Full-Length Transcriptome Analysis of the Ichthyotoxic Harmful Alga Heterosigma akashiwo (Raphidophyceae) Using Single-Molecule Real-Time Sequencing.

The raphidophyte Heterosigma akashiwo is a harmful algal species. The bloom of this organism has been associated with the massive mortality of fish in many coastal waters. To investigate the molecular mechanism of H. akashiwo blooms, having a reliable reference transcriptome of this species is essential. Therefore, in this study, a full-length transcriptome of H. akashiwo was obtained by single-molecule real-time sequencing. In total, 45.44 Gb subread bases were generated, and 16,668 unigenes were obtained after the sequencing data processing. A total of 8666 (52.00%) unigenes were successfully annotated using seven public databases. Among them, mostly phosphorus and nitrogen metabolism genes were detected. Moreover, there were 300 putative transcription factors, 4392 putative long non-coding RNAs, and 7851 simple sequence repeats predicted. This study provides a valuable reference transcriptome for understanding how H. akashiwo blooms at a molecular level.

Deficiency of lipopolysaccharide binding protein facilitates adipose browning, glucose uptake and oxygen consumption in mouse embryonic fibroblasts via activating PI3K/Akt/mTOR pathway and inhibiting autophagy.

This study aimed to explore the role of lipopolysaccharide-binding protein (LBP) in adipose browning. Mouse embryonic fibroblasts (MEFs) were treated with differentiation induction reagents and Perifosine (Akt inhibitor), with the transfection of Atg5, short hairpin RNA targeting LBP (shLBP), and Atg5 (shAtg5). The expression levels of LBP, inflammatory markers , brown fat markers, lipid metabolism marker, autophagy markers, insulin signaling-related molecules , p-mTOR, mTOR, p-Akt, Akt, p-PI3K, and PI3K were quantified or determined by Western blot, qRT-PCR, and immunofluorescence assay. The formation of lipid was examined through Oil red O staining assay. The consumption of oxygen was assessed using a Seahorse XF96 analyzer, and the uptake of glucose was evaluated by [3H]-2-deoxy-D-glucose uptake assay. Deficiency of LBP promoted adipose browning, oxygen consumption, glucose uptake, and insulin sensitivity in differentiated MEFs, where it inhibited inflammation and autophagy. All of the effects above were reversed by Atg5 overexpression. Meanwhile, the knockdown of Atg5 strengthened the activation of PI3K/Akt/mTOR pathway induced by the depletion of LBP, while Perifosine partly reversed the activation of differentiated MEFs. The knockdown of LBP facilitated adipose browning, glucose uptake, and oxygen consumption in MEFs via the activation of PI3K/Akt/mTOR pathway and the inhibition of autophagy.

Transcriptomic response of the harmful algae Heterosigma akashiwo to polyphosphate utilization and phosphate stress.

Phosphorus (P) is one of the major macronutrients necessary for phytoplankton growth. In some parts of the ocean, however, P is frequently scarce, hence, there is limited phytoplankton growth. To cope with P deficiency, phytoplankton evolved a variety of strategies, including, utilization of different P sources. Polyphosphate (polyP) is ubiquitously present and serves an essential function in aquatic environments, but it is unclear if and how this polymer is utilized by phytoplankton. Here, we examined the physiological and molecular responses of the widely present harmful algal bloom (HAB) species, Heterosigma akashiwo in polyP utilization, and in coping with P-deficiency. Our results revealed that two forms of inorganic polyP, namely, sodium tripolyphosphate and sodium hexametaphosphate, support H. akashiwo growth as efficiently as orthophosphate. However, few genes involved in polyP utilization have been identified. Under P-deficient conditions, genes associated with P transport, dissolved organic P utilization, sulfolipid synthesis, and energy production, were markedly elevated. In summary, our results indicate that polyP is bioavailable to H. akashiwo, and this HAB species have evolved a comprehensive strategy to cope with P deficiency.

