Combined serum CTRP7 and CTRP15 levels as a novel biomarker for insulin resistance and type 2 diabetes mellitus.

Aims: This study aimed to examine the alterations in the serum CTRP7 and CTRP15 concentrations in patients newly diagnosed with type 2 diabetes mellitus (T2DM) and to assess the diagnostic potential of the log10 (CTRP7+CTRP15) for insulin resistance (IR) and T2DM. Methods: Serum CTRP7, CTRP15, and adiponectin levels were measured using an enzyme-linked immunosorbent assay (ELISA). Bioinformatics analysis was conducted to investigate CTRP7 and CTRP15-related genes and metabolic signaling pathways. Results: Log10 (CTRP7+CTRP15) levels were notably elevated in the impaired glucose tolerance (IGT) and T2DM cohorts compared with those in the normal control (NGT) cohort. Log10(CTRP7+CTRP15) exhibited positive correlations with HOMA-IR, area under the glucose curve (AUCg), HbA1c%, triglyceride (TG), visceral adiposity index (VAI), body mass index (BMI), and free fatty acid (FFA), levels but negative correlations with adiponectin. Multivariate stepwise regression analysis revealed that HOMA-IR, BMI, HbA1c and FFA levels were independent factors affecting the log10 (CTRP7+CTRP15). Logistic regression analysis revealed that log10 (CTRP7+CTRP15) was independently associated with T2DM and significantly associated with increased risk. Receiver operating characteristic (ROC) curve analysis indicated that the predictive value of log10 (CTRP7+CTRP15) for T2DM and IR was superior to that of CTRP7 or CTRP15 alone. Intervention studies demonstrated that insulin, FFAs and acute exercise contribute to the elevation of serum CTRP7 levels, while hyperglycemia inhibited CTRP7 secretion. Short-term changes in blood glucose, insulin, FFA and acute exercise had minimal effects on serum CTRP15 levels. Bioinformatics analysis revealed that CTRP7 and CTRP15 interact with multiple metabolism-related genes and are enriched in glucose and lipid metabolism-related pathways. Conclusion: Log10 (CTRP7+CTRP15) may serve as a valuable diagnostic marker for the management of metabolic-related diseases, particularly T2DM and IR.

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

The Expression of MAFB Gene in Circulating Monocytes Is Related to Chronic Inflammatory Status in T2DM Patients.

Immune cell-mediated chronic inflammation is one of the causes of type 2 diabetes mellitus (T2DM). Therefore, identifying inflammatory markers in circulating immune cells is highly important for predicting insulin resistance (IR) and the occurrence of T2DM. In this study, we discovered that differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) from T2DM patients were associated with innate immunity and chronic inflammatory responses through bulk transcriptome sequencing (bulk RNA-seq). Gene integration analysis revealed that nine DEGs were upregulated, and receiver operating characteristic (ROC) curve analysis revealed that V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB), a candidate biomarker, has a certain predictive value for T2DM. In population-based cohort studies, we found that MAFB expression was significantly upregulated in the PBMCs of T2DM patients and was significantly correlated with homeostasis model assessment of IR (HOMA-IR), tumor necrosis factor-α (TNF-α), adiponectin (Adipoq), etc. We further evaluated the sensitivity and specificity of MAFB and other clinical parameters for predicting and diagnosing T2DM and found that MAFB expression in PBMCs had a positive effect on the prediction and diagnosis of T2DM. Finally, single-cell RNA sequencing (scRNA-seq) analysis revealed that the increase in MAFB expression was mainly in nonclassical monocytes. Our results suggest that increased MAFB expression in circulating monocytes may mediate chronic inflammatory status in patients with T2DM. Therefore, MAFB gene expression in circulating monocytes has certain clinical significance for predicting and assisting in the diagnosis of T2DM.

Mesenchymal stem cells-based drug delivery systems for diabetic foot ulcer: A review.

The complication of diabetes, which is known as diabetic foot ulcer (DFU), is a significant concern due to its association with high rates of disability and mortality. It not only severely affects patients' quality of life, but also imposes a substantial burden on the healthcare system. In spite of efforts made in clinical practice, treating DFU remains a challenging task. While mesenchymal stem cell (MSC) therapy has been extensively studied in treating DFU, the current efficacy of DFU healing using this method is still inadequate. However, in recent years, several MSCs-based drug delivery systems have emerged, which have shown to increase the efficacy of MSC therapy, especially in treating DFU. This review summarized the application of diverse MSCs-based drug delivery systems in treating DFU and suggested potential prospects for the future research.

