PubMedPro - 母义明、肖新华

PPARγ links maternal malnutrition and abnormal glucose and lipid metabolism in the offspring of mice. Yi chuan = Hereditas Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that regulate gene transcription. PPARs play essential roles in modulating cell differentiation, development, and metabolism (carbohydrate, lipid, protein). Here, we investigated whether PPARγ plays a role in linking maternal malnutrition and aberrant metabolism in the offspring of mice. After feeding dams with high fat (HF) and low protein (LP) diet during pregnancy and lactation, we examined the effects on the offspring at weaning (age of 3-week). The results showed that the LP offspring had lower body weight and length than the control. The HF offspring had heavier body weight and longer body length than LP. The blood glucose levels in HF group were significantly higher at 30 min and 60 min after intraperitoneal glucose administration and the area under curve was also significantly larger than the control. The blood glucose levels in HF group were significantly higher at 30 min than LP. HF group had elevated total cholesterol levels and LP group had decreased total cholesterol levels compared with the control. All results were statistically significant as examined by t-test. More importantly, PPARγ expression levels detected by qRT-PCR were significantly increased in HF and LP groups compared with the control. In conclusion, maternal HF and LP diet during pregnancy and lactation can induce impaired glucose and lipid metabolism in the early life of mouse offspring, where PPARγ may play an important role. 10.16288/j.yczz.2015.01.010

Evidence of a relationship between infant birth weight and later diabetes and impaired glucose regulation in a Chinese population. Xiao Xinhua,Zhang Zhen-Xin,Cohen Harvey Jay,Wang Heng,Li Wenhui,Wang Tong,Xu Tao,Liu Aimin,Gai Ming-Ying,Ying Shen,Schmitz Ole,Yi Zeng Diabetes care OBJECTIVE:The aim of this study was to determine the influence of birth weight, a marker of fetal growth, on the development of later impaired glucose metabolism throughout the life span of people living in China. RESEARCH DESIGN AND METHODS:We recorded detailed anthropometric data including height, weight, and health status and measured blood glucose levels and insulin concentrations after fasting and at 120 min of a standard oral glucose tolerance test from 2,019 eligible subjects born between 1921 and 1954 to investigate the risk of developing type 2 diabetes and impaired glucose regulation (IGR). RESULTS:The diabetes and IGR groups were characterized by significantly lower birth weight (P < 0.001), smaller head circumference (P < 0.001), smaller ponderal index (P = 0.007), and shorter length (P = 0.004) compared with those in the normal glucose tolerance group. Using multiple logistic regression analysis, we observed that birth weight remained significantly associated with diabetes and IGR after adjustments for possible confounding variables at birth and in adult life such as sex, age, central obesity, smoking status, alcohol consumption, dyslipidemia, family history of diabetes, and occupational status (P = 0.027). There was a significantly increased risk of getting diabetes and IGR for those with low birth weight (odds ratio 1.748 [95% CI 1.018-3.001], P = 0.043). CONCLUSIONS:The results confirm that lower birth weight is an independent risk factor for later diabetes or IGR and show for the first time that this risk factor also applies for a Chinese population. 10.2337/dc07-1130

Low birth weight is associated with components of the metabolic syndrome. Xiao Xinhua,Zhang Zhen-Xin,Li Wen-Hui,Feng Kai,Sun Qi,Cohen Harvey Jay,Xu Tao,Wang Heng,Liu Ai-Min,Gong Xiao-Ming,Shen Ying,Yi Zeng Metabolism: clinical and experimental The purpose of the study was to investigate the association between birth weight and number of metabolic syndrome (MetS) components in an urban Chinese cohort. Individuals (N = 2019) who were born between 1921 and 1954 at the Peking Union Medical College Hospital and who had detailed obstetric records volunteered to take part and were examined by medical personnel in a clinical setting between May 2003 and April 2005. Data of birth outcome and results on clinic examination in adulthood were analyzed using analysis of variance and multivariate ordinal regression to estimate the association between birth weight and MetS. Metabolic syndrome was defined as per the National Cholesterol Education Program Adult Treatment Panel III. The prevalence of MetS was 26.74%, whereas 55.43% of the subjects had at least 2 components of MetS. Subjects who presented with all 5 components of MetS exhibited a significantly lower birth weight and higher age, body mass index, and waist circumference at follow-up. Multivariate ordinal regression analysis revealed that, as compared with those with birth weights of 3000 to 3500 g, subjects who had birth weights of less than 2500 g were 66% more likely to develop a greater number of MetS components in adulthood (95% confidence interval, 1.18-2.34; P = .004), whereas those with birth weights between 2500 and 3000 g were 33% more likely to develop a greater number of MetS components as adults (95% confidence interval, 1.09-1.63; P = .005). The present study demonstrated the relationship between low birth weight and increased presentation of MetS components in Chinese adults. 10.1016/j.metabol.2009.12.001

DNA methylation: the pivotal interaction between early-life nutrition and glucose metabolism in later life. Zheng Jia,Xiao Xinhua,Zhang Qian,Yu Miao The British journal of nutrition Traditionally, it has been widely acknowledged that genes together with adult lifestyle factors determine the risk of developing some metabolic diseases such as insulin resistance, obesity and diabetes mellitus in later life. However, there is now substantial evidence that prenatal and early-postnatal nutrition play a critical role in determining susceptibility to these diseases in later life. Maternal nutrition has historically been a key determinant for offspring health, and gestation is the critical time window that can affect the growth and development of offspring. The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that exposures during early life play a critical role in determining the risk of developing metabolic diseases in adulthood. Currently, there are substantial epidemiological studies and experimental animal models that have demonstrated that nutritional disturbances during the critical periods of early-life development can significantly have an impact on the predisposition to developing some metabolic diseases in later life. The hypothesis that epigenetic mechanisms may link imbalanced early-life nutrition with altered disease risk has been widely accepted in recent years. Epigenetics can be defined as the study of heritable changes in gene expression that do not involve alterations in the DNA sequence. Epigenetic processes play a significant role in regulating tissue-specific gene expression, and hence alterations in these processes may induce long-term changes in gene function and metabolism that persist throughout the life course. The present review focuses on how nutrition in early life can alter the epigenome, produce different phenotypes and alter disease susceptibilities, especially for impaired glucose metabolism. 10.1017/S0007114514002827

Maternal high-fat diet modulates hepatic glucose, lipid homeostasis and gene expression in the PPAR pathway in the early life of offspring. Zheng Jia,Xiao Xinhua,Zhang Qian,Yu Miao,Xu Jianping,Wang Zhixin International journal of molecular sciences Maternal dietary modifications determine the susceptibility to metabolic diseases in adult life. However, whether maternal high-fat feeding can modulate glucose and lipid metabolism in the early life of offspring is less understood. Furthermore, we explored the underlying mechanisms that influence the phenotype. Using C57BL/6J mice, we examined the effects on the offspring at weaning from dams fed with a high-fat diet or normal chow diet throughout pregnancy and lactation. Gene array experiments and quantitative real-time PCR were performed in the liver tissues of the offspring mice. The offspring of the dams fed the high-fat diet had a heavier body weight, impaired glucose tolerance, decreased insulin sensitivity, increased serum cholesterol and hepatic steatosis at weaning. Bioinformatic analyses indicated that all differentially expressed genes of the offspring between the two groups were mapped to nine pathways. Genes in the peroxisome proliferator-activated receptor (PPAR) signaling pathway were verified by quantitative real-time PCR and these genes were significantly up-regulated in the high-fat diet offspring. A maternal high-fat diet during pregnancy and lactation can modulate hepatic glucose, lipid homeostasis, and gene expression in the PPAR signaling in the early life of offspring, and our results suggested that potential mechanisms that influences this phenotype may be related partially to up-regulate some gene expression in the PPAR signalling pathway. 10.3390/ijms150914967

Maternal protein restriction induces early-onset glucose intolerance and alters hepatic genes expression in the peroxisome proliferator-activated receptor pathway in offspring. Zheng Jia,Xiao Xinhua,Zhang Qian,Yu Miao,Xu Jianping,Wang Zhixin Journal of diabetes investigation AIMS/INTRODUCTION:Maternal undernutrition during pregnancy and/or lactation can alter the offspring's response to environmental challenges, and thus increases the risk of the development of metabolic diseases at a later age. However, whether maternal protein restriction can modulate glucose metabolism in the early life of offspring is less understood. Furthermore, we explored the potential underlying mechanisms that illustrate this phenotype. MATERIALS AND METHODS:To test this hypothesis, we examined the offspring of C57BL/6J mice at weaning to determine the effects of feeding their mothers a low-protein diet or normal chow diet throughout pregnancy and lactation. Gene array experiments and quantitative real-time polymerase chain reaction were utilized to explore the altered hepatic genes expression. RESULTS:The offspring of dams fed a low-protein diet had a lower birthweight and bodyweight, impaired glucose tolerance, decreased insulin sensitivity, and decreased serum cholesterol at weaning. Using gene array experiments, 253 differentially expressed genes were identified in the liver tissues of the offspring between the two groups. Bioinformatic analyses showed that all differentially expressed genes were mapped to 11 pathways. We focused on the 'peroxisome proliferator-activated receptor signaling pathway,' because peroxisome proliferator-activated receptors have emerged as central regulators of glucose and lipid homeostasis. Quantitative real-time polymerase chain reaction was utilized for the validation of genes in the pathway. CONCLUSIONS:A maternal low-protein diet during pregnancy and lactation promotes early-onset glucose intolerance in the offspring mice, and the altered hepatic genes expression in peroxisome proliferator-activated receptor signaling pathway could play role in regulating this phenomenon. 10.1111/jdi.12303