Association of continuous glucose monitoring-derived time in range with major amputation risk in diabetic foot osteomyelitis patients undergoing amputation.

Objective: The metrics generated from continuous glucose monitoring (CGM), such as time in range (TIR), are strongly correlated with diabetes complications. This study explored the association of perioperative CGM-derived metrics with major amputation risk in patients with diabetic foot osteomyelitis (DFO). Methods: This study recruited 55 DFO patients with grade 3-4 wounds according to the Wagner Diabetic Foot Ulcer Classification System, all of whom underwent CGM for 5 days during the perioperative period. The CGM-derived metrics were defined in accordance with the most recent international consensus recommendations. Results: Patients with major amputation had significantly less TIR and higher time below range (TBR) (all p < 0.05). In binary logistic regression analyses, a lower TIR was associated with the risk of major amputation (odds ratio: 0.83 (95% confidence interval: 0.71-0.99), p = 0.039). This association remained statistically significant after adjustments for age, sex, body mass index, type of diabetes, smoking, drinking, durations of diabetes and DFU, ankle-brachial index, albumin, estimated-glomerular filtration rate, Society for Vascular Surgery wound, ischemia, and foot infection (WIfi) stage, multidrug-resistant organisms, and hemoglobin A1c. Further adjustment for the mean amplitude of glycemic excursion (MAGE) reduced this association. TBR was also independently associated with the risk of major amputation (odds ratio: 1.60 (95% confidence interval: 1.17-2.18), p = 0.003); this association persisted after adjustment for MAGE. Conclusion: Perioperative TIR (3.9-10.0 mmol/L) and TBR (<3.9 mmol/L) were significantly associated with major amputation in hospitalized patients with DFO.

Identification of the Key Pathways and Genes in Hypoxia Pulmonary Arterial Hypertension Following Intrauterine Growth Retardation.

High-throughput sequencing and weighted gene co-expression network analysis (WGCNA) were used to identify susceptibility modules and genes in liver tissue for the hypoxic pulmonary arterial hypertension (PAH) animal model following intrauterine growth retardation (IUGR). A total of 5,000 genes were clustered into eight co-expression modules via WGCNA. Module blue was mostly significantly correlated with the IUGR-hypoxia group. Gene Ontology analysis showed that genes in the module blue were mainly enriched in the fatty acid metabolic process, lipid modification, and fatty acid catabolic process. The Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the genes in module blue were mainly associated with fatty acid metabolism, PPAR signaling pathway, and biosynthesis of unsaturated fatty acids. In addition, the maximal clique centrality method was used to identify the hub genes in the subnetworks, and the obtained results were verified using real-time quantitative PCR. Finally, we identified that four genes including Cyp2f4, Lipc, Acadl, and Hacl1 were significantly associated with IUGR-hypoxia. Our study identified a module and several key genes that acted as essential components in the etiology of the long-term metabolic consequences in hypoxia PAH following IUGR.

Isolation and characterization of a high-efficiency algicidal bacterium Pseudoalteromonas sp. LD-B6 against the harmful dinoflagellate Noctiluca scintillans.

The dinoflagellate Noctiluca scintillans is a harmful algal species that is globally distributed and poses a certain threat to marine ecosystems. Recent research has shown that the application of algicidal bacteria is a promising method to prevent and control such harmful algal blooms (HABs), given its advantages of safety and efficiency. In this study, a strain of algicidal bacterium LD-B6 with high efficiency against N. scintillans was isolated from the coastal waters of Lianyungang, China. 16S rDNA sequence analysis showed that the strain LD-B6 belongs to the genus Pseudoalteromonas. Furthermore, the algicidal effect of LD-B6 on N. scintillans was investigated. The results showed that strain LD-B6 exerted strong algicidal activity against N. scintillans. After 12 h of bacterial culture addition to algal cultures at a 2% final volume rate, the algicidal activity reached 90.5%, and the algicidal activity of LD-B6 was influenced by the density of N. scintillans. In addition, the algicidal bacterium LD-B6 was found to indirectly lyse algal cells by secreting extracellular compounds. These algicidal compounds were stable, indicating that they are not proteins. Importantly, strain LD-B6 was broadly general, showing varying degrees of lysing effects against five of the six algal species tested. On the basis of the described studies above, the algicidal powder was also initially developed. In summary, the isolated bacterial strain LD-B6 shows the potent algicidal capability to serve as a candidate algicidal bacterium against N. scintillans blooms.