Hedgehog interacting protein as a circulating biomarker in women with obesity: a cross-sectional study and intervention studies.

BACKGROUND: Although a study found a significant increase in serum hedgehog interacting protein (HHIP) concentrations in impaired fasting blood glucose, impaired glucose tolerance and newly diagnosed T2DM patients, the variation in circulating HHIP levels in obese individuals remains unknown. PATIENTS AND METHODS: Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for differentially expressed genes and signal pathways. The study is comprised of a total of 452 young women, including 248 obese individuals and 204 controls. Circulating HHIP and Adipoq levels were determined with ELISA kits. Euglycemic-hyperinsulinemic clamps (EHC) and oral glucose tolerance test (OGTT) were conducted in every subject. 32 women were given metformin and 49 were given liraglutide treatment for 6 weeks. The study was registered with www.chictr.org.cn (ChiCTR2000032878 and ChiCTR1800019776). RESULTS: Obesity was significantly associated with the cAMP signal pathway, and HHIP was a secreted protein related to cAMP signalling, as determined by KEGG analysis. In this population-based cohort study, we found that the level of circulating HHIP was significantly elevated in obese women, and positively correlated with body mass index and blood glucose, blood lipid, insulin, homeostasis model assessment of insulin resistance, dehydroepiandrostenedione sulphate, and luteinizing hormone, while negatively correlated with M-value and Adipoq. Insulin resistance (IR) and ove™rweight/obesity were associated with the higher HHIP concentration. OGTT and EHC tests revealed that the levels of circulating HHIP were regulated by blood glucose but to a less extent by insulin. After therapy with metformin and liraglutide, circulating HHIP levels were decreased, whereas Adipoq levels increased significantly. CONCLUSIONS: Our findings support HHIP as a potential biomarker for predicting obesity and IR. In addition, drugs targeting HHIP may be a new strategy to treat obesity.

Prevalence and risk factors for subjective cognitive decline and the correlation with objective cognition among community-dwelling older adults in China: Results from the Hubei memory and aging cohort study.

INTRODUCTION: The prevalence and risk factors for subjective cognitive decline (SCD) and its correlation with objective cognition decline (OCD) among community-dwelling older adults is inconsistent. METHODS: Older adults underwent neuropsychological and clinical evaluations to reach a consensus on diagnoses. RESULTS: This study included 7486 adults without mild cognitive impairment and dementia (mean age: 71.35 years [standard deviation = 5.40]). The sex-, age-, and residence-adjusted SCD prevalence was 58.33% overall (95% confidence interval: 58.29% to 58.37%), with higher rates of 61.25% and 59.87% in rural and female subgroups, respectively. SCD global and OCD language, SCD memory and OCD global, SCD and OCD memory, and SCD and OCD language were negatively correlated in fully adjusted models. Seven health and lifestyle factors were associated with an increased risk for SCD. DISCUSSION: SCD affected 58.33% of older adults and may indicate concurrent OCD, which should prompt the initiation of preventative intervention for dementia. HIGHLIGHTS: SCD affects 58.33% of older adults in China. SCD may indicate concurrent objective cognitive decline. Difficulty finding words and memory impairments may indicate a risk for AD. The presence of SCD may prompt preventative treatment initiation of MCI or dementia. Social network factors may be initial targets for the early prevention of SCD.

Correlation between serum lipid profiles and cognitive impairment in old age: a cross-sectional study.