Foamy monocytes form early and contribute to nascent atherosclerosis in mice with hypercholesterolemia. Xu Lu,Dai Perrard Xiaoyuan,Perrard Jerry L,Yang Donglin,Xiao Xinhua,Teng Ba-Bie,Simon Scott I,Ballantyne Christie M,Wu Huaizhu Arteriosclerosis, thrombosis, and vascular biology OBJECTIVE:To examine infiltration of blood foamy monocytes, containing intracellular lipid droplets, into early atherosclerotic lesions and its contribution to development of nascent atherosclerosis. APPROACH AND RESULTS:In apoE(-/-) mice fed Western high-fat diet (WD), >10% of circulating monocytes became foamy monocytes at 3 days on WD and >20% of monocytes at 1 week. Foamy monocytes also formed early in blood of Ldlr(-/-)Apobec1(-/-) (LDb) mice on WD. Based on CD11c and CD36, mouse monocytes were categorized as CD11c(-)CD36(-), CD11c(-)CD36(+), and CD11c(+)CD36(+). The majority of foamy monocytes were CD11c(+)CD36(+), whereas most nonfoamy monocytes were CD11c(-)CD36(-) or CD11c(-)CD36(+) in apoE(-/-) mice on WD. In wild-type mice, CD11c(+)CD36(+) and CD11c(-)CD36(+), but few CD11c(-)CD36(-), monocytes took up cholesteryl ester-rich very low-density lipoproteins (CE-VLDLs) isolated from apoE(-/-) mice on WD, and CE-VLDL uptake accelerated CD11c(-)CD36(+) to CD11c(+)CD36(+) monocyte differentiation. Ablation of CD36 decreased monocyte uptake of CE-VLDLs. Intravenous injection of DiI-CE-VLDLs in apoE(-/-) mice on WD specifically labeled CD11c(+)CD36(+) foamy monocytes, which infiltrated into nascent atherosclerotic lesions and became CD11c(+) cells that were selectively localized in atherosclerotic lesions. CD11c deficiency reduced foamy monocyte infiltration into atherosclerotic lesions. Specific and consistent depletion of foamy monocytes (for 3 weeks) by daily intravenous injections of low-dose clodrosome reduced development of nascent atherosclerosis. CONCLUSIONS:Foamy monocytes, which form early in blood of mice with hypercholesterolemia, infiltrate into early atherosclerotic lesions in a CD11c-dependent manner and play crucial roles in nascent atherosclerosis development. 10.1161/ATVBAHA.115.305609

Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic POMC promoter methylation in mouse offspring. Zheng Jia,Xiao Xinhua,Zhang Qian,Yu Miao,Xu Jianping,Wang Zhixin,Qi Cuijuan,Wang Tong Metabolic brain disease Substantial evidence demonstrated that maternal dietary nutrients can significantly determine the susceptibility to developing metabolic disorders in the offspring. Therefore, we aimed to investigate the later-life effects of maternal and postweaning diets interaction on epigenetic modification of the central nervous system in the offspring. We examined the effects of dams fed a high-fat, high-sucrose (FS) diet during pregnancy and lactation and weaned to FS diet continuously until 32 weeks of age. Then, DNA methylation and gene expressions of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in the offspring. Offspring of FS diet had heavier body weight, impaired glucose tolerance, decreased insulin sensitivity and higher serum leptin level at 32-week age (p < 0.05). The expression of POMC and MC4R genes were significantly increased in offspring exposed to FS diet during gestation, lactation and into 32-week age (p < 0.05). Consistently, hypomethylation of POMC promoter in the hypothalamus occurred in the FS diet offspring (p < 0.05), compared with the C group. However, no methylation was detected of MC4R promoter in both the two groups. Furthermore, POMC-specific methylation (%) was negatively associated with glucose response to a glucose load (r = -0.273, p = 0.039). Maternal and post-weaning high-fat diet predisposes the offspring for obesity, glucose intolerance and insulin resistance in later life. Our findings can advance our thinking around the DNA methylation status of the promoter of the POMC and MC4R genes between long-term high-fat, high-sucrose diet and glucose homeostasis in mouse. 10.1007/s11011-015-9678-9

The effects of maternal and post-weaning diet interaction on glucose metabolism and gut microbiota in male mice offspring. Zheng Jia,Xiao Xinhua,Zhang Qian,Yu Miao,Xu Jianping,Qi Cuijuan,Wang Tong Bioscience reports Substantial studies demonstrated that maternal nutrition can significantly determine the susceptibility to developing some metabolic diseases in offspring. However, investigations into the later-life effects of these diets on gut microbiota in the offspring are limited. Our objective was to explore the effects of maternal and post-weaning diet interaction on offspring's gut microbiota and glucose metabolism in later life. The male offspring of dams fed on either a high-fat (HF) diet or control (C) diet and then weaned to either a HF or C diet, generating four groups: C-C, HF-C, C-HF and HF-HF (n=8 in each group). The C-C offspring had lower body weight than C-HF group at 16 weeks of age (P<0.01) and both C-HF and HF-HF offspring had higher body weight than C-C group at 24 and 32 weeks of age (P<0.001 respectively). The blood glucose (BG) levels of the male offspring from the C and HF dams weaned HF diet were significantly higher at 30 min, 60 min and 120 min (P<0.001) after intraperitoneal glucose administration compared with those of the C-C group. The C-HF group had higher BG at 30 min than HF-HF group (P<0.01). Furthermore, area under the curve (AUC) in C-HF and HF-HF groups was also significantly larger than C-C group (P<0.001). Fasting BG and homoeostasis model assessment of insulin resistance (HOMA-IR) of the offspring were significantly higher in C-HF and HF-HF groups than C-C group at 32 weeks of age (P<0.05). Operational taxonomic unit (OTU), Chao and Shannon indexes showed a significantly lower diversity in C-HF offspring compared with HF-C and C-C groups (P<0.05). The dominant phyla of all the groups were Bacteroidetes, Firmicutes and Proteobacteria, which also showed significantly different percentages in the group (P<0.05). Furthermore, it is indicated that Lactobacillus and Bacteroides were significantly associated with glucose response to a glucose load (P<0.05). In conclusion, maternal and post-weaning diet interaction predisposes the offspring to aberrant glucose metabolism and alterations of gut microbiota in later life. Our study is novel in focusing on the effects of maternal and post-weaning diet interaction on offspring gut microbiota and glucose metabolism in later life. 10.1042/BSR20160103

Early Life Fructose Exposure and Its Implications for Long-Term Cardiometabolic Health in Offspring. Zheng Jia,Feng Qianyun,Zhang Qian,Wang Tong,Xiao Xinhua Nutrients It has become increasingly clear that maternal nutrition can strongly influence the susceptibility of adult offspring to cardiometabolic disease. For decades, it has been thought that excessive intake of fructose, such as sugar-sweetened beverages and foods, has been linked to increased risk of obesity, type 2 diabetes, and cardiovascular disease in various populations. These deleterious effects of excess fructose consumption in adults are well researched, but limited data are available on the long-term effects of high fructose exposure during gestation, lactation, and infancy. This review aims to examine the evidence linking early life fructose exposure during critical periods of development and its implications for long-term cardiometabolic health in offspring. 10.3390/nu8110685

Zinc alpha2 glycoprotein alleviates palmitic acid-induced intracellular lipid accumulation in hepatocytes. Xiao Xinhua,Li Han,Qi Xiaoyan,Wang Yadi,Xu Canxin,Liu Gexin,Wen Gebo,Liu Jianghua Molecular and cellular endocrinology Zinc alpha2 glycoprotein (ZAG) plays an important role in stimulating fat mobilization and lipolysis in adipose tissue, but its role in hepatic lipid metabolism remains unclear. Palmitic acid (PA) was used to stimulate HepG2 cells with ZAG overexpression or ZAG knock down (shRNA). Overexpression of ZAG significantly inhibited lipogenesis, promoted lipolysis and fatty acid β-oxidation, and attenuated PA-induced intracellular fat accumulation. Moreover, ZAG overexpression dramatically stimulated adiponectin expression in HepG2 cells. In contrast, knockdown of ZAG notably inhibited fatty acid β-oxidation, increased lipogenesis and lipid accumulation. Collectively, these data suggest that ZAG has the potential to alleviate hepatosteatosis, making it a promising therapeutic target for fatty liver. 10.1016/j.mce.2016.06.003

Effects of Maternal Chromium Restriction on the Long-Term Programming in MAPK Signaling Pathway of Lipid Metabolism in Mice. Zhang Qian,Sun Xiaofang,Xiao Xinhua,Zheng Jia,Li Ming,Yu Miao,Ping Fan,Wang Zhixin,Qi Cuijuan,Wang Tong,Wang Xiaojing Nutrients It is now broadly accepted that the nutritional environment in early life is a key factor in susceptibility to metabolic diseases. In this study, we evaluated the effects of maternal chromium restriction in vivo on the modulation of lipid metabolism and the mechanisms involved in this process. Sixteen pregnant C57BL mice were randomly divided into two dietary treatments: a control (C) diet group and a low chromium (L) diet group. The diet treatment was maintained through gestation and lactation period. After weaning, some of the pups continued with either the control diet or low chromium diet (CC or LL), whereas other pups switched to another diet (CL or LC). At 32 weeks of age, serum lipid metabolism, proinflammatory indexes, oxidative stress and anti-oxidant markers, and DNA methylation status in adipose tissue were measured. The results indicated that the maternal low chromium diet increased body weight, fat pad weight, serum triglyceride (TG), low-density lipoprotein cholesterol (LDL), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and oxidized glutathione (GSSG). There was a decrease in serum reduced/oxidized glutathione (GSH/GSSG) ratio at 32 weeks of age in female offspring. From adipose tissue, we identified 1214 individual hypomethylated CpG sites and 411 individual hypermethylated CpG sites in the LC group when compared to the CC group. Pathway analysis of the differential methylation genes revealed a significant increase in hypomethylated genes in the mitogen-activated protein kinase (MAPK) signaling pathway in the LC group. Our study highlights the importance of the MAPK signaling pathway in epigenetic changes involved in the lipid metabolism of the offspring from chromium-restricted dams. 10.3390/nu8080488