A Prediction Model for Prediabetes Risk in Middle-Aged and Elderly Populations: A Prospective Cohort Study in China.

BACKGROUND: To investigate indicators for prediabetes risk and construct a prediction model for prediabetes incidences in China. METHODS: In this study, 551 adults aged 40-70 years had normal glucose tolerance (NGT) and normal hemoglobin A1c (HbA1c) levels at baseline. Baseline data including demographic information, anthropometric measurements, and metabolic profile measurements were collected. The associations between possible indicators and prediabetes were assessed by the Cox proportional-hazards model. The predictive values were evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: During an average of 3.35 years of follow-up, the incidence of prediabetes was found to be 19.96% (n = 110). In the univariate analyses, fasting plasma glucose (FPG), fasting serum insulin (FINS), 2 h plasma glucose (2hPG), HbA1c, serum uric acid (SUA), waist circumference (WC), smoking, and family history of diabetes (FHD) were found to be significantly correlated with prediabetes. In the multivariable analyses, WC (hazard ratio (HR): 1.032; 95% confidence interval (CI): 1.010, 1.053; p = 0.003), FHD (HR: 1.824; 95% CI: 1.250, 2.661; p = 0.002), HbA1c (HR: 1.825; 95% CI: 1.227, 2.714; p = 0.003), and FPG (HR: 2.284; 95% CI: 1.556, 3.352; p < 0.001) were found to be independent risk factors for prediabetes. A model that encompassed WC, FHD, HbA1c, and FPG for predicting prediabetes exhibited the largest discriminative ability (AUC: 0.702). CONCLUSIONS: WC, FHD, HbA1c, and FPG are independently correlated with the risk of prediabetes. Furthermore, the combination of these predictors enhances the predictive accuracy of prediabetes.

Maternal undernutrition modulates hepatic MicroRNAs expression in the early life of offspring.

Emerging studies revealed that a poor intrauterine environment elicited by maternal nutrient restriction (MNR) is associated with an increased risk of metabolic diseases in adulthood. Previous research has shown that microRNAs (miRNAs) exert pivotal roles in modulating molecular pathways involved in disease pathogenesis and progression. In this respect, we herein examined miRNA profiles in samples of liver from offspring whose mothers were fed either with a 50% food-restricted diet or standard laboratory chow during pregnancy. Our findings enumerated that miR-181a, involved in lipid metabolism, was found to be downregulated in the liver of MNR offspring at 1 day of age when compared to that of control offspring. We also noted that overexpression of miR-181a reduced the lipid droplets after treatment with oleic acid for 48 h, which suppressed the expressions levels of SIRT1, FOXO1, KLF6 and PPARγ in BRL-3A cells, while the opposite results were observed with decreased expression of miR-181a. Furthermore, the luciferase reporter assay confirmed the direct interactions between miR-181a with KLF6 and SIRT1. In adults, the MNR offspring elucidated increased TG content, decreased expression of miR-181a, and increased expressions levels of SIRT1, FOXO1, KLF6, and PPARγ in liver tissues. Collectively, these findings provided novel evidence that MNR could regulate miRNAs expression, which might be related to lipid metabolism in MNR offspring.

Metabolic Syndrome and Its Components Are Associated With Altered Amino Acid Profile in Chinese Han Population.

