Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)protect against diabetic cardiovascular diseases and nephropathy.However,their activity in diabetic retinopathy(DR)remains unclear.Our retrospective cohort study inv...Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)protect against diabetic cardiovascular diseases and nephropathy.However,their activity in diabetic retinopathy(DR)remains unclear.Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications,suggesting their advantage in DR treatment.By single-cell RNA-sequencing analysis and immunostaining,we observed a high expression of GLP-1R in retinal endothelial cells,which was down-regulated under diabetic conditions.Treatment of GLP-1 RAs significantly restored the receptor expression,resulting in an improvement in retinal degeneration,vascular tortuosity,avascular vessels,and vascular integrity in diabetic mice.GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs.Additionally,the treatment attenuated STING signaling activation in retinal endothelial cells,which is typically activated by leaked mitochondrial DNA.Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes.Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling.This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.展开更多
Type 2 diabetes(T2D)is highly associated with obesity.However,the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic i...Type 2 diabetes(T2D)is highly associated with obesity.However,the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder.Mucosal-associated invariant T(MAIT)cells,which are innate-like T cells that recognize bacterial metabolites,have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity.By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D,we found an elevation in CD27^(-)negative(CD27−)MAIT cells producing a high level of IL-17 under T2D obese conditions,which could be positively correlated with impaired glucose metabolism in obese people.We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities.Specifically,accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17^(-)producing CD27−MAIT cell expansion and could be associated with T2D risk in obese individuals.Overall,these results suggest that an aberrant gut microbiota–immune axis in obese people may drive or exacerbate T2D.Importantly,CD27−MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies.Our findings extend current knowledge regarding the clinical relevance of body mass index(BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.展开更多
Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regu...Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.展开更多
基金supported by grants from the National Natural Science Foundation of China(82000782,82270886,82070811)the Foster Program for NSFC at the Third Affiliated Hospital of Sun Yat-Sen University(2020G2RPYQN11,China)+3 种基金China International Medical Foundation(2018-N-01)the Science and Technology Plan Project of Guangzhou City(2024A03J0002,China)Key Area R&D Program of Guangdong Province(2019B020227003,China)Sci-Tech Research Development Program of Guangzhou City(202201020589,China).
文摘Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)protect against diabetic cardiovascular diseases and nephropathy.However,their activity in diabetic retinopathy(DR)remains unclear.Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications,suggesting their advantage in DR treatment.By single-cell RNA-sequencing analysis and immunostaining,we observed a high expression of GLP-1R in retinal endothelial cells,which was down-regulated under diabetic conditions.Treatment of GLP-1 RAs significantly restored the receptor expression,resulting in an improvement in retinal degeneration,vascular tortuosity,avascular vessels,and vascular integrity in diabetic mice.GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs.Additionally,the treatment attenuated STING signaling activation in retinal endothelial cells,which is typically activated by leaked mitochondrial DNA.Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes.Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling.This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.
基金This study was funded by the National Key R&D Program of China(2017YFA0105803)the National Natural Science Foundation of China(32000621 and 81770826)+3 种基金the Key Area R&D Program of Guangdong Province(2019B020227003)the Science and Technology Plan Project of Guangzhou City(202102010338 and 202007040003)the 5010 Clinical Research Projects of Sun Yat-sen University(2015015)the Dengfeng Plan High-level Hospital Construction Opening Project of Foshan Fourth People’s Hospital(FSSYKF-2020009).
文摘Type 2 diabetes(T2D)is highly associated with obesity.However,the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder.Mucosal-associated invariant T(MAIT)cells,which are innate-like T cells that recognize bacterial metabolites,have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity.By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D,we found an elevation in CD27^(-)negative(CD27−)MAIT cells producing a high level of IL-17 under T2D obese conditions,which could be positively correlated with impaired glucose metabolism in obese people.We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities.Specifically,accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17^(-)producing CD27−MAIT cell expansion and could be associated with T2D risk in obese individuals.Overall,these results suggest that an aberrant gut microbiota–immune axis in obese people may drive or exacerbate T2D.Importantly,CD27−MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies.Our findings extend current knowledge regarding the clinical relevance of body mass index(BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.
基金This work was supported in part by the Hickam Endowed Chair,Gastroenterology,Medicine,Indiana University and the Indiana University Health e Indiana University School of Medicine Strategic Research Initiative,the Research Career Scientist to Dr.Alpini from the United States Department of Veteran’s Affairs,Biomedical Laboratory Research and Development Service and National Institutes of Health(NIH)grants DK054811,DK110035,and DK076898 to Drs.G.Alpini and S.Glaser.In addition,this work was supported in whole or in part by grants from the American Diabetes Association(ADA)(1-10-BS-76 to C.Wu)the National Institutes of Health(DK095828 and DK124854 to C.Wu).
文摘Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.
