A Role for Oncostatin M in the Impairment of Glucose Homeostasis in Obesity

Abstract Context Oncostatin M (OSM) plays a key role in inflammation, but its regulation and function during obesity is not fully understood. Objective The aim of this study was to evaluate the relationship of OSM with the inflammatory state that leads to impaired glucose homeostasis in obesity. We also assessed whether OSM immunoneutralization could revert metabolic disturbances caused by a high-fat diet (HFD) in mice. Design 28 patients with severe obesity were included and stratified into two groups: (1) glucose levels <100 mg/dL and (2) glucose levels >100 mg/dL. White adipose tissue was obtained to examine OSM gene expression. Human adipocytes were used to evaluate the effect of OSM in the inflammatory response, and HFD-fed C57BL/6J mice were injected with anti-OSM antibody to evaluate its effects. Results OSM expression was elevated in subcutaneous and visceral fat from patients with obesity and hyperglycemia, and correlated with Glut4 mRNA levels, serum insulin, homeostatic model assessment of insulin resistance, and inflammatory markers. OSM inhibited adipogenesis and induced inflammation in human adipocytes. Finally, OSM receptor knockout mice had increased Glut4 mRNA levels in adipose tissue, and OSM immunoneutralization resulted in a reduction of glucose levels and Ccl2 expression in adipose tissue from HFD-fed mice. Conclusions OSM contributes to the inflammatory state during obesity and may be involved in the development of insulin resistance.

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Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance

Acta Endocrinologica ◽

10.1530/eje.0.1490331 ◽

2003 ◽

Vol 149 (4) ◽

pp. 331-335 ◽

Cited By ~ 350

Author(s):

JV Silha ◽

M Krsek ◽

JV Skrha ◽

P Sucharda ◽

BL Nyomba ◽

...

Keyword(s):

Insulin Resistance ◽

Body Mass Index ◽

Adipose Tissue ◽

Statistical Significance ◽

Model Assessment ◽

Fasting Insulin ◽

Homeostasis Model Assessment ◽

Glucose Levels ◽

Obese Subjects ◽

The Relationship

OBJECTIVE: Adipose tIssue regulates insulin sensitivity via the circulating adipocytokines, leptin, resistin and adiponectin. The objective of this study was to compare the levels of resistin, adiponectin and leptin in lean and obese subjects and determine the relationship between circulating adipocytokines and insulin resistance. METHODS: We examined plasma levels of resistin, adiponectin and leptin in 17 lean subjects with a mean body mass index (BMI) of approximately 23 and 34 non-diabetic obese individuals with a mean BMI approximately 33. Insulin resistance was assessed using the homeostasis model assessment ratio (HOMA-R) formula derived from fasting insulin and glucose levels. RESULTS: Resistin levels were not significantly different between the two groups but were significantly higher in women compared with men, 35.4+/-6.5 (s.e.) vs 15.4+/-2.9 microg/L, P<0.01. Resistin did not correlate with BMI but did significantly correlate with HOMA-R, P<0.01, and this correlation remained significant after adjustment for gender and BMI. Adiponectin levels were significantly lower in obese compared with lean subjects, P<0.005, and higher in women, P<0.001, but showed no significant correlation with HOMA-R. Leptin levels were significantly higher in obese subjects and women and correlated with HOMA-R and resistin. DISCUSSION: In this small group of patients we demonstrated that insulin resistance correlated most strongly with leptin levels. A significant correlation between resistin levels and insulin resistance was also observed. Although a similar trend was apparent for adiponectin, the correlation with insulin resistance did not achieve statistical significance.

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Complement Factor C3 Methylation and mRNA Expression Is Associated to BMI and Insulin Resistance in Obesity

Genes ◽

10.3390/genes9080410 ◽

2018 ◽

Vol 9 (8) ◽

pp. 410 ◽

Cited By ~ 7

Author(s):

Daniel Castellano-Castillo ◽

Isabel Moreno-Indias ◽

Jose Carlos Fernandez-Garcia ◽

Mercedes Clemente-Postigo ◽

Manuel Castro-Cabezas ◽

...