Objective: Recent studies have found that the levels of plasma amino acids, such as branched-chain amino acids and aromatic amino acids, were associated with visceral obesity, insulin resistance, future development of diabetes and cardiovascular diseases. However, few studies have involved a Chinese Han population. This study aimed to examine the association between amino acid profile and metabolic syndrome (MetS) and its components in the Chinese Han population. Methods: This is a cross-sectional study, which enrolled a cohort of 473 participants from a community. We employed the isotope internal standard method to determine the plasma concentrations of 28 amino acids using high-performance liquid chromatography-tandem mass spectrometry (LC/MS). Participants were divided into MetS (n = 72) and non-MetS groups (n = 401) to analyze the association between amino acids and MetS and its components. Results: The prevalence of MetS was 15.2% according to the criteria. Plasma concentrations of isoleucine (Ile), leucine (Leu), valine (Val), tyrosine (Tyr), tryptophan (Trp), phenylalanine (Phe), glutamic acid (Glu), aspartic acid (Asp), alanine (Ala), histidine (His), methionine (Met), asparagine (Asn), and proline (Pro) were significantly higher in the MetS group than those in the non-MetS group (P < 0.05), but taurine (Tau) was significantly lower (P < 0.05). When MetS components were increased, the concentrations of these 13 amino acids significantly increased (P < 0.05), but Tau concentration was significantly decreased (P < 0.05). We extracted the amino acid profile by principal component analysis (PCA), PC1 and PC2, which extracted from the 14 amino acids, were significantly associated with MetS (odds ratio, 95% confidence interval: 1.723, 1.325-2.085 and 1.325, 1.043-1.684, respectively). A total of 260 non-MetS participants were followed up effectively, and 42 participants developed new-onset MetS within 5 years. We found that the amino acid profile of PC1 was linked to the occurrence of future MetS. Decreased Tau was correlated with the future development of MetS. Conclusion: Participants with MetS exhibit an abnormal amino acid profile, and its components gradually increase when these amino acids are altered. Amino acid PCA profile can be employed for assessing and monitoring MetS risk. Finally, decreased Tau may be linked to the future development of MetS.

LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1.

BACKGROUND: Skeletal muscle is essential for glucose and lipid metabolism. Growing evidence reveals the importance of long non-coding RNAs (LncRNAs) in metabolism. This study aimed to investigate the function of LncRNA H19 (H19) in lipid metabolism of skeletal muscle and its potential mechanisms. METHODS: Glucose tolerance, serum insulin and lipid content in serum and skeletal muscle were determined in control and H19-overexpressed db/db mice. Lipid metabolism was evaluated in H19-overexpressed or H19-silencing muscle cells by detecting lipid contents and mitochondria related functions. The underlying mechanisms were explored by RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP). RESULTS: H19 was downregulated in skeletal muscle of db/db mice. H19 overexpression in db/db mice inhibited lipid ectopic deposition in skeletal muscle, meanwhile improved glucose intolerance and insulin resistance as compared with control db/db mice treated with ad-GFP. Furthermore, overexpression of H19 reversed FFA-induced lipid accumulation and increased cellular respiration in muscle cells, while H19 knockdown exhibited opposite effects in muscle cells. Mechanistically, H19 interacted with heterogeneous nuclear ribonucleoprotein (hnRNPA1) which was validated by RNA pulldown and RIP analysis, which increased translation of fatty acid oxidation closely related genes PGC1a and CPT1b. CONCLUSION: Our data suggest that overexpression of H19 ameliorates insulin resistance by reducing ectopic lipid accumulation in skeletal muscle. The possible underlying mechanisms are that overexpression of lncRNAH19 promotes fatty acids oxidation via targeting of hnRNPA1. Video abstract.

Association of dietary patterns with the newly diagnosed diabetes mellitus and central obesity: a community based cross-sectional study.