Maternal high-calorie diet is associated with altered hepatic microRNA expression and impaired metabolic health in offspring at weaning age. Zheng Jia,Zhang Qian,Mul Joram D,Yu Miao,Xu Jianping,Qi Cuijuan,Wang Tong,Xiao Xinhua Endocrine High-calorie diet (HCD) feeding in mice predisposes offspring for impaired glucose homeostasis and obesity. However, the mechanisms underlying these detrimental effects of maternal nutrition, especially during early life of offspring, are incompletely understood. MicroRNAs (miRNAs) are small non-coding RNAs that can regulate target gene expression. Here we hypothesized that impaired metabolic health in offspring from HCD-fed dams at weaning is associated with dysregulated expression of hepatic miRNAs. Dams were fed a chow diet (CD; 11.4 % kcal fat, 62.8 % from carbohydrate, 25.8 % from protein) or HCD (58 % kcal from fat; 25.6 % from carbohydrate, 16.4 % from protein) during gestation and lactation, and metabolic health was assessed in male offspring at weaning. Hepatic levels of miRNAs and target genes were investigated in offspring from CD- or HCD-fed dams using gene and protein expression. Maternal HCD feeding impaired metabolic health in offspring compared to offspring from CD-fed dams. Microarray analysis indicated that expressions of miR-615-5p, miR-3079-5p, miR-124*, and miR-101b* were downregulated, whereas miR-143* was upregulated, in livers from offspring from HCD-fed dams. Our functional enrichment analysis indicated that the target genes of these differentially expressed miRNAs, including tumor necrosis factor-α (TNF-α) and mitogen-activated protein kinase 1 (MAPK1), were mapped to inflammatory pathways. Finally, we verified that both mRNA and protein levels of the pro-inflammatory modulators TNF-α and MAPK1 were significantly increased in livers of offspring from HCD-fed dams at weaning. Maternal HCD feeding predisposes offspring to a higher body weight and impaired glucose metabolism at weaning. To the best of knowledge, our study is the first to show that maternal HCD consumption impairs metabolic health, modulates hepatic miRNA expression, and increases markers of hepatic inflammation in offspring as early as at weaning age. 10.1007/s12020-016-0959-9

Maternal Chromium Restriction Leads to Glucose Metabolism Imbalance in Mice Offspring through Insulin Signaling and Wnt Signaling Pathways. Zhang Qian,Sun Xiaofang,Xiao Xinhua,Zheng Jia,Li Ming,Yu Miao,Ping Fan,Wang Zhixin,Qi Cuijuan,Wang Tong,Wang Xiaojing International journal of molecular sciences An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a chromium-restricted diet (CR) throughout pregnancy and the lactation period. After weaning, some offspring continued the diet diagram (CD-CD or CR-CR), while other offspring were transferred to another diet diagram (CD-CR or CR-CD). At 32 weeks of age, glucose metabolism parameters were measured, and the liver from CR-CD group and CD-CD group was analyzed using a gene array. Quantitative real-time polymerase chain reaction (qPCR) and Western blot were used to verify the result of the gene array. A maternal chromium-restricted diet resulted in obesity, hyperglycemia, hyperinsulinemia, increased area under the curve (AUC) of glucose in oral glucose tolerance testing and homeostasis model assessment of insulin resistance (HOMA-IR). There were 463 genes that differed significantly (>1.5-fold change, < 0.05) between CR-CD offspring (264 up-regulated genes, 199 down-regulated genes) and control offspring. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis revealed that the insulin signaling pathway and Wnt signaling pathway were in the center of the gene network. Our study provides the first evidence that maternal chromium deficiency influences glucose metabolism in pups through the regulation of insulin signaling and Wnt signaling pathways. 10.3390/ijms17101767

The effect of maternal chromium status on lipid metabolism in female elderly mice offspring and involved molecular mechanism. Zhang Qian,Sun Xiaofang,Xiao Xinhua,Zheng Jia,Li Ming,Yu Miao,Ping Fan,Wang Zhixin,Qi Cuijuan,Wang Tong,Wang Xiaojing Bioscience reports Maternal malnutrition leads to the incidence of metabolic diseases in offspring. The purpose of this project was to examine whether maternal low chromium could disturb normal lipid metabolism in offspring, altering adipose cell differentiation and leading to the incidence of lipid metabolism diseases, including metabolic syndrome and obesity. Female C57BL mice were given a control diet (CD) or a low chromium diet (LCD) during the gestational and lactation periods. After weaning, offspring was fed with CD or LCD. The female offspring were assessed at 32 weeks of age. Fresh adipose samples from CD-CD group and LCD-CD group were collected. Genome mRNA were analysed using Affymetrix GeneChip Mouse Gene 2.0 ST Whole Transcript-based array. Differentially expressed genes (DEGs) were analysed based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis database. Maternal low chromium irreversibly increased offspring body weight, fat-pad weight, serum triglyceride (TG) and TNF-α. Eighty five genes increased and 109 genes reduced in the offspring adipose of the maternal low chromium group. According to KEGG pathway and String analyses, the PPAR signalling pathway may be the key controlled pathway related to the effect of maternal low chromium on female offspring. Maternal chromium status have long-term effects of lipid metabolism in female mice offspring. Normalizing offspring diet can not reverse these effects. The potential underlying mechanisms are the disturbance of the PPAR signalling pathway in adipose tissue. 10.1042/BSR20160362

Maternal Low-Protein Diet Modulates Glucose Metabolism and Hepatic MicroRNAs Expression in the Early Life of Offspring †. Zheng Jia,Xiao Xinhua,Zhang Qian,Wang Tong,Yu Miao,Xu Jianping Nutrients Emerging studies revealed that maternal protein restriction was associated with increased risk of type 2 diabetes mellitus in adulthood. However, the mechanisms of its effects on offspring, especially during early life of offspring, are poorly understood. Here, it is hypothesized that impaired metabolic health in offspring from maternal low-protein diet (LPD) is associated with perturbed miRNAs expression in offspring as early as the weaning age. We examined the metabolic effects on the C57BL/6J mice male offspring at weaning from dams fed with LPD or normal chow diet (NCD) throughout pregnancy and lactation. Maternal LPD feeding impaired metabolic health in offspring. Microarray profiling indicated that mmu-miR-615, mmu-miR-124, mmu-miR-376b, and mmu-let-7e were significantly downregulated, while, mmu-miR-708 and mmu-miR-879 were upregulated in LPD offspring. Bioinformatic analysis showed target genes were mapped to inflammatory-related pathways. Serum tumor necrosis factor-α (TNF-α) levels were higher and interleukin 6 (IL-6) had a tendency to be elevated in the LPD group. Finally, both mRNA and protein levels of IL-6 and TNF-α were significantly increased in the LPD group. Our findings provide novel evidence that maternal LPD can regulate miRNAs expression, which may be associated with chronic inflammation status and metabolic health in offspring as early as the weaning age. 10.3390/nu9030205

Maternal chromium restriction modulates miRNA profiles related to lipid metabolism disorder in mice offspring. Zhang Qian,Xiao Xinhua,Zheng Jia,Li Ming,Yu Miao,Ping Fan,Wang Zhixin,Qi Cuijuan,Wang Tong,Wang Xiaojing Experimental biology and medicine (Maywood, N.J.) Increasing evidence shows that maternal nutrition status has a vital effect on offspring susceptibility to obesity. MicroRNAs are related to lipid metabolism processes. This study aimed to evaluate whether maternal chromium restriction could affect miRNA expression involved in lipid metabolism in offspring. Weaning C57BL/6J mice born from mothers fed with normal control diet or chromium-restricted diet were fed for 13 weeks. The adipose miRNA expression profile was analyzed by miRNA array analysis. At 16 weeks old, pups from dams fed with chromium-restricted diet exhibit higher body weight, fat weight, and serum TC, TG levels. Six miRNAs were identified as upregulated in the RC group compared with the CC group, whereas eight miRNAs were lower than the threshold level set in the RC group. In the validated target genes of these differentially expressed miRNA, the MAPK signaling pathway serves an important role in the influence of early life chromium-restricted diet on lipid metabolism through miRNA. Long-term programming on various specific miRNA and MAPK signaling pathway may be involved in maternal chromium restriction in the adipose of female offspring. Impact statement For the first time, our study demonstrates important miRNA differences in the effect of maternal chromium restriction in offspring. These miRNAs may serve as "bridges" between the mother and the offspring by affecting the MAPK pathway. 10.1177/1535370217719059

Maternal nutrition and the developmental origins of osteoporosis in offspring: Potential mechanisms and clinical implications. Zheng Jia,Feng Qianyun,Zheng Sheng,Xiao Xinhua Experimental biology and medicine (Maywood, N.J.) Osteoporosis, the most frequent metabolic disorder of bone, is a complex disease with a multifactorial origin that is influenced by genes and environments. However, the pathogenesis of osteoporosis has not been fully elucidated. The theory of "Developmental Origins of Health and Disease" indicates that early life environment exposure determines the risks of cardiometabolic diseases in adulthood. However, investigations into the effects of maternal nutrition and nutrition exposure during early life on the development of osteoporosis are limited. Recently, emerging evidence has strongly suggested that maternal nutrition has long-term influences on bone metabolism in offspring, and epigenetic modifications maybe the underlying mechanisms of this process. This review aimed to address maternal nutrition and its implications for the developmental origins of osteoporosis in offspring. It is novel in providing a theoretical basis for the early prevention of osteoporosis. Impact statement Our review aimed to address maternal nutrition and its implications for the developmental origins of osteoporosis in offspring, that can novelly provide a theoretical basis for the early prevention of osteoporosis. 10.1177/1535370218779024