Background: The correlation between cognitive function and lipid profiles, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, is inconsistent. Aims: This cross-sectional study investigated the association between serum lipid levels and the prevalence of cognitive impairment among community-dwelling older adults and explored this difference in association by gender and urban-rural residency. Methods: Participants aged 65 and above in urban and rural areas were recruited between 2018 and 2020, selected from the Hubei Memory and Aging Cohort Study. Detailed neuropsychological evaluations, clinical examinations and laboratory tests were conducted in community health service centres. Multivariate logistic regression was used to analyse the correlation between serum lipid profiles and the prevalence of cognitive impairment. Results: We identified 1 336 cognitively impaired adults (≥65 years)-1 066 with mild cognitive impairment and 270 with dementia-from 4 746 participants. Triglycerides level was correlated with cognitive impairment in the total sample (χ2=6.420, p=0.011). In gender-stratified multivariate analysis, high triglycerides in males reduced the risk of cognitive impairment (OR: 0.785, 95% CI: 0.623 to 0.989, p=0.040), and high LDL-C in females increased the risk of cognitive impairment (OR: 1.282, 95% CI: 1.040 to 1.581, p=0.020). In both gender-stratified and urban-rural stratified multivariate analyses, high triglycerides reduced the risk of cognitive impairment in older urban men (OR: 0.734, 95% CI: 0.551 to 0.977, p=0.034), and high LDL-C increased the risk of cognitive impairment in older rural women (OR: 1.830, 95% CI: 1.119 to 2.991, p=0.016). Conclusions: There are gender and urban-rural differences in the correlation of serum lipids with cognitive impairment. High triglycerides levels may be a protective factor for cognitive function in older urban men, while high LDL-C levels may be a risk factor for cognitive function in older rural women.

Impaired Humoral Immunity Identified in Inactivated SARS-CoV-2 Vaccine Recipients without Anti-Spike RBD Antibodies.

Inactivated SARS-CoV-2 vaccines have been deployed in a significant portion of the world population, who have widely varied responses to vaccination. Understanding this differential response would help the development of new vaccines for non-responders. Here, we conducted surveillance of anti-Spike receptor-binding domain (RBD) antibody levels in a large cohort of 534 healthy Chinese subjects vaccinated with two doses of inactivated SARS-CoV-2 vaccines. We show that the positive rate of antibodies among vaccinated subjects rapidly wanes as the interval between antibody testing and vaccination increases (14 to 119 days: 81.03%, 363 of 448 subjects; 120 to 149 days: 46.43%, 13 of 28 subjects; more than 150 days: 20%, 1 of 5 subjects). However, the antibodies were maintained at high levels in 16 convalescent COVID-19 patients at more than 150 days after recovery. We also found that increased age and body mass index are associated with decreased antibody levels. Vaccinated subjects who fail to produce antibodies display impaired B-cell activating humoral immunity, which was confirmed in COVID-19 patients without antibodies detected at 4 to 18 days after diagnosis. IMPORTANCE Our study illustrates the immune responses engaged by encountering antigen, highlighting the critical roles of B-cell activating humoral immunity in the body's antibody production.

Reduced plasma levels of RGM-A predict stroke-associated pneumonia in patients with acute ischemic stroke: A prospective clinical study.

Background: Stroke-induced immunodepression syndrome is considered the major etiology of stroke-associated pneumonia (SAP). Repulsive guidance molecule A (RGM-A) is an immunomodulatory protein that is closely related to inflammation and immune responses. To explore the relationship between RGM-A and SAP and facilitate the early identification of patients at high risk of developing SAP, we investigated the predictive value of RGM-A in SAP. Methods: We enrolled 178 patients with acute ischemic stroke (AIS) and finally analyzed 150 patients, among whom 69 had SAP and 81 had non-SAP. During the same period, 40 patients with community-acquired pneumonia and 40 healthy participants were included as controls. SAP was defined according to the modified US Centers for Disease Control and Prevention criteria. Blood samples were collected at 24 h, 48 h, 3 days, 4 to 7 days, and 8 to 14 days after stroke onset. An enzyme-linked immunosorbent assay was used to detect the plasma levels of RGM-A and interleukin-6. Results: The plasma RGM-A levels were significantly decreased in both patients with community-acquired pneumonia and those with AIS, and the decline was most pronounced in patients with SAP (P < 0.001). RGM-A started to decline within 24 h after stroke in the SAP group, and the lowest levels were detected on day 3 and days 4 to 7 (P < 0.001). The RGM-A levels in the SAP group were lower than those in the non-SAP group at all blood collection time points (P < 0.05). In the logistic regression analyses, RGM-A was a protective factor for SAP after adjusting for confounders (adjusted odds ratio = 0.22, 95% confidence interval = 0.091-0.538, P = 0.001). Receiver operating characteristic curve analysis showed that the area under the curve for RGM-A was 0.766 (0.091-0.538; P = 0.001), the cutoff value was 4.881 ng/mL, and the sensitivity and specificity were 80.00 and 76.36%, respectively. Conclusions: We demonstrated that reduced plasma levels of RGM-A might help in the early identification of high-risk patients with SAP and predict the occurrence of SAP in patients with AIS. RGM-A might provide new clues to a potential alternative therapy for SAP.