AIM: The purpose of this study was to investigate the association of dietary patterns with the risk of insulin resistance (IR), diabetes mellitus (DM), and central obesity in China. METHODS: We performed a cross-sectional study on 1432 participants, aged 40-65 years in Hangzhou, Zhejiang province, China. Dietary intake was assessed using a semi-quantitative food frequency questionnaire. RESULTS: Factor analysis extracted four major dietary patterns: vegetable-fruits, rice-meat, seafood-eggs, and sweet-fast. The vegetable-fruits pattern was inversely associated with HOMA-IR (p < 0.001 in both genders), while sweet-fast food pattern was significantly associated with higher HOMA-IR (p = 0.002 in male, and p < 0.001 in female). The vegetables-fruits pattern was inversely correlated with visceral fat area (VFA) (p = 0.029 in males, and p = 0.017 in females), while sweet-fast food pattern presented a significant direct association (p < 0.001 in male) with VFA in males. There was no association observed between the rice-meat pattern or the seafood-eggs pattern and HOMA-IR or VFA. After adjustment for potential confounding factors, participants in the highest tertile of vegetable-fruits pattern showed a significantly lower risk of DM in both males and females (OR: 0.30, 95% CI: 0.13-0.70 in male, and OR: 0.28, 95% CI: 0.11-0.72 in female), and lower risk of central obesity was observed in males (OR: 0.50, 95% CI: 0.29-0.86 in male). Conversely, participants in the highest tertile of sweet-fast food pattern had higher risk of DM (OR: 2.58, 95% CI: 1.23-5.88 in male), and central obesity (OR: 2.85, 95% CI: 1.67-4.86 in male) only in male. While neither the rice-meat pattern nor the seafood-eggs pattern showed significant association with DM or central obesity in both genders. CONCLUSIONS: Our findings indicated low risk of IR, DM, and central obesity with vegetable-fruits pattern while inverse relation with sweet-fast food pattern.

Socioeconomic status is associated with global diabetes prevalence.

The incidence of diabetes is increasing globally. We investigated the relationship between diabetes prevalence and patient socioeconomic status across multiple countries. We searched PubMed to identify population-based surveys reporting diabetes prevalence between 1990 and May 2016. Search results were filtered, and Human Development Index (HDI) values from the United Nations Development Programme were used to assess socioeconomic status for a given nation. Our analysis included 45 national surveys from 32 countries. Diabetes prevalence was positively correlated with national HDI (r = 0.421 P = 0.041) in developing countries, and negatively correlated with HDI (r = -0.442 P = 0.045) in developed countries. Diabetes prevalence trends were the same in women and men, although men were associated with increased diabetes risk in developed countries (r = 0.459 P = 0.048). Thus, diabetes prevalence rises with increasing HDI in developing countries, and this is reversed in developed countries. Ours is the first study to investigate the relationship between diabetes and socioeconomic status at global level using HDI values. These results will aid in evaluating global diabetes prevalence and risk with respect to patient socioeconomic status, and will be useful in the development of policies that help reduce disease incidence.

Association of PI3K/AKT/mTOR pathway genetic variants with type 2 diabetes mellitus in Chinese.

AIMS: Genetic variations in the PI3K/AKT/mTOR signaling pathway may be associated with an increasing risk of obesity and diabetes. In this study, we aimed to test whether polymorphisms in the PIK3CA (catalytic subunit of PI3K), AKT1, AKT2, and FRAP1 (mTOR) genes were associated with the risk of type 2 diabetes mellitus (T2DM) among Chinese population. METHODS: A case-control study was conducted and included 248 cases with T2DM and 101 controls. A total of 28 tagSNPs from the 4 genes were chosen based on HapMap datasets and these were genotyped using a MassARRAY Compact Analyzer. RESULTS: Individuals carrying the rs2494746 CG/GG or rs2494738GA/GG genotype in AKT1 had a higher risk of T2DM, compared with those carrying homozygous variants (adjusted OR=1.79, 95% CI: 1.05-3.05, P=0.03 for rs2494746; adjusted OR=1.58, 95% CI: 1.19-2.10, P=0.02 for rs2494738). Furthermore, we found that haplotype GC in the AKT1 gene comprised rs2494738 and rs3803304, indicating a significant association with T2DM (OR=1.08, 95% CI: 1.01-1.15, P=0.03). Finally, generalized multifactor dimensionality reduction (GMDR) analysis indicated that the best interactive model included 3 polymorphisms: rs2494746 (AKT1), rs4802071 (AKT2), and rs4845856 (FRAP1). CONCLUSIONS: Our study suggests that PI3K/AKT/mTOR pathway genes may participate in the development of T2DM.