Maternal chromium restriction induces insulin resistance in adult mice offspring through miRNA. Zhang Qian,Sun Xiaofang,Xiao Xinhua,Zheng Jia,Li Ming,Yu Miao,Ping Fan,Wang Zhixin,Qi Cuijuan,Wang Tong,Wang Xiaojing International journal of molecular medicine Increasing evidence suggests that undernutrition during the fetal period may lead to glucose intolerance, impair the insulin response and induce insulin resistance (IR). Considering the importance of chromium (Cr) in maintaining carbohydrate metabolism, the present study aimed to determine the effects of maternal low Cr (LC) on glucose metabolism in C57BL mice offspring, and the involved mechanisms. Weaned C57BL mice were born from mothers fed a control diet or LC diet, and were then fed a control or LC diet for 13 weeks. Subsequently, the liver microRNA (miRNA/miR) expression profile was analyzed by miRNA array analysis. A maternal LC diet increased fasting serum glucose (P<0.05) and insulin levels (P<0.05), homeostasis model assessment of IR index (P<0.01), and the area under curve for glucose concentration during oral glucose tolerance test (P<0.01). In addition, 8 upregulated and 6 downregulated miRNAs were identified in the maternal LC group (fold change ≥2, P<0.05). miRNA‑gene networks, Kyoto Encyclopedia of Genes and Genomes pathway analysis of differentially expressed miRNAs, and miRNA overexpression in HepG2 cells revealed the critical role of insulin signaling, via miR‑327, miR‑466f‑3p and miR‑223‑3p, in the effects of early life Cr restriction on glucose metabolism. In conclusion, maternal Cr restriction may irreversibly increase IR, which may involve a specific miRNA affecting the insulin signaling pathway. 10.3892/ijmm.2017.3328

Improved Glucose and Lipid Metabolism in the Early Life of Female Offspring by Maternal Dietary Genistein Is Associated With Alterations in the Gut Microbiota. Zhou Liyuan,Xiao Xinhua,Zhang Qian,Zheng Jia,Li Ming,Yu Miao,Wang Xiaojing,Deng Mingqun,Zhai Xiao,Li Rongrong Frontiers in endocrinology Maternal over-nutrition can lead to metabolic disorders in offspring, whereas maternal dietary genistein may have beneficial effects on the metabolic health of offspring. Our objective was to determine whether maternal dietary genistein could attenuate the detrimental effects of a maternal high-fat diet on their offspring's metabolism and to explore the role of the gut microbiota on their offspring's glucose and lipid metabolism. C57BL/6 female mice were fed either a high-fat diet without genistein (HF), high-fat diet with low-dose genistein (0.25 g/kg diet) (HF.LG), high-fat diet with high-dose genistein (0.6 g/kg diet) (HF.HG) or normal control diet (Control) for 3 weeks prior to breeding and throughout gestation and lactation. The female offspring in the HF group had lower birth weights and glucose intolerance and higher serum insulin, triacylglycerol (TG) and total cholesterol (TC) levels at weaning compared with the Control group. Offspring from HF.LG dams had increased birth weight, improved glucose tolerance, and decreased fasting insulin, whereas the serum TG and TC levels were decreased in HF.HG offspring in comparison with HF offspring. The significant enrichment of and in offspring from genistein-fed dams might play vital roles in improving glucose homeostasis and insulin sensitivity, and the significantly increased abundance of and in the HF.HG group may be associated with the decreased serum levels of TG and TC. In conclusion, maternal dietary genistein negates the harmful effects of a maternal high-fat diet on glucose and lipid metabolism in female offspring, in which the altered gut microbiota plays crucial roles. The ability of maternal genistein intake to improve offspring metabolism is important since this intervention could fight the transmission of diabetes to subsequent generations. 10.3389/fendo.2018.00516

The role of gut microbiota in the effects of maternal obesity during pregnancy on offspring metabolism. Zhou Liyuan,Xiao Xinhua Bioscience reports Obesity is considered a global epidemic. Specifically, obesity during pregnancy programs an increased risk of the offspring developing metabolic disorders in addition to the adverse effects on the mother Large numbers of human and animal studies have demonstrated that the gut microbiota plays a pivotal role in obesity and metabolic diseases. Similarly, maternal obesity during pregnancy is associated with alterations in the composition and diversity of the intestine microbial community. Recently, the microbiota in the placenta, amniotic fluid, and meconium in healthy gestations has been investigated, and the results supported the "in utero colonization hypothesis" and challenged the traditional "sterile womb" that has been acknowledged worldwide for more than a century. Thus, the offspring microbiota, which is crucial for the immune and metabolic function and further health in the offspring, might be established prior to birth. As a detrimental intrauterine environment, maternal obesity influences the microbial colonization and increases the risk of metabolic diseases in offspring. This review discusses the role of the microbiota in the impact of maternal obesity during pregnancy on offspring metabolism and further analyzes related probiotic or prebiotic interventions to prevent and treat obesity and metabolic diseases. 10.1042/BSR20171234

Influence of Maternal Inulin-Type Prebiotic Intervention on Glucose Metabolism and Gut Microbiota in the Offspring of C57BL Mice. Zhang Qian,Xiao Xinhua,Zheng Jia,Li Ming,Yu Miao,Ping Fan,Wang Tong,Wang Xiaojing Frontiers in endocrinology Maternal obesity leads to glucose intolerance in the offspring. Changes in the gut microbiota are being increasingly implicated in the pathogenesis of diabetes. We hypothesized that inulin intervention during gestation and lactation improves glucose metabolism disorders in mouse offspring from high-fat diet (HD)-fed dams. Female C57BL mice were fed a control diet or HD for 4 weeks before mating. After mating, pregnant mice were randomly divided into three groups through gestation and lactation: control diet (CD) group, HD group, and HD treated with inulin (HD-inulin) group. At weaning, glucose metabolic status was assessed. Gut microbial DNA from offspring cecal contents was isolated and processed for metagenomic shotgun sequencing, and taxonomic and functional profiling were performed. Offspring from dams in the HD-inulin groups demonstrated reduced fasting blood glucose, decreased blood glucose area under the curve during the oral glucose tolerance test, and reduced fasting serum insulin and HOMA-IR compared to offspring from dams in the HD group. Nineteen differentially abundant bacterial species were identified between the HD-inulin and HD groups. The HD-inulin group displayed significantly greater abundances of , and species and lower abundances of , and species. Differentially abundant bacterial species among the three groups were involved in 38 metabolic pathways, including several glucose and lipid metabolism pathways. Our results show that early inulin intervention in HD-fed mouse dams moderates offspring glucose metabolism and gut dysbiosis. 10.3389/fendo.2019.00675

A Maternal High-Fat Diet Induces DNA Methylation Changes That Contribute to Glucose Intolerance in Offspring. Zhang Qian,Xiao Xinhua,Zheng Jia,Li Ming,Yu Miao,Ping Fan,Wang Tong,Wang Xiaojing Frontiers in endocrinology Overnutrition is a critical contributor to the susceptibility of diabetes by programming, although the exact mechanism is not clear. In this paper, we aimed to study the long-term effect of a maternal high-fat (HF) diet on offspring through epigenetic modifications. Five-week-old female C57BL6/J mice were fed a HF diet or control diet for 4 weeks before mating and throughout gestation and lactation. At postnatal week 3, pups continued to consume a HF or switched to a control diet for 5 weeks, resulting in four groups of offspring differing by their maternal and postweaning diets. The maternal HF diet combined with the offspring HF diet caused hyperglycemia and insulin resistance in male pups. Even after changing to the control diet, male pups exposed to the maternal HF diet still exhibited hyperglycemia and glucose intolerance. The livers of pups exposed to a maternal HF diet had a hypermethylated insulin receptor substrate 2 () gene and a hypomethylated mitogen-activated protein kinase kinase 4 () gene. Correspondingly, the expression of the gene decreased and that of increased in pups exposed to a maternal HF diet. Maternal overnutrition programs long-term epigenetic modifications, namely, and gene methylation in the offspring liver, which in turn predisposes the offspring to diabetes later in life. 10.3389/fendo.2019.00871

Real-World Experience of Adding Metformin in Pregnant Women with Type 1 Diabetes in a Chinese Population: A Retrospective Cohort. Ping Fan,Deng Mingqun,Zhai Xiao,Song Yingna,Xiao Xinhua Diabetes therapy : research, treatment and education of diabetes and related disorders INTRODUCTION:Glycemic control in pregnant women with type 1 diabetes (T1D) is challenging with only insulin, and the incidence rate of adverse perinatal outcomes is high. Increasing data have indicated the safety and effect of metformin in pregnancy; however, no relevant data are available in pregnant women with T1D. We aimed to investigate glycemic control and perinatal outcomes in pregnant women with T1D in a Chinese population and explored the role of metformin in these patients. METHODS:We obtained data of 38 pregnant women with T1D who received regular antenatal care and delivered at Peking Union Medical College Hospital (PUMCH) between 1 January 2006 and 31 May 2018. The perinatal outcomes of T1D patients who added metformin as adjunct treatment and those who remained on insulin-alone therapy were compared retrospectively. RESULTS:Being overweight was common (35.1%) in pregnant women with T1D. On average, the insulin dose increased by 35.30 ± 22.60 unit/day during pregnancy. The cesarean delivery rate was high (65.8%), and fetal macrosomia was the main reason. The change of HbA1c in the metformin-insulin group was more prominent than in the insulin-only group (- 1.47 ± 1.17% vs. - 0.90 ± 1.13%, p = 0.05). There was no statistically significant difference in perinatal outcomes between the two groups. CONCLUSIONS:The incidence of adverse perinatal outcomes in pregnant women with T1D was high. This study innovatively suggested that metformin could be safe and could contribute to improving glucose management in pregnant women with T1D. 10.1007/s13300-019-0618-2