Keyword(s):

Insulin Resistance ◽

Dna Methylation ◽

Adipose Tissue ◽

Messenger Rna ◽

Density Lipoprotein ◽

Complement Factor ◽

Mrna Levels ◽

Model Assessment ◽

Tissue Samples ◽

Obese Class

Epigenetic marks, and especially DNA methylation, are becoming an important factor in obesity, which could help to explain its etiology and associated comorbidities. Adipose tissue, now considered as an important endocrine organ, produces complement system factors. Complement component 3 (C3) turns out to be an important protein in metabolic disorders, via either inflammation or the C3 subproduct acylation stimulating protein (ASP) which directly stimulates lipid storage. In this study, we analyze C3 DNA methylation in adipose tissue from subjects with a different grade of obesity. Adipose tissue samples were collected from subjects with a different degree of obesity determined by their body mass index (BMI) as: Overweight subjects (BMI ≥ 25 and <30), obese class 1/2 subjects (BMI ≥ 30 and <40) and obese class 3 subjects (BMI ≥ 40). C3 DNA methylation was measured for 7 CpGs by pyrosequencition using the Pyromark technology (Qiagen, Madrid Spain). C3 messenger RNA (mRNA) levels were analyzed by pre-designed Taqman assays (Applied biosystems, Foster City, CA, USA) and ASP/C3a was measured using a ELISA kit. The data were analyzed using the statistic package SPSS. C3 DNA methylation levels were lower in the morbid obese group. Accordingly, C3 methylation correlated negatively with BMI and leptin. However, C3 mRNA levels were more associated with insulin resistance, and positive correlations with insulin, glucose and homeostasis model assessment-estimated insulin resistance (HOMA-IR) existed. ASP correlated negatively with high density lipoprotein (HDL) cholesterol. C3 methylation levels were associated to adiposity variables, such as BMI and leptin, while the C3 mRNA levels were associated to glucose metabolism.

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Visfatin levels in non-obese, obese, and insulin resistant adolescents

Paediatrica Indonesiana ◽

10.14238/pi56.5.2016.291-6 ◽

2017 ◽

Vol 56 (5) ◽

pp. 291

Author(s):

Indra Ihsan ◽

Eka Agustia Rini ◽

Rismawati Yaswir

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Serum Insulin ◽

Enzyme Linked Immunosorbent Assay ◽

Model Assessment ◽

Fasting Serum ◽

Obese Adolescents ◽

Insulin Resistant ◽

Resistant Group ◽

Visfatin Level

Background Adipose tissue is not merely a site for energy storage, but is also the largest endocrine organ, secreting various adipocytokines. Plasma visfatin, an adipocytokine predominantly secreted from visceral adipose tissue, has insulin-mimetic effects, and has been closely linked to insulin resistance.Objective To compare plasma visfatin levels between obese and non-obese adolescents, as well as between obese adolecents with and without insulin resistance.Methods This cross-sectional study was conducted in students who attended three senior high schools in Padang. Subjects comprised 28 obese and 28 non-obese adolescents. The age of the subjects ranged from 14-18 years. Obesity criteria were based on body mass index (BMI) measurements. Fasting serum glucose level was measured by glucose hexokinase photometry and serum insulin was measured by chemiluminesence immunoassay. Plasma visfatin was measured by enzyme-linked immunosorbent assay (ELISA). The insulin resistance index was estimated from fasting serum insulin and glucose levels using the homeostatic model assessment for insulin resistance (HOMA-IR). Differences in the variables were tested using independent T-test and Mann-Whitney test, depending on the distribution of the variables.Results The mean plasma visfatin level was significantly higher in the obese than in the control group [2.55 (SD 1.54) vs. 1.61 (SD 0.64) ng/mL, respectively; (P=0.005)]. The insulin resistant group had significantly higher mean plasma visfatin level than the non-resistant group [3.61 (SD 1.59) vs. 1.96 (SD 1.18) ng/mL, respectively; (P=0.004)].Conclusion Obese adolescents with insulin resistance have signifcantly higher plasma visfatin levels compared to those without insulin resistance.