Impaired adipose expansion caused by liver X receptor activation is associated with insulin resistance in mice fed a high-fat diet.

Liver X receptors (LXR) are deemed as potential drug targets for atherosclerosis, whereas a role in adipose tissue expansion and its relation to insulin sensitivity remains unclear. To assess the metabolic effects of LXR activation by the dual LXRα/ß agonist T0901317, C57BL/6 mice fed a high-fat diet (HFD) were treated with T0901317 (30 mg/kg once daily by intraperitoneal injection) for 3 weeks. Differentiated 3T3-L1 adipocytes were used for analysing the effect of T0901317 on glucose uptake. The following results were obtained from this study. T0901317 reduced fat mass, accompanied by a massive fatty liver and lower serum adipokine levels in HFD mice. Increased adipocyte apoptosis was found in epididymal fat of T0901317-treated HFD mice. In addition, T0901317 treatment promoted basal lipolysis, but blunted the anti-lipolytic action of insulin. Furthermore, LXR activation antagonised PPARγ target genes in epididymal fat and PPARγ-PPRE-binding activity in 3T3-L1 adipocytes. Although the glucose tolerance was comparable to that in HFD mice, the insulin response during IPGTT was significantly higher and the insulin tolerance was significantly impaired in T0901317-treated HFD mice, indicating decreased insulin sensitivity by T0901317 administration, and which was further supported by impaired insulin signalling found in epididymal fat and decreased insulin-induced glucose uptake in 3T3-L1 adipocytes by T0901317 administration. In conclusion, these findings reveal that LXR activation impairs adipose expansion by increasing adipocyte apoptosis, lipolysis and antagonising PPARγ-mediated transcriptional activity, which contributes to decreased insulin sensitivity in whole body. The potential of LXR activation being a therapeutic target for atherosclerosis might be limited by the possibility of exacerbating insulin resistance.

[Correlation between serum free fatty acid level and estimated glomerular filtration rate in type 2 diabetic patients].

OBJECTIVE: To investigate the relationship between serum free fatty acid (FFA) level and glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 442 T2DM patients treated in Sir Run Run Shaw Hospital from January 2013 to June 2015 were retrospectively analyzed and divided into three groups according to estimated glomerular filtration rate (eGFR) levels using modified modification of diet in renal disease (MDRD) formula: eGFR≥90 ml·min(-1)·1.73 m(-2)group (group A, 227 cases), 60 ml·min(-1)·1.73 m(-2)≤eGFR<90 ml·min(-1)·1.73 m(-2)group (group B, 118 cases), and eGFR<60 ml·min(-1)·1.73 m(-2)group (group C, 97 cases). In addition, 50 body mass index (BMI)-matched non-diabetic subjects were selected as control group. Fasting serum FFA level was measured in each group, and its relationship with eGFR was analyzed. RESULTS: FFA level in group C[(450±203)µmol/L]was significantly higher than that in group A[(326±167)µmol/L], group B[(394±184)µmol/L]and control group[(320±90)µmol/L](all P<0.05). Meanwhile, FFA level in group B was higher compared with that in group A (P<0.05). However, no statistical difference was found in FFA level between group A and Control group (P>0.05). Multiple linear regression analysis using eGFR as the dependent variable demonstrated that uric acid (UA), FFA, triglyceride (TG), total cholesterol (TC), albuminuria, hypertension, smoking and duration of diabetes were all independent risk factors for decreased eGFR (all P<0.05). CONCLUSION: The present results suggest that increased FFA level might be involved in the development of diabetic nephropathy.

