Xirong Guo

Pre-Pregnancy Body Mass Index in Relation to Infant Birth Weight and Offspring Overweight/Obesity: A Systematic Review and Meta-Analysis

Background Overweight/obesity in women of childbearing age is a serious public-health problem. In China, the incidence of maternal overweight/obesity has been increasing. However, there is not a meta-analysis to determine if pre-pregnancy body mass index (BMI) is related to infant birth weight (BW) and offspring overweight/obesity. Methods Three electronic bibliographic databases (MEDLINE, EMBASE and CINAHL) were searched systematically from January 1970 to November 2012. The dichotomous data on pre-pregnancy overweight/obesity and BW or offspring overweight/obesity were extracted. Summary statistics (odds ratios, ORs) were used by Review Manager, version 5.1.7. Results After screening 665 citations from three electronic databases, we included 45 studies (most of high or medium quality). Compared with normal-weight mothers, pre-pregnancy underweight increased the risk of small for gestational age (SGA) (odds ratios [OR], 1.81; 95% confidence interval [CI], 1.76–1.87); low BW (OR, 1.47; 95% CI, 1.27–1.71). Pre-pregnancy overweight/obesity increased the risk of being large for gestational age (LGA) (OR, 1.53; 95% CI, 1.44–1.63; and OR, 2.08; 95% CI; 1.95–2.23), high BW (OR, 1.53; 95% CI, 1.44–1.63; and OR, 2.00; 95% CI; 1.84–2.18), macrosomia (OR, 1.67; 95% CI, 1.42–1.97; and OR, 3.23; 95% CI, 2.39–4.37), and subsequent offspring overweight/obesity (OR, 1.95; 95% CI, 1.77–2.13; and OR, 3.06; 95% CI, 2.68–3.49), respectively. Sensitivity analyses revealed that sample size, study method, quality grade of study, source of pre-pregnancy BMI or BW had a strong impact on the association between pre-pregnancy obesity and LGA. No significant evidence of publication bias was observed. Conclusions Pre-pregnancy underweight increases the risk of SGA and LBW; pre-pregnancy overweight/obesity increases the risk of LGA, HBW, macrosomia, and subsequent offspring overweight/obesity. A potential effect modification by maternal age, ethnicity, gestational weight gain, as well as the role of gestational diseases should be addressed in future studies.

Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes.

Hyperglycemia and high free fatty acids (FFAs) are two well-known characteristics of type 2 diabetes, and are also implicated in the etiology of insulin resistance. However, their roles in mitochondrial dysfunction of white adipocytes are not well-studied. In this study, we investigated the effects of high glucose (25 mM), high free fatty acids (FFAs, 1mM), or a combination of both high glucose+high FFAs on mitochondrial function in differentiated 3T3-L1 adipocytes after 48 h of treatment. We found that high glucose, high FFAs, or high glucose+high FFAs reduced insulin-stimulated glucose uptake in differentiated 3T3-L1 adipocytes. In addition, the mitochondria became smaller and more compact. Levels of the mitofusion protein mfn1 decreased and levels of the mitofission protein Drp1 increased as compared to controls. NRF1 was downregulated, and PGC-1 beta levels were diminished in the high glucose and high glucose+high FFAs conditions. Levels of PGC-1 alpha and mtTFA mRNA were greatly downregulated. No difference was found in the mitochondrial DNA (mtDNA) and intracellular ATP levels of treated cells compared to control cells. Cells treated with high glucose or high FFAs accumulated significant amounts of reactive oxygen species (ROS) and displayed a loss of the mitochondrial membrane potential. High glucose and high glucose+high FFAs led to similar decreases in intramitochondrial calcium concentration, although high FFAs had no effect. Therefore, high glucose and high FFAs can regulate insulin sensitivity, and mitochondrial dysfunction may occur in this process.