Birthweight correlates with later metabolic abnormalities in Chinese patients with maturity-onset diabetes of the young type 2. Fu Junling,Wang Tong,Liu Jieying,Wang Xiaojing,Li Ming,Xiao Xinhua Endocrine PURPOSE:Glucokinase-maturity onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. The aim of this study is to investigate the relationship of birthweight and cardiometabolic characteristics in MODY2 patients. METHODS:Genetic screening for GCK mutations from 192 classical MODY families was performed, and birthweight and clinical profiles of 76 patients from 25 families with identified GCK mutations were collected. RESULTS:Mutations in GCK were identified in 25 (13%) of the 192 families. Four novel (c.1334 G > C, c.1289_1294delTGACGC, c.584 T > C, and c.30delC) and twenty-one previously reported mutations were identified and cosegregated with the clinical phenotypes of MODY2 within the pedigrees. MODY2 patients presented a mean birthweight of 3.11 ± 0.44 kg. Additionally, birthweight was negatively correlated with 2 h-postprandial glucose (r = -0.426, P = 0.006), glycated albumin (r = -0.462, P = 0.035), glycated hemoglobin (r = -0.529, P = 0.001), total cholesterol (r = -0.430, P = 0.016), and low-density lipoprotein cholesterol (LDL-C) (r = -0.383, P = 0.033) levels after adjustment for age, gender and BMI. Importantly, among the patients who inherited mutations from their mothers, 7 patients whose mothers were treated with insulin during pregnancy had particularly lower birthweight (2.83 ± 0.39 vs. 3.37 ± 0.39 kg; P = 0.003), higher total cholesterol (6.15 ± 0.43 vs. 4.06 ± 0.16 mmol/L; P = 0.002) and LDL-C (4.05 ± 0.35 vs. 2.21 ± 0.13 mmol/L; P = 0.001) levels compared to the other 21 patients whose mothers received no treatment. CONCLUSIONS:The correlations between birthweight and cardiometabolic indexes indicated that MODY2 patients with lower birthweight (<3.1 kg) should be monitored and treated more actively to prevent metabolic abnormalities, particularly dyslipidemia. Importantly, prenatal genic diagnosis is highly recommended to avoid inappropriate treatment in pregnancy leading to lower birthweight of offspring. 10.1007/s12020-019-01929-6

Maternal Genistein Intake Mitigates the Deleterious Effects of High-Fat Diet on Glucose and Lipid Metabolism and Modulates Gut Microbiota in Adult Life of Male Mice. Zhou Liyuan,Xiao Xinhua,Zhang Qian,Zheng Jia,Deng Mingqun Frontiers in physiology Adverse early-life exposures program increased risk of chronic metabolic diseases in adulthood. However, the effects of genistein supplementation in early life on metabolic health in later life are largely unclear. Our objective was to investigate whether maternal genistein intake could mitigate the deleterious influence of a maternal high-fat diet on glucose and lipid metabolism in offspring and to explore the role of gut microbiota in mediating the transgenerational effects. C57BL/6 female mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.6 /kg diet) (HFG) or normal control diet (C) for 3 weeks before pregnancy and throughout pregnancy and lactation. The male offspring had access to normal chow diet from weaning to 24 weeks of age. Then the content of inguinal subcutaneous adipose tissue (SAT) and epididymal visceral adipose tissue (VAT) were weighed. Glucose tolerance test (GTT), the level of serum insulin and lipid profiles were analyzed. The caecal contents were collected for 16S rDNA sequencing. The results showed that maternal genistein intake could significantly reduce blood glucose levels during GTT, fasting insulin levels, VAT mass and serum triglyceride levels as well as increase high-density lipoprotein cholesterol in adult male offspring. Significant decrease of germs from the Tenericutes phylum and enrichment of as well as SCFA (short-chain fatty acid)-producing bacteria, including , and , in offspring of genistein fed dams might play crucial roles in the improvement of glucose and lipid metabolism. Overall, early-life genistein intake attenuated the harmful effects of maternal HF on metabolism in adult offspring and the protective effects were associated with the alterations in gut microbiota, which provides new evidence and targets for mitigate the poor effects of adverse early-life exposures on metabolic health in later life. 10.3389/fphys.2019.00985

Maternal Inulin Supplementation Alters Hepatic DNA Methylation Profile and Improves Glucose Metabolism in Offspring Mice. Frontiers in physiology SCOPE:As a prebiotic, inulin may have a protective effect on glucose metabolism. However, the mechanism of inulin treatment on glucose intolerance in offspring exposed to a maternal high-fat (HF) diet is still not clear. Here, we examined the hepatic DNA methylation profile to determine how maternal inulin supplementation modified glucose metabolism in offspring mice. PROCEDURES:Female mice were fed a HF diet, control diet (CON), or a HF diet with inulin supplementation (HF-inulin) during gestation and lactation. Upon weaning, pup livers were obtained. A hepatic genome DNA methylation array was performed. RESULTS:Pups exposed to a maternal HF diet exhibited glucose intolerance and insulin resistance. Maternal inulin treatment moderated glucose metabolism. A DNA methylation array identified differentially methylated regions associated with 970 annotated genes from pups exposed to a HF diet in response to maternal inulin treatment. In particular, the wingless-type MMTV integration site family member 5A () gene was hypermethylated, and the phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (), phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (), and phosphoinositide-3-kinase regulatory subunit 2 () genes were hypomethylated in inulin-treated pups. Consistently, hepatic gene expression was reduced and , , and gene expression were increased in the inulin group. CONCLUSION:Maternal inulin treatment improved glucose intolerance by changing DNA methylation and gene expression of and in mice exposed to a maternal HF diet. 10.3389/fphys.2020.00070

"Gut Microbiota-Circadian Clock Axis" in Deciphering the Mechanism Linking Early-Life Nutritional Environment and Abnormal Glucose Metabolism. Zhou Liyuan,Kang Lin,Xiao Xinhua,Jia Lijing,Zhang Qian,Deng Mingqun International journal of endocrinology The prevalence of diabetes mellitus (DM) has been increasing dramatically worldwide, but the pathogenesis is still unknown. A growing amount of evidence suggests that an abnormal developmental environment in early life increases the risk of developing metabolic diseases in adult life, which is referred to as the "metabolic memory" and the Developmental Origins of Health and Disease (DOHaD) hypothesis. The mechanism of "metabolic memory" has become a hot topic in the field of DM worldwide and could be a key to understanding the pathogenesis of DM. In recent years, several large cohort studies have shown that shift workers have a higher risk of developing type 2 diabetes mellitus (T2DM) and worse control of blood glucose levels. Furthermore, a maternal high-fat diet could lead to metabolic disorders and abnormal expression of clock genes and clock-controlled genes in offspring. Thus, disorders of circadian rhythm might play a pivotal role in glucose metabolic disturbances, especially in terms of early adverse nutritional environments and the development of metabolic diseases in later life. In addition, as a peripheral clock, the gut microbiota has its own circadian rhythm that fluctuates with periodic feeding and has been widely recognized for its significant role in metabolism. In light of the important roles of the gut microbiota and circadian clock in metabolic health and their interconnected regulatory relationship, we propose that the "gut microbiota-circadian clock axis" might be a novel and crucial mechanism to decipher "metabolic memory." The "gut microbiota-circadian clock axis" is expected to facilitate the future development of a novel target for the prevention and intervention of diabetes during the early stage of life. 10.1155/2019/5893028

Identification of key genes and pathways in syphilis combined with diabetes: a bioinformatics study. Li Wei,Luo Chunyi,Xie Xiaoping,Xiao Yongjian,Zhao Feijun,Cai Jialun,Zhou Xiangping,Zeng Tiebing,Fu Bo,Wu Yimou,Xiao Xinhua,Liu Shuangquan AMB Express We noticed that syphilis patients seem to be more susceptible to diabetes and the lesions often involve the kidneys, but the pathogenesis is not yet completely understood. In this study, microarray analysis was performed to investigate the dysregulated expressed genes (DEGs) in rabbit model of syphilis combined with diabetes. A total of 1045 genes were identified to be significantly differentially expressed, among which 571 were up-regulated and 474 were down-regulated (≥ 2.0fold, p < 0.05). Using the database visualization and integration discovery for the Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis. The downregulated DEGs were significantly enriched for biosynthesis of antibiotics, carbon metabolism and protein digestion, while the upregulated DEGs were mainly enriched for cancer and PI3K-Akt signaling pathway. Molecular Complex Detection (MCODE) plugins were used to visualize protein-protein interaction (PPI) network of DEGs and Screening for hub genes and gene modules. ALB, FN1, CASP3, MMP9, IL8, CTGF, STAT3, IGF1, VCAM-1 and HGF were filtrated as the hub genes according to the degree of connectivity from the PPI network. To the best of our knowledge, this study is the first to comprehensively identify the expression patterns of dysregulated genes in syphilis combined with diabetes, providing a basis for revealing the underlying pathogenesis of syphilis combined with diabetes and exploring the goals of therapeutic intervention. 10.1186/s13568-020-01009-3

Interaction between early environment and genetic predisposition instigates the metabolically obese, normal weight phenotype in children: findings from the BCAMS study. European journal of endocrinology OBJECTIVE:A subset of normal-weight individuals appears predisposed to obesity-related cardiometabolic abnormalities. Studies of this metabolically obese, normal weight (MONW) phenotype in youth are scarce. We aimed to identify early environmental and genetic factors associated with MONW in children. METHODS:Overall, 1475 normal-weight Chinese children aged 6-18 were recruited from the Beijing Children and Adolescents Metabolic Syndrome study cohort. Birthweight, childhood lifestyle, socio-economic factors, and 20 genetic variants previously shown to be associated with BMI or glucose metabolism in East Asian adults were examined for their association with the MONW phenotype. MONW was defined by exhibiting any metabolic syndrome component. RESULTS:After adjusting for covariates including BMI, low birthweight and low levels of physical activity, fruit consumption, parental education and household income, as well as CDKAL1 rs2206734 genotype were independent predictors of the MONW phenotype (all P < 0.05). Moreover, rs2206734 interacted with birthweight to predict the MONW phenotype (Pinteraction = 0.0008). Among high (>75th percentile) birthweight individuals, each C allele at this locus was associated with a 62% reduced risk of MONW (OR = 0.38; 95% CI = 0.26-0.58; P = 5.71 × 10-6), while no such genetic associations were found in intermediate or low birthweight individuals (P > 0.1). This CDKAL1-MONW relationship in high birthweight individuals was especially strong in the presence of favorable childhood environmental factors (high levels of physical activity, fruit consumption, parental education and household income) (Pinteraction = 0.013). CONCLUSIONS:Our findings provided the novel evidence that early environment (especially birthweight) and genetics, along with their interaction with one another, play important roles in predicting the MONW phenotype among children. 10.1530/EJE-19-0755