Impact of Physical Activity on Glycemic Control and Insulin Resistance: A Study of Community-dwelling Diabetic Patients in Eastern China.

Objective The aim of this study was to evaluate the relationship of various intensities of physical activity with glycemic control and insulin resistance in eastern China. Methods A population-based, cross-sectional study was conducted in eastern China. The subjects included 604 community-dwelling people. The participants were classified as insufficiently active (IA); sufficiently active (SA) and very active (VA) according to the International Physical Activity Questionnaire (IPAQ). Insulin sensitivity was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Related social, biological, lifestyle factors and clinical characteristics were recorded and used as potential confounders. Results The cohort of 604 type 2 diabetes patients were classified according to the activity level: 107 subjects who were classified as IA, 329 met the criteria for SA, and the rest were VA. The proportion of obese patients, smokers, patients with hypertension, and the body weight, body mass index (BMI), waist circumference, hemoglobin A1c protein (HbA1c), and 2-h postprandial blood glucose (2hPG) were significantly lower in the SA and VA groups than in the IA group (p<0.05 or 0.01). The SA group had lower levels of fasting blood glucose (FPG) and HOMA-IR than the IA and VA groups (p<0.05 or 0.01). HOMA-IR was positively correlated with FPG, 2hPG, HbA1c, waist circumference and BMI. HOMA-IR was negatively correlated with the total walking activity (p<0.05). After adjusting for FPG, 2hPG, HbA1c, waist circumference and BMI among the groups, a partial correlation analysis showed a correlation between HOMA-IR and the total walking activity. Conclusion Physical activity is a significant factor regarding glycemic control and insulin sensitivity, although SA and walking may be superior to VA for ameliorating insulin sensitivity.

Inverse Relationship between Serum Lipoxin A4 Level and the Risk of Metabolic Syndrome in a Middle-Aged Chinese Population.

Metabolic syndrome (MetS) has been identified to be associated with a state of chronic, low-grade inflammation in adipose tissue. Lipoxins are endogenously generated from arachidonic acid, and exhibit anti-inflammatory actions. Currently, there is no available cohort study identifying the association between serum lipoxins level and MetS. Here we investigate the relationship between serum lipoxin A4 (LXA4) level and the risk of incident MetS in a middle-aged Chinese population. A total 624 participants aged 40-65 years were enrolled at baseline, with 417 (including 333 MetS absence) of them were followed up at 2.5 years. Abdominal visceral fat area (VFA) and abdominal subcutaneous fat area (SFA) were determined using MRI. Serum lipoxin A4 levels were measured by ELISA. At baseline, serum LXA4 levels were significantly correlated with a cluster of traditional MetS risk factors related to obesity (P ≤ 0.05). A higher incidence of new Mets was found in the participants of the lowest tertile of LXA4 levels as compared with that in participants of the highest tertile (P = 0.025). Low serum LXA4 levels [OR 2.607(1.151-5.909), P = 0.022] and high VFA [OR 2.571(1.176-5.620), P = 0.018] were associated with an increased incident Mets, respectively, which remained statistically significant after adjustment for age, gender, current smoking, and alcohol drinking status. Logistic regression analysis suggested a combination of low serum LXA4 levels and high WC/VFA might optimize the prediction of incident Mets in middle-aged Chinese population [OR 4.897/4.967, P = 0.009/0.003]. Decrease in serum LXA4 level and increase in VFA are independent predictors of incident Mets in a population-based cohort, and a combination of them enhances the prognostic value of incident Mets. Taken together, our data suggest that serum LXA4 levels might be useful for early detection and prevention of Mets.