Vitamin C protects against hypoxia, inflammation, and ER stress in primary human preadipocytes and adipocytes.

Dysregulation of adipose tissue involves increased cellular hypoxia, ER stress, and inflammation and altered adipokine production, contributing to the aetiology of obesity-related diseases including type 2 diabetes and cardiovascular disease. This study aimed to investigate the effects of Vitamin C supplementation on these processes in primary human preadipocytes and adipocytes. Treatment of preadipocytes and adipocytes with the proinflammatory cytokine TNFα and palmitic acid (PA), to mimic the obesogenic milieu, significantly increased markers of hypoxia, ER stress and inflammation and reduced secretion of high molecular weight (HMW) adiponectin. Importantly, Vitamin C abolished TNFα+PA induced hypoxia and significantly reduced the increases in ER stress and inflammation in both cell types. Vitamin C also significantly increased the secretion of HMW adiponectin from adipocytes. These findings indicate that Vitamin C can reduce obesity-associated cellular stress and thus provide a rationale for future investigations.

GPHB5 Is a Biomarker in Women With Metabolic Syndrome: Results From Cross-Sectional and Intervention Studies.

Background: Animal studies have found that GPHB5 has a similar effect on system metabolism as TSH. However, the relationship between GPHB5 and metabolic diseases remains unknown. This study investigates the relationship between GPHB5 and MetS in young women. Methods: Bioinformatics analysis was undertaken to explore the relationship between GPHB5 and metabolic-related genes and signaling pathways. EHC and OGTT were performed on all individuals. Lipid-infusion, physical activity, and cold-exposure tests were performed on healthy individuals. Serum GPHB5 concentrations were measured by an ELISA kit. Results: PPI network showed that 11 genes interacted with GPHB5, in which POMC and KISS1R were involved in glucose and lipid metabolism. GO analysis showed 56 pathways for BP and 16 pathways for MF, in which OPRM1 and MCR families were related to energy metabolism. KEGG analysis found that GPHB5 is associated with lipolysis and neuroactive ligand-receptor interaction pathways. The levels of circulating GPHB5 were significantly increased, while serum adiponectin levels were lower in MetS women compared with healthy women. Obese/overweight individuals had lower adiponectin levels and higher GPHB5 levels. Circulating GPHB5 levels were positively correlated with BMI, WHR, blood pressure, FBG, 2 h-BG, HbA1c, FIns, 2h-Ins, LDL-C, FFA, HOMA-IR, and AUCg, etc. but negatively correlated with HDL-C, adiponectin, and M-values. Serum GPHB5 levels did not change significantly during the OGTT, EHC, and lipid infusion. Physical activity and cold-exposure tests did not lead to changes in GPHB5 levels. GLP-1RA treatment resulted in a significant decrease in serum GPHB5 levels. Conclusions: GPHB5 may be a biomarker for MetS.

CTRP7 Is a Biomarker Related to Insulin Resistance and Oxidative Stress: Cross-Sectional and Intervention Studies In Vivo and In Vitro.

Objective: CTRP7 is a cytokine that is known to be associated with obesity. However, its relationship with insulin resistance (IR) and metabolic diseases remains unknown. The aim of this study is to investigate the relationship between CTRP7 and IR under in vivo and in vitro conditions. Methods: CTRP7 expression in mice and hepatocytes was determined using RT-qPCR and western blotting. Circulating CTRP7 concentrations were measured with an ELISA kit. EHC, OGTT, lipid-infusion, physical activity, and cold-stimulation experiments were performed in humans and mice. SOD, GSH, and MDA were measured by commercial kits. ROS levels were detected using dichlorofluorescein diacetate. Results: The expression levels of CTRP7 protein in the liver and fat of ob/ob and db/db mice were higher than that of WT mice. Individuals with IGT, T2DM, and obesity had higher circulating CTRP7 levels. CTRP7 levels were associated with HOMA-IR, obesity, and other metabolic parameters. During OGTT, serum CTRP7 levels gradually decreased, while CTRP7 levels significantly increased during EHC in response to hyperinsulinemia in healthy individuals without IR. In addition, lipid infusion-induced IR further increased serum CTRP7 levels in healthy adults. Physical activity increased serum CTRP7 levels in healthy individuals and CTRP7 protein expression in iWAT and skeletal muscle in mice. Under in vitro conditions, the expression of the CTRP7 protein was inhibited in a glucose concentration-dependent manner but was promoted by FFAs and insulin stimulation in hepatocytes. Furthermore, CTRP7 overexpression facilitated oxidative stress and suppressed the phosphorylation of insulin signaling molecules in hepatocytes. Conclusions: Our evidence shows that CTRP7 could be a useful biomarker and potential treatment target in IR and metabolic disorders.