Maternal sitagliptin treatment attenuates offspring glucose metabolism and intestinal proinflammatory cytokines IL-6 and TNF-α expression in male rats. Zhang Qian,Xiao Xinhua,Zheng Jia,Li Ming,Yu Miao,Ping Fan,Wang Tong,Wang Xiaojing PeerJ Increasing evidence shows that maternal overnutrition may increase the risk of diabetes in offspring. We hypothesized that maternal sitagliptin intervention may improve glucose intolerance through gut targeting. Female Sprague-Dawley (SD) rats were fed a normal diet (ND) or a high-fat diet (HFD) for 4 weeks before mating. ND pregnant rats were divided into two subgroups: ND group (ND alone) and the ND-sitagliptin group (ND combined with 10 mg/kg/day sitagliptin treatment). HFD pregnant rats were randomized to one of two groups: HFD group (HFD alone) and the HFD-sitagliptin group (HFD combined with 10 mg/kg/day sitagliptin treatment) during pregnancy and lactation. Glucose metabolism was assessed in offspring at weaning. Intestinal gene expression levels were investigated. Maternal sitagliptin intervention moderated glucose intolerance and insulin resistance in male pups. Moreover, maternal sitagliptin treatment inhibited offspring disordered intestinal expression of proinflammatory markers, including interleukin-6 (), , and tumor necrosis factor (), at weaning and reduced intestinal IL-6, TNF-α expression by immunohistochemical staining and serum IL-6, TNF-α levels. However, maternal sitagliptin intervention did not affect offspring serum anti-inflammatory cytokine IL-10 level. Our results are the first to show that maternal sitagliptin intervention moderated glucose metabolism in male offspring. It may be involved with moderating intestinal IL-6 and TNF-α expression in male rat offspring. 10.7717/peerj.10310

Maternal Exercise Improves High-Fat Diet-Induced Metabolic Abnormalities and Gut Microbiota Profiles in Mouse Dams and Offspring. Zhou Liyuan,Xiao Xinhua,Li Ming,Zhang Qian,Yu Miao,Zheng Jia,Deng Mingqun Frontiers in cellular and infection microbiology Early-life overnutrition programs increased risks of metabolic disorders in adulthood. Regular exercise has been widely accepted to be an effective measure to maintain metabolic health. However, the intergenerational effects of maternal exercise and the specific mechanism are largely unclear. Our objective was to investigate whether maternal exercise could alleviate the metabolic disturbances induced by early-life overnutrition in both dams and offspring and to explore the role of gut microbiota in mediating the effects. C57BL/6 female mice were randomly divided into three groups: the control group, which were fed a normal control diet; high-fat group, which received a high-fat diet; and high-fat with exercise intervention group, which was fed a high-fat diet and received a voluntary wheel running training. The diet intervention started from 3 weeks prior to mating and lasted throughout pregnancy and lactation. The exercise intervention was only prior to and during pregnancy. The male offspring got free access to normal chow diet from weaning to 24 weeks of age. Glucose tolerance test and biochemical parameters were detected in dams at weaning and offspring at 8 and 24 weeks of age. Their cecal contents were collected for the 16 s rDNA amplicon sequencing. The results showed that maternal high-fat diet resulted in significant glucose intolerance, insulin resistance, and lipid profiles disorders in both dams and offspring. Maternal exercise markedly improved insulin sensitivity in dams and metabolic disorders in offspring from young into adulthood. The decrease in unfavorable bacteria and the persistent enrichment of short-chain fatty acids-producers from mothers to adult offspring, particularly the genus , were all associated with the improvement of metabolism by maternal exercise. Overall, maternal exercise could significantly mitigate the detrimental effects of a maternal high-fat diet on metabolism in both dams and male offspring. The continuous alterations in gut microbiota might be a critical factor in deciphering the metabolic benefits of maternal exercise, which provides some novel evidence and targets for combating metabolic diseases. 10.3389/fcimb.2020.00292

Recombinant Treponema pallidum protein Tp0768 promotes proinflammatory cytokine secretion of macrophages through ER stress and ROS/NF-κB pathway. Applied microbiology and biotechnology In response to danger signals, macrophages rapidly produce many inflammatory cytokines that trigger the cascade release of inflammatory mediators, leading to tissue damage, which is an important cause of clinical manifestations of syphilis at all stages. However, we still know very little about the specific mechanism of this process. Tp0768 is an infection-stage-dependent antigen that plays an important role in the infection of Treponema pallidum. In this study, we demonstrated that Tp0768 stimulation of macrophages can cause IL-1β, IL-6, and IL-8 mRNA expression levels to increase in a dose- and time-dependent manner. Further research showed that Tp0768 activated ER stress and the ROS/NF-κB pathway in macrophages. Inhibition of ER stress and the ROS/NF-κB pathway inhibited the expression of IL-1β, IL-6, and IL-8 induced by Tp0768. In addition, pretreatment with a PERK pathway inhibitor significantly reduced the expression of the NF-κB and JNK pathways, while also downregulating the expression of IL-1β, IL-6, and IL-8. Tp0768 stimulation can activate IRE1α/XBP-1 signaling and participate in the induction of inflammatory cytokines through the JNK pathway. These findings indicate that Tp0768 promotes the secretion of proinflammatory cytokines IL-1β, IL-6, and IL-8 by macrophages through ER stress and the ROS/NF-κB pathway, which are also involved in the activation of the NF-κB and JNK pathways that are induced by the PERK pathway and activation of IRE1α/XBP-1 signaling. KEY POINTS: • This study found for the first time that the recombinant Treponema pallidum protein Tp0768 promotes the production of IL-1β, IL-6, and IL-8 by macrophages through ER stress. • Recombinant Treponema pallidum protein Tp0768 regulates the ROS/NF-κB pathway through ER stress. • ER stress-related pathway PERK induces the expression of IL-1β, IL-6, and IL-8 by activating the NF-κB pathway and the JNK pathway. • IRE1α can induce the splicing of XBP-1mRNA and activate the JNK pathway. 10.1007/s00253-020-11018-8

Mesenchymal stem cells modified by FGF21 and GLP1 ameliorate lipid metabolism while reducing blood glucose in type 2 diabetic mice. Xue Binghua,Xiao Xiuxiao,Yu Tingting,Xiao Xinhua,Xie Jing,Ji Qiuhe,Wang Li,Na Tao,Meng Shufang,Qian Lingjia,Duan Haifeng Stem cell research & therapy OBJECTIVE:The purpose of this study was to investigate the therapeutic effects of genetically modified mesenchymal stem cells (MSCs) in the treatment of type 2 diabetes mellitus (T2DM) in order to identify a new method for treating diabetes that differs from traditional medicine and to provide a new means by which to fundamentally improve or treat diabetes. METHODS:MSCs derived from adipose tissue were modified to overexpress FGF21 and GLP1, which was achieved through lentiviral particle transduction. The cells were transplanted into BKS.Cg-Dock7m+/+Leprdb/Nju mice (T2DM mouse model). Injections of physiological saline (0.1 mL) and liraglutide (0.5 mg/kg) were used as negative and positive controls, respectively. ELISA or Western blotting was used for protein analysis, and quantitative real-time PCR was used for gene expression analysis. RESULTS:Genetic modification had no effects on the morphology, differentiation ability, or immunophenotype of MSCs. Moreover, MSC-FGF21+GLP1 cells exhibited significantly increased secretion of FGF21 and GLP1. In the T2DM mouse model, the transplantation of MSC-FGF21+GLP1 cells ameliorated the changes in blood glucose and weight, promoted the secretion of insulin, enhanced the recovery of liver structures, and improved the profiles of lipids. Moreover, FGF21 and GLP1 exerted synergistic effects in the regulation of glucolipid metabolism by controlling the expression of insulin, srebp1, and srebp2. CONCLUSION:Stem cell treatment based on MSCs modified to overexpress the FGF21 and GLP1 genes is an effective approach for the treatment of T2DM. 10.1186/s13287-021-02205-z

Clinical characteristics of endocrinopathies in Chinese patients with hereditary haemochromatosis. Wu Han,Yu Miao,Xiao Cheng,Zhang Qian,Xiao Xinhua Diabetes/metabolism research and reviews AIMS:Hereditary haemochromatosis (HH) is a genetic disorder characterised by systemic iron overload and can lead to end-organ failure. However, very few data on this disorder, especially those on endocrine gland involvement in Chinese populations, are currently available. This study aimed to analyse the clinical features of endocrinopathies in patients with HH to generate concern among endocrinologists and improve the management of this disorder. MATERIALS AND METHODS:Chinese patients with HH-related endocrine dysfunction were enrolled at Peking Union Medical College Hospital from January 2010 to December 2018. All clinical data were analysed and summarised. RESULTS:A total of six patients were enrolled in this study, comprising five men and one woman; the average age was 36.5 ± 13.3 years. Mean serum ferritin concentration was 4508.8 ± 1074.3 ng/ml, and median transferrin saturation was 97.9% (96.6%-110.0%). Endocrine gland involvement associated with HH included the pancreas (5/6 patients), the adenohypophysis (5/6 patients) and the bones (1/6 patients); secondary endocrinopathies consisted of diabetes mellitus, hypogonadism, adrenal insufficiency and osteoporosis. Based on phlebotomy and iron chelation therapy, five patients were treated with exogenous insulin preparations, and three patients were treated with exogenous sex hormone replacement therapy. The clinical symptoms of five patients improved, although one patient died of hepatic encephalopathy and multiple organ failure. CONCLUSIONS:HH can cause multiple endocrinopathies. The possibility of HH should be carefully considered in patients with endocrine gland dysfunctions and concomitant elevated serum ferritin levels. Endocrine gland function should also be assessed and followed up in patients with a clear diagnosis of HH. 10.1002/dmrr.3448

[Effects of conditioned media for rat bone marrow-derived mesenchymal stem cells on palmitic acid-induced insulin resistance in HepG2 cells]. Sun Xiaoya,Hao Haojie,Han Weidong,Mu Yiming Zhonghua nei ke za zhi OBJECTIVE:To study the effect of conditioned media for rat bone marrow mesenchymal stem cells (BMSCs-CM) on palmitic acid (PA)-induced insulin resistance (IR) in HepG2 cells and its underlying molecular mechanisms. METHODS:HepG2 cells were treated with or without BMSCs-CM and L-DMEM in the presence or absence of PA.Glucose utilization in HepG2 cells were detected with PAS, glucose and glycogen measurements. Western blotting was used to assess the expression of phospho-insulin receptor substrate (p-IRS), phosphatidylinositol 3-kinase (PI3K) and p-AKT. RESULTS:(1) Incubation of HepG2 cells with 0.25 mmol/L PA for 24 hours significantly increased the glucose concentration and decreased the glycogen content (P<0.05) in the media. (2) Treatment with BMSCs-CM significantly ameliorated the glucose and glycogen alteration in cells pretreated with PA (P<0.05), however, no obvious effect of BMSCs-CM on the cell glucose and glycogen production. (3) BMSCs-CM treatment also increased protein expression of p-IRS, PI3K and p-AKT in PA incubated HapG2 cells (P<0.05). The effect of BMSCs-CM on PI3K and p-AKT expression could be mimicked upon addition of 740Y-P, a PI3K agonist, but abolished by LY294002, a PI3K specific inhibitor. CONCLUSIONS:BMSCs-CM could improve the insulin sensitivity in HepG2 cells pretreated with PA through upregulation of insulin signaling component expression.