Trends in Overweight and Obesity among Children and Adolescents in China from 1981 to 2010: A Meta-Analysis

Background Overweight/obesity is a serious public health problem that affects a large part of the world population across all age and racial/ethnic groups. However, there has not been a meta-analysis of the prevalence of childhood and adolescent overweight/obesity in China during the past 30 years. Methods The China National Knowledge Infrastructure and Wanfang DATA, MEDLINE, EMBASE and Cumulative Index to Nursing and Allied Health Literature were searched for relevant studies published between January 1970 and June 2012. The prevalence of overweight/obesity over time was pooled using Stata/SE, version 9. Summary statistics (odds ratios, ORs) were used to compare sex-specific and urban-rural preponderance of overweight/obesity using Review Manager. Results After screening 1326 papers, we included 35 papers (41 studies), most of medium quality. The prevalence of overweight/obesity increased from 1.8% (95% confidence interval [CI], 0.4%–3.1%) and 0.4% (95% CI, −0.1% to −0.8%) respectively in 1981–1985 to 13.1% (95% CI, 11.2%–15.0%) and 7.5% (95% CI, 6.6%–8.4%) respectively in 2006–2010. The average annual increase was 8.3% and 12.4% respectively. Boys were more likely to be overweight/obese than girls (OR, 1.36; 95% CI, 1.24–1.49 and OR, 1.68; 95% CI, 1.52–1.86 respectively). The prevalence of overweight/obesity was higher in urban areas than in rural areas (OR, 1.66; 95% CI, 1.54–1.79 and OR, 1.97; 95% CI, 1.68–2.30 respectively). For age-specific subgroup analyses, both overweight and obesity increased more rapidly in the toddler stage than in other developmental stages. Sensitivity analyses showed that sample-size differences, study quality, overweight/obesity criteria and geographical distribution affected overweight/obesity prevalence. Conclusions Toddlers and urban boys were at particularly high risk; the prevalence in these groups increased more rapidly than in their counterparts. Public health prevention strategies are urgently needed to modify health behaviors of children and adolescents and control overweight/obesity in China.

Feeder-Free Derivation of Human Induced Pluripotent Stem Cells with Messenger RNA

The therapeutic promise of induced pluripotent stem cells (iPSCs) has spurred efforts to circumvent genome alteration when reprogramming somatic cells to pluripotency. Approaches based on episomal DNA, Sendai virus, and messenger RNA (mRNA) can generate “footprint-free” iPSCs with efficiencies equaling or surpassing those attained with integrating viral vectors. The mRNA method uniquely affords unprecedented control over reprogramming factor (RF) expression while obviating a cleanup phase to purge residual traces of vector. Currently, mRNA-based reprogramming is relatively laborious due to the need to transfect daily for ~2 weeks to induce pluripotency, and requires the use of feeder cells that add complexity and variability to the procedure while introducing a route for contamination with non-human-derived biological material. We accelerated the mRNA reprogramming process through stepwise optimization of the RF cocktail and leveraged these kinetic gains to establish a feeder-free, xeno-free protocol which slashes the time, cost and effort involved in iPSC derivation.

Genetic Polymorphisms in Adipokine Genes and the Risk of Obesity: A Systematic Review and Meta‐Analysis