Hepatic lipid accumulation induced by a high-fat diet is regulated by Nrf2 through multiple pathways.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is reportedly involved in hepatic lipid metabolism, but the results are contradictory, and the underlying mechanism remains unclear. Here, we focused on elucidating the effects of Nrf2 on hepatic adipogenesis and on determining the possible underlying mechanism. We established a non-alcoholic fatty liver disease (NAFLD) model in a high-fat diet (HFD)-fed Nrf2 knockout (Nrf2 KO) mice; further, a cell model of lipid accumulation was established using mouse primary hepatocytes (MPHs) treated with free fatty acids (FAs). Using these models, we investigated the relationship between Nrf2 and autophagy and its role in the development of NAFLD. We observed that Nrf2 expression levels were upregulated in patients with NAFLD and diet-induced obese mice. Nrf2 deficiency led to hepatic lipid accumulation in vivo and in vitro, in addition to, promoting lipogenesis mainly by increasing SREBP-1c activity. Moreover, Nrf2 deficiency attenuated autophagic flux and inhibited the fusion of autophagosomes and lysosomes in vivo and in vitro. Decreased autophagy caused reduced lipolysis in the liver. Importantly, chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase assay results proved that Nrf2 bound to the LAMP1 promoter and regulated its transcriptional activity. Accordingly, we report that Nrf2-LAMP1 interaction plays an indispensable role in Nrf2-regulated hepatosteatosis. Our data collectively confirm that Nrf2 deficiency promotes hepatosteatosis by enhancing SREBP-1c activity and attenuating autophagy. Our findings provide a novel multi-pathway effect of Nrf2 on lipid metabolism in the liver. We believe that multi-target intervention of Nrf2 is a novel strategy for the treatment of NAFLD.

GNG2 acts as a tumor suppressor in breast cancer through stimulating MRAS signaling.

G-protein gamma subunit 2 (GNG2) is involved in several cell signaling pathways, and is essential for cell proliferation and angiogenesis. However, the role of GNG2 in tumorigenesis and development remains unclear. In this study, 1321 differentially expressed genes (DEGs) in breast cancer (BC) tissues were screened using the GEO and TCGA databases. KEGG enrichment analysis showed that most of the enriched genes were part of the PI3K-Akt signaling pathway. We identified GNG2 from the first five DEGs, its expression was markedly reduced in all BC subtype tissues. Cox regression analysis showed that GNG2 was independently associated with overall survival in patients with luminal A and triple-negative breast cancers (TNBC). GNG2 over-expression could significantly block the cell cycle, inhibit proliferation, and promote apoptosis in BC cells in vitro. In animal studies, GNG2 over-expression inhibited the growth of BC cells. Further, we found that GNG2 significantly inhibited the activity of ERK and Akt in an MRAS-dependent manner. Importantly, GNG2 and muscle RAS oncogene homolog (MRAS) were co-localized in the cell membrane, and the fluorescence resonance energy transfer (FRET) experiment revealed that they had direct interaction. In conclusion, the interaction between GNG2 and MRAS likely inhibits Akt and ERK activity, promoting apoptosis and suppressing proliferation in BC cells. Increasing GNG2 expression or disrupting the GNG2-MRAS interaction in vivo could therefore be a potential therapeutic strategy to treat BC.

Population-attributable fractions of risk factors for all-cause dementia in China rural and urban areas: a cross-sectional study.