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Targeted inhibition of CD74 attenuates adipose COX-2-MIF-mediated M1 macrophage polarization and retards obesity-related adipose tissue inflammation and insulin resistance

Clinical Science ◽

10.1042/cs20180041 ◽

2018 ◽

Vol 132 (14) ◽

pp. 1581-1596 ◽

Cited By ~ 10

Author(s):

Pei-Chi Chan ◽

Ting-Ni Wu ◽

Ying-Chuan Chen ◽

Chieh-Hua Lu ◽

Martin Wabitsch ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Mrna Levels ◽

Model Assessment ◽

M1 Macrophage ◽

Cox 2 ◽

Highly Correlated ◽

Targeted Inhibition

Adipose tissue (AT) inflammation is crucial to the development of obesity-associated insulin resistance. Our aim was to investigate the contribution of cyclooxygenase-2 (COX-2)/macrophage migration inhibitory factor (MIF)-mediated cross-talk between hypertrophic adipocytes and macrophages to the etiology of AT inflammation and the involvement of CD74 using human SGBS adipocytes, THP-1 macrophages and mice fed a high-fat (HF) diet. The MIF and CD74 mRNA levels in the adipocytes and stromal vascular cells (SVCs) of white fat were highly correlated with body weight (BW), homeostatic model assessment for insulin resistance (HOMA-IR), and adipose macrophage marker expression levels, especially those in SVCs. COX-2 inhibition suppressed the elevation of MIF production in HF white adipocytes as well as palmitate and hypoxic-treated SGBS adipocytes. Treatment of adipocytes transfected with shCOX-2 and siMIF or subjected to MIF depletion in the medium reversed the pro-inflammatory responses in co-incubated THP-1 cells. Inhibition of NF-κB activation reversed the COX2-dependent MIF secretion from treated adipocytes. The targeted inhibition of macrophage CD74 prevented M1 macrophage polarization in the above co-culture model. The COX-2-dependent increases in CD74 gene expression and MIF release in M1-polarized macrophages facilitated the expression of COX-2 and MIF in co-cultured SGBS adipocytes. CD74 shRNA intravenous injection suppressed HF-induced AT M1 macrophage polarization and inflammation as well as insulin resistance in mice. The present study suggested that COX-2-mediated MIF secretion through NF-κB activation from hypertrophic and hypoxic adipocytes as well as M1 macrophages might substantially contribute to the phenotypic switch of AT macrophages through CD74 in obesity. Inhibition of CD74 could attenuate AT inflammation and insulin resistance in the development of HF diet-induced obesity.

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Lower Zinc-α2-Glycoprotein Production by Adipose Tissue and Liver in Obese Patients Unrelated to Insulin Resistance

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0758 ◽

2009 ◽

Vol 94 (11) ◽

pp. 4499-4507 ◽

Cited By ~ 67

Author(s):

David M. Selva ◽

Albert Lecube ◽

Cristina Hernández ◽

Juan A. Baena ◽

José M. Fort ◽

...

Keyword(s):