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening.

Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 µmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction.

Regulation of insulin resistance and adiponectin signaling in adipose tissue by liver X receptor activation highlights a cross-talk with PPARγ.

Liver X receptors (LXRs) have been recognized as a promising therapeutic target for atherosclerosis; however, their role in insulin sensitivity is controversial. Adiponectin plays a unique role in maintaining insulin sensitivity. Currently, no systematic experiments elucidating the role of LXR activation in insulin function based on adiponectin signaling have been reported. Here, we investigated the role of LXR activation in insulin resistance based on adiponectin signaling, and possible mechanisms. C57BL/6 mice maintained on a regular chow received the LXR agonist, T0901317 (30 mg/kg.d) for 3 weeks by intraperitoneal injection, and differentiated 3T3-L1 adipocytes were treated with T0901317 or GW3965. T0901317 treatment induced significant insulin resistance in C57BL/6 mice. It decreased adiponectin gene transcription in epididymal fat, as well as serum adiponectin levels. Activity of AMPK, a key mediator of adiponectin signaling, was also decreased, resulting in decreased Glut-4 membrane translocation in epididymal fat. In contrast, adiponectin activity was not changed in the liver of T0901317 treated mice. In vitro, both T0901317 and GW3965 decreased adiponectin expression in adipocytes in a dose-dependent manner, an effect which was diminished by LXRα silencing. ChIP-qPCR studies demonstrated that T0901317 decreased the binding of PPARγ to the PPAR-responsive element (PPRE) of the adiponectin promoter in a dose-dependent manner. Furthermore, T0901317 exerted an antagonistic effect on the expression of adiponectin in adipocytes co-treated with 3 µM Pioglitazone. In luciferase reporter gene assays, T0901317 dose-dependently inhibited PPRE-Luc activity in HEK293 cells co-transfected with LXRα and PPARγ. These results suggest that LXR activation induces insulin resistance with decreased adiponectin signaling in epididymal fat, probably due to negative regulation of PPARγ signaling. These findings indicate that the potential of LXR activation as a therapeutic target for atherosclerosis may be limited by the possibility of exacerbating insulin resistance-related disease.

[The correlation between serum uric acid level and abdominal obesity or metabolic syndrome].

OBJECTIVE: To investigate the relationship between serum uric acid (UA) level and abdominal obesity or metabolic syndrome (MS). METHODS: A total of 875 subjects, with 350 males and 525 females, aged 40-65 years old, were enrolled in this study. The clinical and biochemical data were collected and MRI was used to assess the visceral and subcutaneous adipose tissues. The relationships between UA level and abdominal obesity or MS were analyzed, and the cut-off values of UA for abdominal obesity and MS were determined. RESULTS: Raised risks of abdominal obesity(OR = 4.35, 95%CI 1.91-9.90 in males; OR = 5.44, 95%CI 2.41-12.31 in females) and MS(OR = 4.47, 95%CI 2.08-9.62 in males; OR = 11.62, 95%CI 3.43-39.37 in females) were observed with the increase of UA level. The multiple logistic regression analysis showed that UA was an independent risk factor for hypertriglyceridemia(OR = 2.23, 95%CI 1.02-4.87 in males; OR = 3.04, 95%CI 1.49-6.23 in females) in all subjects and for abdominal obesity(OR = 3.23, 95%CI 1.32-7.91) and hypertension (OR = 2.35, 95%CI 1.37-4.05) in the females. Among the females, the regression line analyzed by simple correlation indicated that the UA level of 244.0 µmol/L was corresponded to the visceral adipose tissue area of 80 cm(2). The optimal cut-off point of UA for the diagnosis of MS was 258.8 µmol/L determined by the receiver operating characteristic curve. CONCLUSIONS: The level of UA is closely correlated with abdominal obesity and MS in the middle-aged Chinese. The elevated UA level is an independent risk factor for abdominal obesity and MS in the female.