BACKGROUND: The prevalence of dementia in China, particularly in rural areas, is consistently increasing; however, research on population-attributable fractions (PAFs) of risk factors for dementia is scarce. METHODS: We conducted a cross-sectional survey, namely, the China Multicentre Dementia Survey (CMDS) in selected rural and urban areas from 2018 to 2020. We performed face-to-face interviews and neuropsychological and clinical assessments to reach a consensus on dementia diagnosis. Prevalence and weighted PAFs of eight modifiable risk factors (six classical: less childhood education, hearing impairment, depression, physical inactivity, diabetes, and social isolation, and two novels: olfactory decline and being unmarried) for all-cause dementia were estimated. RESULTS: Overall, CMDS included 17,589 respondents aged ≥ 65 years, 55.6% of whom were rural residents. The age- and sex-adjusted prevalence for all-cause dementia was 9.11% (95% CI 8.96-9.26), 5.19% (5.07-5.31), and 11.98% (11.8-12.15) in the whole, urban, and rural areas of China, respectively. Further, the overall weighted PAFs of the eight potentially modifiable risk factors were 53.72% (95% CI 52.73-54.71), 50.64% (49.4-51.89), and 56.54% (55.62-57.46) in the whole, urban, and rural areas of China, respectively. The eight risk factors' prevalence differed between rural and urban areas. Lower childhood education (PAF: 13.92%) and physical inactivity (16.99%) were primary risk factors in rural and urban areas, respectively. CONCLUSIONS: The substantial urban-rural disparities in the prevalence of dementia and its risk factors exist, suggesting the requirement of resident-specific dementia-prevention strategies.

Circulating CTRP7 Is a Potential Predictor for Metabolic Syndrome.

Background: Previous animal studies have revealed that CTRP7 is related to energy metabolism. However, little is known regarding the relationship between CTRP7 and metabolic diseases in humans. Hence, this study was designed to explore the association between CTRP7 and MetS through a cross-sectional study and multiple intervention studies. Methods: A total of 624 individuals were enrolled in this study. The levels of CTRP7 and APN were determined by ELISA kit. HEC, OGTT and lipid infusion were performed in heathy individuals to investigate the association of CTRP7 and glucose, insulin and FFA. Bioinformatics analysis was then undertaken to identify genes and signaling pathways associated with CTRP7. The relationship between CTRP7 with MetS components was also evaluated. Results: In MetS patients, serum CTRP7 concentrations were significantly higher than in healthy controls, and was positively correlated with WC, BP, FBG, 2h-BG and TG, but negatively correlated with HDL-C and APN. Multivariate logistic regression analysis uncovered that CTRP7 was strongly correlated with the occurrence of MetS. In addition, circulating levels of CTRP7 in patients with two or more MetS components were higher than those with one MetS component. In the intervention studies, OGTTs resulted in a significant reduction in serum CTRP7 concentration. However, the increase in insulin levels caused by EHC and the increase of FFA caused by lipid-infusion led to the significant increase of serum CTRP7 concentration. Meanwhile, bioinformatics analysis revealed that CTRP7 was strongly associated with metabolism-related genes and signal pathways, which further illustrate the association of CTRP7 with whole-body metabolism. Conclusions: Serum CTRP7 is increased in MetS patients, which may be a biomarker related to metabolic diseases. Clinical Trial Registration Number: ChiCTR2000032878.

Serum Fetuin-B Levels Are Elevated in Women with Metabolic Syndrome and Associated with Increased Oxidative Stress.

Previous studies on serum fetuin-B (fetuin-like protein IRL685) have investigated its association with T2DM; however, the reason for the variation in serum fetuin-B and its regulatory factors in metabolic disease remain unclear. Here, we evaluated serum fetuin-B levels in women with newly diagnosed MetS and performed multiple interventions to investigate the role of fetuin-B in the pathogenesis of MetS. Serum fetuin-B levels were assessed using ELISA. Bioinformatics analysis was performed to analyze fetuin-B-related genes and signaling pathways. Additionally, oxidative stress parameters were measured in the in vitro study. For subgroup analyses, we performed EHC, OGTT, and treatment with a GLP-1RA to investigate the regulatory factors of serum fetuin-B. We found that in comparison with healthy subjects, serum fetuin-B levels were markedly increased in women with MetS. Further, serum fetuin-B showed a positive correlation with WHR, FAT%, TG, FBG, HbA1c, FIns, HOMA-IR, VAI, and LAP. Bioinformatics analysis revealed that most fetuin-B-related core genes were involved in cholesterol metabolism and fat decomposition. Consistent with this finding, multivariate regression analysis showed that triglyceride content and WHR were independently associated with serum fetuin-B. We also observed that serum fetuin-B levels were markedly elevated in healthy subjects after glucose loading and in women with MetS during EHC. In vitro, overexpression of fetuin-B promoted oxidative stress in HepG2 cell. After 6 months of treatment with a GLP-1RA, serum fetuin-B levels in women with MetS decreased following an improvement in metabolism and insulin sensitivity. Therefore, serum fetuin-B is associated with MetS, which may serve as a biomarker of oxidative stress. This trial is registered with ChiCTR-OCC-11001422.