Adipose-derived mesenchymal stem cells ameliorate hyperglycemia through regulating hepatic glucose metabolism in type 2 diabetic rats. Xie Min,Hao Hao Jie,Cheng Yu,Xie Zong Yan,Yin Ya Qi,Zhang Qi,Gao Jie Qing,Liu Hong Yu,Mu Yi Ming,Han Wei Dong Biochemical and biophysical research communications Infusion of mesenchymal stem cells (MSCs) has been identified in the rapid alleviation in hyperglycemia of diabetic individuals, but the mechanism involved has not been adequately explained by these cells' potential role in modulating system insulin sensitivity and islet regeneration. In this study, we demonstrated adipose-derived mesenchymal stem cells (ASCs) produced significantly lower blood glucose via promoting hepatic glycogen synthesis and inhibiting hepatic glucose production within 24 h after infusion in T2DM rats. In vitro, HepG2 cells treated with palmitate (PA) were used as a model of hepatic glucose metabolism disorder to confirm that ASCs stimulates the phosphorylation of hepatic AMP-activated protein kinase (AMPK) to restores hepatic glucose metabolism in type 2 diabetes. In summary, this study indicated that ASCs improve hyperglycemia via regulating hepatic glucose metabolism. Additionally, the effect of ASCs on hepatic glucose metabolism depended on the AMPK signaling pathway. Thus, this is the new research of the molecular mechanisms of MSCs administration to improve glucose metabolism, and it may indicate a new treatment target of MSCs in T2DM. 10.1016/j.bbrc.2016.12.125

M2 macrophages infusion ameliorates obesity and insulin resistance by remodeling inflammatory/macrophages' homeostasis in obese mice. Zhang Qi,Hao Haojie,Xie Zongyan,Cheng Yu,Yin Yaqi,Xie Min,Huang Hong,Gao Jieqing,Liu Hongyu,Tong Chuan,Zang Li,Mu Yiming,Han Weidong Molecular and cellular endocrinology OBJECTIVE:The role of M2 macrophages infusion in dealing with obesity is still little known. In this study, the therapeutic effects of M2 macrophages infusion were investigated. METHODS:High fat diet (HFD) was used to induce obesity in C57BL/6N mice. 5 × 10 M2 macrophages, derived from the bone marrow, were injected into obese mice through the tail vein twice with an interval of one week. RESULTS:One week after the second injection, weight of inguinal adipose pad was significantly decreased. Accordingly, the adipocyte size of epididymal and inguinal adipose tissue (EAT and INAT) shrank. To our interest, we found that the infused M2 macrophages were homed to EAT, reversing the disturbed homeostasis of high M1 to low M2 in obese mice. Meanwhile, EAT with remodeled macrophages' homeostasis expressed less MCP-1, accompanying with decreased recruitment of inflammatory CCR2CX3CR1Ly6C monocytes from the blood in M2 infusion group. Further, increased M2 in EAT contribute to enhanced expression of UCP1 expression in EAT, which helped to ameliorate insulin resistance and, subsequently, improve the serum level of triglycerides (TG) and low density lipoprotein cholesterol (LDL-c). CONCLUSIONS:These findings highlighted that M2 macrophages infusion could ameliorate obesity as well as obesity-related insulin resistance, suggesting an effective and healthy weight loss strategy. 10.1016/j.mce.2017.01.005

Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance by suppressing NLRP3 inflammasome-mediated inflammation in type 2 diabetes rats. Sun Xiaoya,Hao Haojie,Han Qingwang,Song Xiaoyan,Liu Jiejie,Dong Liang,Han Weidong,Mu Yiming Stem cell research & therapy BACKGROUND:Insulin resistance is one of the most common and important pathological features of type 2 diabetes (T2D). Recently, insulin resistance is increasingly considered to be associated with systemic chronic inflammation. Elevated levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in blood are predictive indicators of the development of T2D. Mesenchymal stem cell (MSC)-based therapies have been proven to have potential immunomodulation and anti-inflammatory properties through their paracrine effects; however, the mechanism for the anti-inflammatory effect of MSCs in enhancing insulin sensitivity is still uncertain. METHODS:In the present experiment, we used HepG2 cells, a human hepatoma cell line, and a MSC-HepG2 transwell culturing system to investigate the anti-inflammatory mechanism of human umbilical cord-derived MSCs (UC-MSCs) under palmitic acid (PA) and lipopolysaccharide (LPS)-induced insulin resistance in vitro. Insulin resistance was confirmed by glycogen assay kit and glucose assay kit. Inflammatory factor release was detected by ELISA, gene expression was tested by quantitative real-time PCR, and insulin signaling activation was determined by western blotting analysis. The changes of inflammatory factors and insulin signaling protein were also tested in T2D rats injected with UC-MSCs. RESULTS:Treating HepG2 cells with PA-LPS caused NLRP3 inflammation activation, including overexpression of NLRP3 and caspase-1, and overproduction of IL-1β and IL-18 as well as TNF-α from HepG2 cells. The elevated levels of these inflammatory cytokines impaired insulin receptor action and thereby prevented downstream signaling pathways, exacerbating insulin resistance in HepG2 cells. Importantly, UC-MSCs cocultured with HepG2 could effectively alleviate PA and LPS-induced insulin resistance by blocking the NLRP3 inflammasome activation and inflammatory agents. Furthermore, knockdown of NLRP3 or IL-1β partially improved PA and LPS-induced insulin signaling impairments in the presence of UC-MSCs. Similarly, UC-MSC infusion significantly ameliorated hyperglycemia in T2D rats and decreased inflammatory activity, which resulted in improved insulin sensitivity in insulin target tissues. CONCLUSIONS:Our results indicated that UC-MSCs could attenuate insulin resistance and this regulation was correlated with their anti-inflammatory activity. Thus, MSCs might become a novel therapeutic strategy for insulin resistance and T2D in the near future. 10.1186/s13287-017-0668-1

Human umbilical cord-derived mesenchymal stem cells direct macrophage polarization to alleviate pancreatic islets dysfunction in type 2 diabetic mice. Yin Yaqi,Hao Haojie,Cheng Yu,Zang Li,Liu Jiejie,Gao Jieqing,Xue Jing,Xie Zongyan,Zhang Qi,Han Weidong,Mu Yiming Cell death & disease Progressive pancreatic β-cell dysfunction is recognized as a fundamental pathology of type 2 diabetes (T2D). Recently, mesenchymal stem cells (MSCs) have been identified in protection of islets function in T2D individuals. However, the underlying mechanisms remain elusive. It is widely accepted that β-cell dysfunction is closely related to improper accumulation of macrophages in the islets, and a series of reports suggest that MSCs possess great immunomodulatory properties by which they could elicit macrophages into an anti-inflammatory M2 state. In this study, we induced a T2D mouse model with a combination of high-fat diet (HFD) and low-dose streptozotocin (STZ), and then performed human umbilical cord-derived MSCs (hUC-MSCs) infusion to investigate whether the effect of MSCs on islets protection was related to regulation on macrophages in pancreatic islets. hUC-MSCs infusion exerted anti-diabetic effects and significantly promoted islets recovery in T2D mice. Interestingly, pancreatic inflammation was remarkably suppressed, and local M1 macrophages were directed toward an anti-inflammatory M2-like state after hUC-MSC infusion. In vitro study also proved that hUC-MSCs inhibited the activation of the M1 phenotype and induced the generation of the M2 phenotype in isolated mouse bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs) and in THP-1 cells. Further analysis showed that M1-stimulated hUC-MSCs increased the secretion of interleukin (IL)-6, blocking which by small interfering RNA (siRNA) largely abrogated the hUC-MSCs effects on macrophages both in vitro and in vivo, resulting in dampened restoration of β-cell function and glucose homeostasis in T2D mice. In addition, MCP-1 was found to work in accordance with IL-6 in directing macrophage polarization from M1 to M2 state. These data may provide new clues for searching for the target of β-cell protection. Furthermore, hUC-MSCs may be a superior alternative in treating T2D for their macrophage polarization effects. 10.1038/s41419-018-0801-9