Insulin Resistance ◽

Body Mass Index ◽

Adipose Tissue ◽

Body Mass ◽

Control Group ◽

Mrna Levels ◽

Model Assessment ◽

Obese Patients ◽

Obese Subjects

Context: Zinc-α2 glycoprotein (ZAG) has been proposed as a new candidate in the pathogenesis of obesity, but most of the information stems from studies performed in rodents and in vitro assays. Objective: The main aim of the study was to compare serum levels of ZAG and its expression (mRNA levels and protein) in adipose tissue and the liver between obese and nonobese subjects. The relationship between ZAG and insulin resistance was also explored. Design: This was a case-control study. Setting: The study was conducted at a university referral center. Patients and Methods: Samples of serum, sc adipose tissue (SAT), visceral adipose tissue (VAT), and liver were obtained from 20 obese subjects during bariatric surgery. Samples from 10 nonobese patients matched by age and gender were used as a control group. Serum ZAG levels were determined by ELISA. ZAG mRNA levels were measured by real-time PCR and protein content by Western blot. The effect of insulin on liver production of ZAG was assessed using HepG2 cultures. Results: Serum concentration of ZAG (micrograms per milliliter) was significantly lower in obese subjects (40.87 ± 10.45 vs. 63.26 ± 16.40; P = 0.002). ZAG expression was significantly lower in the adipose tissue (SAT and VAT) and liver of obese patients than in control subjects. Significant negative correlations between body mass index and circulating ZAG (r = −0.65, P < 0.001) as well as between body mass index and mRNA ZAG levels in SAT (r = −0.68, P < 0.001) and VAT were detected (r = −0.64, P < 0.001). No relationship was found between ZAG and homeostasis model assessment for insulin resistance and insulin had no effect on ZAG production in vitro. Conclusion: A down-regulation of ZAG in SAT, VAT, and liver exists in obese patients but seems unrelated to insulin resistance. A downregulation of zinc-α2 glycoprotein in adipose tissue and liver exists in obese patients, and it is unrelated to insulin resistance.

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MicroRNA-193b Controls Adiponectin Production in Human White Adipose Tissue

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-1530 ◽

2015 ◽

Vol 100 (8) ◽

pp. E1084-E1088 ◽

Cited By ~ 22

Author(s):

Yasmina Belarbi ◽

Niklas Mejhert ◽

Silvia Lorente-Cebrián ◽

Ingrid Dahlman ◽

Peter Arner ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Adipose Tissue ◽

Nuclear Receptor ◽

White Adipose Tissue ◽

Mrna Levels ◽

Model Assessment ◽

Human Adipocytes ◽

Interacting Protein ◽

Nuclear Transcription Factor

Context: MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression. In white adipose tissue (WAT), recent studies suggest that miRNA levels are altered in various metabolic diseases, including obesity. Objective: The objective of the study was to determine whether adipocyte-expressed miRNAs altered by obesity can regulate adiponectin expression/secretion in fat cells. Design: Eleven miRNAs previously shown to be altered in obese human WAT were overexpressed in human in vitro-differentiated adipocytes followed by assessments of adiponectin levels in conditioned media. Setting: This was cohort study (n = 56) in an academic hospital. Patients: Subcutaneous WAT was obtained from nonobese and obese individuals. Interventions: There were no interventions in this study. Main Outcome Measure(s): Protein and mRNA levels of adiponectin were measured. Results: Of the 11 investigated miRNAs, three (miR-193b/-126/-26a) increased adiponectin secretion when overexpressed in human adipocytes. However, in human WAT only miR-193b expression correlated with adiponectin gene expression and homeostasis model assessment of insulin resistance. Moreover, quantitative PCR of miR-193b in both WAT and isolated adipocytes showed a significant association with serum adiponectin levels. Overexpression of miR-193b altered the gene expression of seven known adiponectin regulators. 3′-untranslated region reporter assays confirmed binding to cAMP-responsive element binding protein 5, nuclear receptor interacting protein 1, and nuclear transcription factor Yα. The effects of miR-193b on nuclear transcription factor Yα expression were confirmed at the protein level. Transfection with individual miRNA target protectors selective for nuclear transcription factor Yα and nuclear receptor interacting protein 1 abolished the stimulatory effect of miR-193b on adiponectin secretion. Conclusions: In human adipocytes, miR-193b controls adiponectin production via pathways involving nuclear transcription factor Yα and possibly nuclear receptor interacting protein 1.