Polymorphisms in adipokine genes, such as leptin (LEP), leptin receptor (LEPR), resistin (RETN), adiponectin (ADIPOQ), interleukin‐1β (IL‐1β), IL‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) may be involved in the development of obesity. We conducted a systematic review of published evidence on the association between different adipokine genes and the risk of obesity. Librarian‐designed searches of PubMed and HuGeNet, review of reference lists from published reviews and content expert advice identified potentially eligible studies. The genotyping information and polymorphisms of different adipokine genes, numbers of genotyped cases and controls and frequencies of genotypes were extracted from 48 eligible studies included in this review. Twenty‐one polymorphisms each associated with obesity in at least one study were identified. Polymorphisms in the adipokine genes, LEP, LEPR, and RETN were not associated with obesity susceptibility, whereas ADIPOQ G276T (T vs. G: odds ratio (OR), 1.59; 95% confidence interval (CI), 1.39–1.81), IL‐1β C3953T (CC vs. CT+TT: OR, 1.61; 95% CI, 1.18–2.20), and TNF‐α G308A (GG vs. GA+AA: OR, 1.19; 95% CI, 1.02–1.39) polymorphisms were associated with an increased risk of obesity. The IL‐6 G174C polymorphism was also associated obesity when using allelic comparisons, the recessive genetic model and the dominant genetic model with OR (95% CI) of 1.95 (1.37–2.77), 1.44 (1.15–1.80), and 1.36 (1.16–1.59), respectively. No significant evidence of publication bias was present. However, these “null” results were underpowered due to a small pooled sample size, and analysis of additional case‐control studies with larger sample sizes should provide further clarifications.

TNF-α induces mitochondrial dysfunction in 3T3-L1 adipocytes

TNF-alpha was the first proinflammatory cytokine identified linking obesity, insulin resistance and chronic inflammation. However, the mechanism of TNF-alpha in the etiology of insulin resistance is still far from clear. Because the mitochondria play an important role in energy metabolism, we investigated whether mitochondrial dysfunction is involved in pathogenesis of TNF-alpha-mediated insulin resistance. First, a fully differentiated insulin-resistant 3T3-L1 adipocyte model was established by incubating with 4 ng/ml TNF-alpha for 4 d, and then the mitochondrial morphology and functions were observed. TNF-alpha treatment induced pronounced morphological changes in the mitochondria, which became smaller and condensed, and some appeared hollow and absent of cristae. Mitochondrial dynamics changes were observed as increased mitofusion protein mfn1 and mitofission protein Drp1 levels compared with controls. No obvious effects on mitochondrial biogenesis were found. PGC-1alpha levels decreased, but no significant changes were found in mtTFA mRNA expression, NRF1mRNA expression and mitochondrial DNA (mtDNA). TNFalpha treatment also led to decreased mitochondrial membrane potential and reduced production of intracellular ATP, as well as accumulation of significant amounts of reactive oxygen species (ROS). Further research is required to determine if mitochondrial dysfunction is involved in the inflammatory mechanism of insulin resistance and may be a potential target for the treatment of insulin resistance.

The role of microRNA-26b in human adipocyte differentiation and proliferation

Recent findings indicate that microRNAs (miRNAs) are involved in the regulatory network of adipogenesis and obesity. Thus far, only a few human miRNAs are known to function as adipogenic regulators, fanning interest in studies on the functional role of miRNAs during adipogenesis in humans. In a previous study, we used a microarray to assess miRNA expression during human preadipocyte differentiation. We found that expression of the miR-26b was increased in mature adipocytes. MiR-26b is an intronic miRNA located in the intron of CTDSP1 (carboxy terminal domain, RNA polymerase II, polypeptide A, small phosphatase 1). Target prediction and Renilla luciferase analyses revealed the phosphatase and tensin homolog gene (PTEN) as a putative target gene. In this study, we found that miR-26b was gradually upregulated during adipocyte differentiation. To understand the roles of miR-26b in adipogenesis, we adopted a loss-of-function approach to silence miR-26b stably in human preadipocytes. We found that miR-26b inhibition effectively suppressed adipocyte differentiation, as evidenced by decreased lipid droplets and the ability of miR-26b to decrease mRNA levels of adipocyte-specific molecular markers and triglyceride accumulation. Furthermore, the cell growth assay revealed that miR-26b inhibition promoted proliferation. Nevertheless, it had no effect on apoptosis. Taken together, these data indicate that miR-26b may be involved in adipogenesis and could be targeted for therapeutic intervention in obesity.

IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytes

Interleukin-6 (IL-6) has emerged as an important cytokine involved in the regulation of metabolism. However, the role of IL-6 in the etiology of obesity and insulin resistance is not fully understood. Mitochondria are key organelles of energy metabolism, and there is growing evidence that mitochondrial dysfunction plays a crucial role in the pathogenesis of obesity-associated insulin resistance. In this study, we determined the direct effect of IL-6 on lipolysis in adipocytes, and the effects of IL-6 on mitochondrial function were investigated. We found that cells treated with IL-6 displayed fewer lipids and an elevated glycerol release rate. Further, IL-6 treatment led to decreased mitochondrial membrane potential, decreased cellular ATP production, and increased intracellular ROS levels. The mitochondria in IL-6-treated cells became swollen and hollow with reduced or missing cristae. However, insulin-stimulated glucose transport was unaltered. PGC-1α, NRF1, and mtTFA mRNA levels were markedly increased, and the mitochondrial contents were also increased. Our results demonstrate that IL-6 can exert a direct lipolytic effect and induce mitochondrial dysfunction. However, IL-6 did not affect insulin sensitivity in adipocytes in vitro. We deduce that in these cells, enhanced mitochondrial biogenesis might play a compensatory role in glucose transport.

The accuracy of the procalcitonin test for the diagnosis of neonatal sepsis: A meta-analysis

Abstract A meta-analysis was performed to assess the accuracy of the procalcitonin (PCT) test for diagnosing neonatal sepsis. The major databases, MEDLINE, EMBASE and the Cochrane Library were searched for studies published between January 1996 and May 2009 that evaluated PCT as a diagnostic marker for neonatal sepsis and provided sufficient data to calculate sensitivity and specificity. Twenty-two studies were included in the analysis. Trials that evaluated the PCT test for the diagnosis of early-onset neonatal sepsis at different time points (birth, 0–12 h, 12–24 h, and 24–48 h) and late-onset neonatal sepsis (LONS) all showed moderate accuracy (Q* = 0.79, 0.86, 0.81, 0.82, and 0.77, respectively). The PCT test was more accurate than the C-reactive protein (CRP) test for the diagnosis of LONS. A sensitivity analysis found that differences in PCT assay producer, gestational age and severity of sepsis in the study population may partially explain the between-studies heterogeneity. The PCT test showed moderate accuracy in diagnosing neonatal sepsis, regardless of differences in diagnostic criteria and time points for testing. For the diagnosis of LONS, the PCT test showed better accuracy than the CRP test. PCT is a valuable additional tool for the diagnosis of neonatal sepsis.

miR-148a is Associated with Obesity and Modulates Adipocyte Differentiation of Mesenchymal Stem Cells through Wnt Signaling

Obesity results from numerous, interacting genetic, behavioral, and physiological factors. Adipogenesis is partially regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that regulate proliferation and differentiation of human adipose-derived mesenchymal stem cells (hMSCs-Ad). In this study, we examined the roles of adipocyte-selective miRNAs in the differentiation of hMSCs-Ad to adipocytes. Results showed that the levels of miR-148a, miR-26b, miR-30, and miR-199a increased in differentiating hMSCs-Ad. Among these miRNAs, miR-148a exhibited significant effects on increasing PPRE luciferase activity (it represents PPAR-dependent transcription, a major factor in adipogenesis) than others. Furthermore, miR-148a expression levels increased in adipose tissues from obese people and mice fed high-fat diet. miR-148a acted by suppressing its target gene, Wnt1, an endogenous inhibitor of adipogenesis. Ectopic expression of miR-148a accelerated differentiation and partially rescued Wnt1-mediated inhibition of adipogenesis. Knockdown of miR-148a also inhibited adipogenesis. Analysis of the upstream region of miR-148a locus identified a 3 kb region containing a functional cAMP-response element-binding protein (CREB) required for miR-148a expression in hMSCs-Ad. The results suggest that miR-148a is a biomarker of obesity in human subjects and mouse model, which represents a CREB-modulated miRNA that acts to repress Wnt1, thereby promoting adipocyte differentiation.