger RNA(mRNA)transcript levels in these adipose tissues were quantified by real-time polymerase chain reaction.The differences between the levels of PPARg protein and phosphorylated PPARg Ser273 were detected by Western blotting.Results:The serum VD level ofGDM women was lower in comparison to that of women with normal glucose tolerance(G1 vs.N1:20.62±7.87 ng/mL vs.25.85±7.29 ng/mL,G2 vs.N2:17.06±6.74 ng/mL vs.21.62±7.18 ng/mL,P<0.05),and the lowest in overweight/obese GDM women.VDR and PPARg mRNA expression was higher in the adipose tissues of GDM women in comparison to that of women with normal glucose tolerance(VDR mRNA:G1 vs.N1:210.00[90.58–311.46]vs.89.34[63.74–159.92],G2 vs.N2:298.67[170.84–451.25]vs.198.28[119.46–261.23],PPARg mRNA:G1 vs.N1:100.72[88.61–123.87]vs.87.52[66.37–100.04],G2 vs.N2:117.33[100.08–149.00]vs.89.90[76.95–109.09],P<0.05),and their expression was the highest in GDM+overweight/obese women.VDR mRNA levels positively correlated with the pre-pregnancy body mass index(BMI),pre-delivery BMI,fasting blood glucose(FBG),homeostasis model assessment of insulin resistance(HOMA-IR),and PPARg mRNA while it negatively correlated with the VD and the adiponectin levels(r=0.395,0.336,0.240,0.190,0.235,–0.350,–0.294,respectively,P<0.05).The degree of PPARg Ser273 phosphorylation increased in obese and GDM pregnant women.PPARg mRNA levels positively correlated with pre-pregnancy BMI,pre-delivery BMI,FBG,HOMA-IR,serum total cholesterol,triglyceride,free fatty acid,and VDR mRNA,while it negatively correlated with the VD and adiponectin levels(r=0.276,0.199,0.210,0.230,0.182,0.214,0.270,0.235,–0.232,–0.199,respectively,P<0.05).Conclusions:Both GDM and overweight/obese women had decreased serum VD levels and up-regulated VDR and PPARg mRNA expression in adipose tissue,which was further higher in the overweight or obese women with GDM.VDmay regulate the formation and differentiation of adipocytes through the VDR and PPARg pathways and participate in the occurrence of GDM.
基金financially supported by grants from the National Natural Science Foundation of China(No.21877081)the China Postdoctoral Science Foundation(No.2021M692210)+2 种基金Guangdong Provincial Key S&T Program(No.2018B030336001)the Shenzhen Science and Technology Innovation Commission(No.JCYJ20200109110001818)the Shenzhen-Hong Kong Institute of brain Science-Shenzhen Fundamental Research institutions(No.2022SHIBS0003)。
文摘Uncontrolled microglial activation is decisively involved in the neuroinflammatory pathogenesis of brain diseases. Consequently, suppression of microglial overactivation appears to be a strategy for the prevention of nerve injury. In this paper, a novel vanadium complex, vanadyl N-(p-N,Ndimethylaminophenylcarbamoylmethyl)iminodiacetate(VO(p-dmada)), was synthesized from vanadyl sulfate and N,N-dimethyl-p-phenylenediamine, which was structurally characterized by Fourier transform infrared spectrum and ESI-MS analysis. The effect of VO(p-dmada) on neuroinflammation was investigated by using the models of lipopolysaccharide(LPS)-induced BV2 microglial cells and BALB/c mice.Our data demonstrated that VO(p-dmada) significantly suppressed microglial activation by downregulating inflammatory mediators and associated proteins, and inactivating nuclear factor-κ B(NF-κ B) signaling pathway. VO(p-dmada) also upregulated peroxisome proliferator activated receptor gamma(PPARγ) by reducing transglutaminase 2 and heat shock protein 60 expression. Co-treatment with PPARγ antagonist GW9662 significantly impeded the inhibitory effect of VO(p-dmada) on LPS-induced neuroinflammation.These cumulative findings demonstrated that VO(p-dmada) is a potential new drug for the treatment of neuroinflammation-related neurodegenerative diseases.
基金Funding for this work was provided by 2017 AASLDF Pinnacle Research Development Award and Rhode Island Foundation#134279.
文摘Background:Non-alcoholic liver disease is of increased concern and contributing to economic burdens not only in developing countries but in developed countries as well.Identifying the biomarker of early diagnosis and early intervention approaches for non-alcoholic liver disease is unmet and required further investigation.Although the alpha-ketoglutarate(a-KG)is recently proposed to be a potential biomarker in differentiating patients with obesity from those with non-alcoholic liver disease,how a-ketoglutatate is involved in the fatty liver progression is not clear.Methods:A high-fat diet(HFD)feeding animal model,liver functional assays,and molecular approaches were adopted to clarify the impact of a-KG in fatty liver progression.Results:In the current study,it was found that dietary a-KG would inhibit weight gain in male and female mice fed with a normal chew or HFD.HFD feeding caused fatty liver in male mice,but a-KG treatment could substantially inhibit hepatic steatosis progression.Biochemical studies revealed the possible linkage of a-KG protective functions to lipid metabolism.Further analysis identified the important role of peroxisome proliferator-activated receptors in beneficial a-KG-mediated effects on fatty liver progression.Conclusions:The current study demonstrates the therapeutic potential of a-KG and how it may be used,via dietary supplementation,as a preventive intervention for non-alcoholic liver disease in obese patients.