Effective and safe delivery of GLP-1AR and FGF-21 plasmids using amino-functionalized dual-mesoporous silica nanoparticles in vitro and in vivo.

Nanomaterials have attracted increased attention because of their excellent drug-carrying capacity. However, these nanomaterials are rarely used in the treatment of metabolic diseases. Liraglutide, a glucagon-like peptide-1 receptor agonist, has been widely used in the treatment of type 2 diabetes mellitus (T2DM). Furthermore, fibroblast growth factor 21 (FGF-21) has been found to improve glucose metabolism and insulin resistance (IR). To investigate whether these two molecules have synergistic effects in vivo, we developed a novel drug delivery system using amino-functionalized and embedded dual-mesoporous silica nanoparticles (N-EDMSNs) to simultaneously carry liraglutide and FGF-21, and observed their biological effects. The resultant N-EDMSNs possessed unique hierarchical porous structures consisting of open large pores (>10 nm) and small mesopores (~2.5 nm) in the silica framework, highly positively charged surfaces and good disperisity in aqueous solution. We found that N-EDMSNs had a high loading capacity for exogenous genes and low toxicity to Hepa1-6 cells. Moreover, N-EDMSNs can simultaneously carry FGF-21 plasmids and liraglutide and successfully transfect them into Hepa1-6 cells. The transfection efficiency of N-EDMSNs was higher than that of Lipofectamine 2000 in vitro. In mice experiments, N-EDMSNs/pFGF21 treatment resulted in higher FGF-21 expression in the liver than pFGF21 treatment with hydrodynamic delivery. Compared with both pFGF21 and liraglutide, N-EDMSNs/pFGF21/Lira treatment significantly reduced the food intake, body weight, and blood glucose; increased the energy expenditure and improved hepatic IR in high-fat diet (HFD)-fed mice. Our results demonstrated that the biological effects of N-EDMSNs/pFGF21/Lira complexes were better than those of pFGF21 combined with liraglutide in vivo.

Genetic ablation of C-reactive protein gene confers resistance to obesity and insulin resistance in rats.

AIMS/HYPOTHESIS: Besides serving as a traditional inflammatory marker, C-reactive protein (CRP) is closely associated with the development of obesity, diabetes and cardiovascular diseases as a metabolic and inflammatory marker. We hypothesise that CRP protein directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker, and that genetic deficiency of CRP will lead to resistance to obesity and insulin resistance. METHODS: Crp gene deletion was achieved by transcription activator-like effector nuclease (TALEN) technology in rats. The Crp knockout animals were placed on either a standard chow diet or a high-fat diet. Phenotypic changes in body weight, glucose metabolism, insulin sensitivity, energy expenditure and inflammation condition were examined. The central impact of CRP deficiency on leptin and insulin hypothalamic signalling, as well as glucose homeostasis, were examined via intracerebral ventricular delivery of leptin and CRP plus glucose clamp studies in the wild-type and Crp knockout rats. RESULTS: CRP deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to high-fat diet. Glucose clamp studies revealed enhanced hepatic insulin signalling and actions. Deficiency of CRP enhanced and prolonged the weight-reducing effect of central injected leptin and promoted the central and peripheral roles of leptin. By contrast, reinstatement of CRP into the hypothalamus of the knockout rats attenuated the effects of central leptin signalling on insulin sensitivity and peripheral glucose metabolism. CONCLUSIONS/INTERPRETATION: This study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes but directly regulates energy balance, body weight, insulin sensitivity and glucose homeostasis through direct regulation of leptin's central effect and hypothalamic signalling.