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COMPARISON OF THE EFFECT OF PTEROCARPUS MARSUPIUM WITH PIOGLITAZONE IN DEXAMETHASONE-INDUCED INSULIN RESISTANCE

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2016.v9s2.13592 ◽

2016 ◽

pp. 211

Author(s):

Narendar Koyagura ◽

I M Nagendra Nayak ◽

M G Jamadar ◽

Ashok M Patil ◽

Sanjit Anand

Keyword(s):

Insulin Resistance ◽

Serum Insulin ◽

Ethanolic Extract ◽

Control Group ◽

Model Assessment ◽

Pterocarpus Marsupium ◽

Glucose Levels ◽

Gum Acacia ◽

Insulin Sensitizing Activity ◽

D 12

ABSTRACT Objective: This study was undertaken to evaluate the preventive effect of heartwood of P. marsupium in dexamethasone-induced hyperinsulinemia and hyperglycemia and compare it with that of pioglitazone. Methods: Male albino wistar rats were divided into five groups (n=6). Plain control group received gum acacia (2%) orally from d 1 to d 12. Dexa control group received gum acacia (2%) orally for d 1 to d 12 and Dexa (8 mg/kg) intraperitoneal (i.p.) from d 7 to d 12, during the study period. Two test groups received ethanolic extract of Pterocarpus marsupium heartwood (PME) (1 and 2 g/kg/) per oral (PO), and standard control group received pioglitazone (60 mg/kg/PO) from d 1 to d 12. During the 12-d study period, the two test groups and standard control group received Dexa (8 mg/kg/i.p.) from d 7 to d 12. On last day of the study, the blood samples were collected by retro-orbital sinus punctureand used for estimation of serum insulin and glucose levels. Homeostatic Model Assessment (HOMA) method was employed to calculate the degree of insulin resistance(IR). Results were analyzed by using one-way analysis of variance followed by Scheffe’s multiple comparison test (p<0.05). Results: Treatment with ethanolic extract of P. marsupium and pioglitazone significantly (p<0.05) reduced the elevated insulin and glucose levels as well as HOMA-IR and HOMA-IS values in dexa treated animals. Conclusion: Ethanolic extract of P. marsupium heartwood effectively countered dexamethasone-induced hyperinsulinemia and hyperglycemia. Insulin-sensitizing activity of P. marsupium heartwood was found to be more effective than pioglitazone. Keywords: Pterocarpus marsupium, Insulin resistance, Hyperinsulinemia, Hyperglycemia.

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Subcutaneous Fat Fibrosis Links Obesity to Insulin Resistance in Chinese Americans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02301 ◽

2018 ◽

Vol 103 (9) ◽

pp. 3194-3204 ◽

Cited By ~ 11

Author(s):

Diana L Alba ◽

Jeffrey A Farooq ◽

Matthew Y C Lin ◽

Anne L Schafer ◽

John Shepherd ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

San Francisco ◽

Body Fat ◽

Subcutaneous Fat ◽

Chinese Americans ◽

Mrna Levels ◽

Model Assessment ◽

Total Body Fat ◽

Total Body

Abstract Objective Type 2 diabetes presents at a lower body mass index (BMI) in Chinese individuals than in white individuals. We sought to determine the role of subcutaneous adipose tissue (SCAT)–intrinsic factors, vs BMI or adiposity per se, in the vulnerability of Chinese individuals to obesity-associated impairment of insulin sensitivity. Research Design and Methods Thirty-two Chinese and 30 white men and women from a cohort in the San Francisco Bay Area underwent anthropometric measurements, body composition (dual-energy X-ray absorptiometry) analyses, and measurement of fasting plasma glucose and insulin. Forty-eight also provided abdominal SCAT samples for transcriptional and biochemical analyses of tissue fibrosis. Results BMI correlated with total body fat in white (r = 0.74, P < 0.001) but not Chinese individuals, whereas BMI correlated with visceral adipose tissue (VAT) accrual in both ethnicities (r = 0.88 and 0.81, respectively; P < 0.01). Insulin resistance (homeostatic model assessment of insulin resistance) worsened with VAT mass, but not total body fat, in Chinese subjects (r = 0.63, P < 0.01), whereas it worsened with both in white individuals. By contrast, SCAT mRNA levels of genes encoding profibrotic proteins rose remarkably along with both BMI and VAT mass in Chinese but not white subjects. Similarly, SCAT levels of hydroxyproline, an indicator of tissue collagen content that correlated with increasing VAT mass, were higher in Chinese vs white subjects, particularly in the setting of relative insulin resistance. Conclusions Our findings dissociate BMI from adiposity in Chinese individuals and instead highlight SCAT fibrosis as a process linked to visceral adiposity and insulin resistance in this group.