The homing of human umbilical cord-derived mesenchymal stem cells and the subsequent modulation of macrophage polarization in type 2 diabetic mice. Yin Yaqi,Hao Haojie,Cheng Yu,Gao Jieqing,Liu Jiejie,Xie Zongyan,Zhang Qi,Zang Li,Han Weidong,Mu Yiming International immunopharmacology Umbilical cord-derived mesenchymal stem cells (UC-MSCs), with both immunomodulatory and pro-regenerative properties, are promising for the treatment of type 2 diabetes mellitus (T2DM). As efficient cell therapy largely relies on appropriate homing to target tissues, knowing where and to what extent injected UC-MSCs have homed is critically important. However, bio-distribution data for UC-MSCs in T2DM subjects are extremely limited. Beneficial effects of UC-MSCs on T2DM subjects are associated with increased M2 macrophages, but no systemic evaluation of M2 macrophages has been performed in T2DM individuals. In this study, we treated T2DM mice with CM-Dil-labelled UC-MSCs. UC-MSC infusion not only exerted anti-diabetic effects but also alleviated dyslipidemia and improved liver function in T2DM mice. To compare UC-MSC migration between T2DM and normal subjects, a collection of normal mice also received UC-MSC transplantation. UC-MSCs homed to the lung, liver and spleen in both normal and T2DM recipients. Specifically, the spleen harbored the largest number of UC-MSCs. Unlike normal mice, a certain number of UC-MSCs also homed to pancreatic islets in T2DM mice, which suggested that UC-MSC homing may be closely related to tissue damage. Moreover, the number of M2 macrophages in the islets, liver, fat and muscle significantly increased after UC-MSC infusion, which implied a strong link between the increased M2 macrophages and the improved condition in T2DM mice. Additionally, an M2 macrophage increase was also observed in the spleen, suggesting that UC-MSCs might exert systemic effects in T2DM individuals by modulating macrophages in immune organs. 10.1016/j.intimp.2018.04.051

Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats. Yu Songyan,Cheng Yu,Zhang Linxi,Yin Yaqi,Xue Jing,Li Bing,Gong Zhengyuan,Gao Jieqing,Mu Yiming Stem cell research & therapy BACKGROUND:Long-term diabetes-associated complications are the major causes of morbidity and mortality in individuals with diabetes. These diabetic complications are closely linked to immune system activation along with chronic, non-resolving inflammation, but therapies to directly reverse these complications are still not available. Our previous study demonstrated that mesenchymal stem cells (MSCs) attenuated chronic inflammation in type 2 diabetes mellitus (T2DM), resulting in improved insulin sensitivity and islet function. Therefore, we speculated that MSCs might exert anti-inflammatory effects and promote the reversal of diabetes-induced kidney, liver, lung, heart, and lens diseases in T2DM rats. METHODS:We induced a long-term T2DM complication rat model by using a combination of a low dose of streptozotocin (STZ) with a high-fat diet (HFD) for 32 weeks. Adipose-derived mesenchymal stem cells (ADSCs) were systemically administered once a week for 24 weeks. Then, we investigated the role of ADSCs in modulating the progress of long-term diabetic complications. RESULTS:Multiple infusions of ADSCs attenuated chronic kidney disease (CKD), nonalcoholic steatohepatitis (NASH), lung fibrosis, and cataracts; improved cardiac function; and lowered serum lipid levels in T2DM rats. Moreover, the levels of inflammatory cytokines in the serum of each animal group revealed that ADSC infusions were able to not only inhibit pro-inflammatory cytokines IL-6, IL-1β, and TNF-α expression but also increase anti-inflammatory cytokine IL-10 systematically. Additionally, MSCs reduced the number of iNOS(+) M1 macrophages and restored the number of CD163(+) M2 macrophages. CONCLUSIONS:Multiple intravenous infusions of ADSCs produced significant protective effects against long-term T2DM complications by alleviating inflammation and promoting tissue repair. The present study suggests ADSCs may be a novel, alternative cell therapy for long-term diabetic complications. 10.1186/s13287-019-1474-8

Decitabine assists umbilical cord-derived mesenchymal stem cells in improving glucose homeostasis by modulating macrophage polarization in type 2 diabetic mice. Gao Jieqing,Cheng Yu,Hao Haojie,Yin Yaqi,Xue Jing,Zhang Qi,Li Lin,Liu Jiejie,Xie Zongyan,Yu Songyan,Li Bing,Han Weidong,Mu Yiming Stem cell research & therapy BACKGROUND:Mesenchymal stem cells (MSCs) have emerged as a promising therapy for type 2 diabetes (T2D). Mechanistic researches demonstrate that the anti-diabetic effect of MSCs is partially mediated by eliciting macrophages into an anti-inflammatory phenotype thus alleviating insulin resistance. However, single MSC infusion is insufficient to ameliorate sustained hyperglycemia or normalize blood glucose levels. In this study, we used decitabine (DAC), which is involved in the regulation of macrophage polarization, to test whether MSCs combined with decitabine can prolong and enhance the anti-diabetic effect in T2D mice. METHODS:High-fat diet (HFD) and streptozocin (STZ) were given to induce T2D mouse model. Successfully induced T2D mice were randomly divided into four groups: T2D group, MSC group, DAC group, and MSC + DAC group. Blood glucose was monitored, and glucose tolerance and insulin sensitivity were evaluated during the entire analysis period. Epididymal fat was extracted for analysis of macrophage phenotype and inflammation in adipose tissue. In vitro, we examined the effect of MSC + DAC on macrophage polarization in bone marrow-derived macrophages (BMDMs) and explore the possible mechanism. RESULTS:MSC infusion effectively improved insulin sensitivity and glucose homeostasis in T2D mice within 1 week, whereas combination therapy of MSCs + DAC extended the anti-diabetic effects of MSCs from 1 to 4 weeks (the end of the observation). Correspondingly, more M2 macrophages in adipose tissue were observed in the combination therapy group over the entire study period. In vitro, compared with the MSC group, MSCs combined with decitabine more effectively polarized M1 macrophages to M2 macrophages. Further analysis showed that the effect of MSC + DAC on macrophage polarization was largely abrogated by the peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662. CONCLUSIONS:Our data suggest that MSCs combined with decitabine can more effectively alleviate insulin resistance and prolong and enhance the anti-diabetic effect of MSCs in T2D mice in part by prompting M2 polarization in a PPARγ-dependent manner. Thus, decitabine may be an applicable addition to MSCs for diabetes therapy. UC-MSCs combined with decitabine activate the IL4R/STAT6/STAT3/PPARγ axis to further promote M2 macrophage polarization in adipose tissue, reduce inflammation, improve insulin sensitivity, and lead to better glucose metabolism and long-term hypoglycemic effects. 10.1186/s13287-019-1338-2

M1 macrophages accelerate renal glomerular endothelial cell senescence through reactive oxygen species accumulation in streptozotocin-induced diabetic mice. Yu Songyan,Cheng Yu,Li Bing,Xue Jing,Yin Yaqi,Gao Jieqing,Gong Zhengyuan,Wang Jie,Mu Yiming International immunopharmacology Cellular senescence is a fundamental aging mechanism leading to tissue dysfunction. Accumulation of senescent cells is observed in the context of diabetes, which plays an important role in the pathogenesis of diabetes and its complications. Macrophages, the most prevalent leucocytes found in diabetic kidney, have been implicated in the modulation of cellular senescence; however, their role and mechanism in cellular senescence of diabetic kidney have not been determined. In this study, we found trends of cellular senescence in the glomeruli of streptozotocin-induced diabetic mice. The onset of glomerular senescence was confirmed by increased SA-β-gal staining, the upregulation of p16INK4a, p21, and p53 protein levels and the increased expression of SASP RNA. The senescent cells in the glomeruli were mainly endothelial cells. We next confirmed that M1 macrophages accumulated in the glomeruli, occurred just shortly before glomerular senescence. Therefore, we examined whether M1 macrophage accumulation is associated with glomerular endothelial cell senescence. Thus, an in vitro co-culture model was established using human renal glomerular endothelial cells (HRGECs) and M1-polarized THP-1 macrophages. Indeed, M1 macrophages induced senescence in HRGECs. Furthermore, intracellular ROS levels and p38 MAPK signalling activation were significantly increased in HRGECs and reducing ROS generation significantly abolished M1 macrophage-mediated endothelial senescence and p38 MAPK activation, suggesting that M1 macrophage-mediated endothelial senescence is largely dependent on ROS. Thus, our results demonstrate that kidney M1 macrophage accumulation is in connection with endothelial cell senescence and strategy to modulate M1 macrophages accumulation is promising to be a new target for immunotherapy for diabetic kidney disease and other age-related diseases. 10.1016/j.intimp.2020.106294

Reversion of early- and late-stage β-cell dedifferentiation by human umbilical cord-derived mesenchymal stem cells in type 2 diabetic mice. Li Bing,Cheng Yu,Yin Yaqi,Xue Jing,Yu Songyan,Gao Jieqing,Liu Jiejie,Zang Li,Mu Yiming Cytotherapy BACKGROUND AIMS:The authors aimed to observe β-cell dedifferentiation in type 2 diabetes mellitus (T2DM) and investigate the reversal effect of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on early- and late-stage β-cell dedifferentiation. METHODS:In high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mice, the authors examined the predominant role of β-cell dedifferentiation over apoptosis in the development of T2DM and observed the reversion of β-cell dedifferentiation by UC-MSCs. Next, the authors used db/db mice to observe the progress of β-cell dedifferentiation from early to late stage, after which UC-MSC infusions of the same amount were performed in the early and late stages of dedifferentiation. Improvement in metabolic indices and restoration of β-cell dedifferentiation markers were examined. RESULTS:In HFD/STZ-induced T2DM mice, the proportion of β-cell dedifferentiation was much greater than that of apoptosis, demonstrating that β-cell dedifferentiation was the predominant contributor to T2DM. UC-MSC infusions significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In db/db mice, UC-MSC infusions in the early stage significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In the late stage, UC-MSC infusions mildly improved glucose homeostasis and partially reversed β-cell dedifferentiation. Combining with other studies, the authors found that the reversal effect of UC-MSCs on β-cell dedifferentiation relied on the simultaneous relief of glucose and lipid metabolic disorders. CONCLUSIONS:UC-MSC therapy is a promising strategy for reversing β-cell dedifferentiation in T2DM, and the reversal effect is greater in the early stage than in the late stage of β-cell dedifferentiation. 10.1016/j.jcyt.2021.01.005