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The anti-diabetic effects of NAG-1/GDF15 on HFD/STZ-induced mice

Scientific Reports ◽

10.1038/s41598-021-94581-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Pattawika Lertpatipanpong ◽

Jaehak Lee ◽

Ilju Kim ◽

Thomas Eling ◽

Seung Yeon Oh ◽

...

Keyword(s):

Serum Insulin ◽

Fasting Blood Glucose ◽

Immunohistochemical Analysis ◽

Diabetic Mouse ◽

Mrna Levels ◽

Model Assessment ◽

Glucose Levels ◽

Lower Body Weight ◽

Homeostatic Model Assessment ◽

Beta Cell Area

AbstractNonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) plays a role in various diseases. Here, the anti-diabetic effects of NAG-1 were evaluated using a high-fat diet/streptozotocin-induced diabetic mouse model. NAG-1-overexpressing transgenic (NAG-1 Tg) mice exhibited lower body weight, fasting blood glucose levels, and serum insulin levels than wild-type (WT) mice. The homeostatic model assessment of insulin resistance scores of NAG-1 Tg mice were lower than those of WT mice. Hematoxylin and eosin staining revealed a smaller lipid droplet size in the adipose tissues, lower lipid accumulation in the hepatocytes, and larger beta cell area in the pancreas of NAG-1 Tg mice than in those of WT mice. Immunohistochemical analysis revealed downregulated expression of cleaved caspase-3, an apoptosis marker, in the beta cells of NAG-1 Tg mice. Adiponectin and leptin mRNA levels were upregulated and downregulated in NAG-1 Tg mice, respectively. Additionally, the expression of IRS1/PI3K/AKT signaling pathway components, especially Foxo1, which regulates gluconeogenesis in the muscle and white adipose tissue, was downregulated in NAG-1 Tg mice. Furthermore, NAG-1 overexpression promoted the expression of As160 in both muscles and adipocytes, and the mRNA levels of the NLRP3 pathway members were downregulated in NAG-1 Tg mice. Our findings suggest that NAG-1 expression alleviates diabetes in mice.

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Maternal Protein Restriction Altered Insulin Resistance and Inflammation-Associated Gene Expression in Adipose Tissue of Young Adult Mouse Offspring in Response to a High-Fat Diet

Nutrients ◽

10.3390/nu12041103 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1103 ◽

Cited By ~ 2

Author(s):

Juhae Kim ◽

Alee Choi ◽

Young Hye Kwon

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Serum Insulin ◽

Protein Restriction ◽

Epididymal Adipose Tissue ◽

Model Assessment ◽

High Fat ◽

Maternal Protein Restriction ◽

Increased Risk

Maternal protein restriction is associated with increased risk of insulin resistance and inflammation in adulthood offspring. Here, we investigated whether maternal protein restriction could alter the risk of metabolic syndrome in postweaning high-fat (HF)-diet-challenged offspring, with focus on epididymal adipose tissue gene expression profile. Female ICR mice were fed a control (C) or a low-protein (LP) diet for two weeks before mating and throughout gestation and lactation, and their male offspring were fed an HF diet for 22 weeks (C/HF and LP/HF groups). A subset of offspring of control dams was fed a low-fat control diet (C/C group). In response to postweaning HF diet, serum insulin level and the homeostasis model assessment of insulin resistance (HOMA-IR) were increased in control offspring. Maternal LP diet decreased HOMA-IR and adipose tissue inflammation, and increased serum adiponectin level in the HF-diet-challenged offspring. Accordingly, functional analysis revealed that differentially expressed genes (DEGs) enriched in cytokine production were downregulated in the LP/HF group compared to the C/HF group. We also observed the several annotated gene ontology terms associated with innate immunity and phagocytosis in down-regulated DEGs between LP/HF and C/C groups. In conclusion, maternal protein restriction alleviated insulin resistance and inflammation in young offspring mice fed a HF diet but may impair development of immune system in offspring.

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