Increased T-helper interferon-γ-secreting cells in obese children

Objective: Leptin, an adipocyte-secreted hormone, has emerged as a potential candidate for the link between obesity and the proinflammatory state. Specifically, leptin modulates T-helper (Th) cells toward a Th1 phenotype, with the secretion of proinflammatory cytokines. The aim of this study was to evaluate the Th1/Th2 balance in obese children and its relation with hormonal and metabolic features. Study design: In 50 obese children and 20 control children, we measured the CD4-positive Th cells that secrete interferon (IFN)-γ or interleukin (IL)-2 (taken as an index of Th1 cells), and IL-4 (taken as an index of Th2 cells) as well as serum glucose, insulin, insulin resistance (IR) index (as homeostasis model assessment model (HOMA)), lipid profile, aminotransferases, leptin and ghrelin. Obese children also underwent dual energy X-ray absorptiometry scan measurements, and liver ultrasound scanning. Results: Geometric mean percentages of IL-2- and IL-4-CD4 secreting cells in obese children were not significantly different from those found in control children. However, the geometric mean percentage of CD4-positive T cells secreting IFN-γ was significantly higher in the obese than in the control (P < 0.0001, t-test) group. Within the entire group of study children, the percentage of IFN-γ-positive cells was positively associated with leptin (P = 0.002), insulin (P < 0.00 005), and HOMA-IR values (P < 0.00 005). However, when these associations were restricted to the group of obese subjects, insulin and HOMA-IR values, but not leptin, retained statistical significance. Yet, in the obese group, the percentage of IFN-γ-positive cells was associated with nonalcoholic steatohepatitis (NASH) (P = 0.001), but not with body mass index-standard deviation score and total body fat mass. Conclusions: In obese children, a shift to Th1-cytokine profile dominated by the production of IFN-γ is related to insulin resistance as well as to NASH independently of anthropometric features and other metabolic characteristics. The prevalent Th1 pattern of secreted cytokines may be regarded as a mechanism contributing to inflammation in obesity.

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A Signal Transducer and Activator of Transcription (Stat)4-independent Pathway for the Development of T Helper Type 1 Cells

Journal of Experimental Medicine ◽

10.1084/jem.188.6.1191 ◽

1998 ◽

Vol 188 (6) ◽

pp. 1191-1196 ◽

Cited By ~ 127

Author(s):

Mark H. Kaplan ◽

Andrea L. Wurster ◽

Michael J. Grusby

Keyword(s):

Delayed Type Hypersensitivity ◽

Th2 Cells ◽

Signal Transducer ◽

T Helper ◽

Th1 Cell ◽

Th Cells ◽

Th Cell ◽

Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

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Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells

Journal of Experimental Medicine ◽

10.1084/jem.20020620 ◽

2002 ◽

Vol 196 (7) ◽

pp. 969-977 ◽

Cited By ~ 190

Author(s):

Andrea L. Wurster ◽

Vikki L. Rodgers ◽

Abhay R. Satoskar ◽

Matthew J. Whitters ◽

Deborah A. Young ◽

...

Keyword(s):

Interferon Γ ◽

Th2 Cells ◽

Th1 Cells ◽

T Helper ◽

Th2 Response ◽

Th Cells ◽

Th Cell ◽

Ifn Γ

The cytokine potential of developing T helper (Th) cells is directly shaped both positively and negatively by the cytokines expressed by the effector Th cell subsets. Here we find that the recently identified cytokine, interleukin (IL)-21, is preferentially expressed by Th2 cells when compared with Th1 cells generated in vitro and in vivo. Exposure of naive Th precursors to IL-21 inhibits interferon (IFN)-γ production from developing Th1 cells. The repression of IFN-γ production is specific in that the expression of other Th1 and Th2 cytokines is unaffected. IL-21 decreases the IL-12 responsiveness of developing Th cells by specifically reducing both signal transducer and activator of transcription 4 protein and mRNA expression. These results suggest that Th2 cell-derived IL-21 regulates the development of IFN-γ–producing Th1 cells which could serve to amplify a Th2 response.

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Interleukin 18 Acts on Memory T Helper Cells Type 1 to Induce Airway Inflammation and Hyperresponsiveness in a Naive Host Mouse

Journal of Experimental Medicine ◽

10.1084/jem.20031368 ◽

2004 ◽

Vol 199 (4) ◽

pp. 535-545 ◽

Cited By ~ 86

Author(s):

Takaaki Sugimoto ◽

Yuriko Ishikawa ◽

Tomohiro Yoshimoto ◽

Nobuki Hayashi ◽

Jiro Fujimoto ◽

...

Keyword(s):

Airway Inflammation ◽

Bronchial Asthma ◽

Allergic Diseases ◽

Th2 Cells ◽

Th1 Cells ◽

T Helper ◽

Inflammatory Protein ◽

Ifn Γ ◽

Factor Α

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-γ production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-γ–expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-γ–expressing Th1 cells, both of which express IL-18 receptor α chain strongly, produce IFN-γ, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor α, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1α upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.

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Dietary determinants of hepatic fat content and insulin resistance in overweight/obese children: a cross-sectional analysis of the Prevention of Diabetes in Kids (PREDIKID) study

British Journal Of Nutrition ◽

10.1017/s0007114519000436 ◽

2019 ◽

Vol 121 (10) ◽

pp. 1158-1165 ◽

Cited By ~ 5

Author(s):

Lide Arenaza ◽

María Medrano ◽

Maddi Oses ◽

Inge Huybrechts ◽

Ignacio Díez ◽

...

Keyword(s):

Insulin Resistance ◽

Dietary Intake ◽

Dietary Habits ◽

Sugar Content ◽

Model Assessment ◽

Obese Children ◽

Cross Sectional ◽

Alcoholic Fatty Liver ◽

Sugar Intake ◽

Hepatic Fat

AbstractPaediatric non-alcoholic fatty liver disease has increased in parallel with childhood obesity. Dietary habits, particularly products rich in sugars, may influence both hepatic fat and insulin resistance (homeostatic model assessment for insulin resistance (HOMA-IR)). The aim of the study was to examine the association of the consumption of foods and food components, dairy desserts and substitutes (DDS), sugar-sweetened beverages (SSB), as well as total and added sugars, with hepatic fat and HOMA-IR. Dietary intake (two non-consecutive 24 h-recalls), hepatic fat (MRI) and HOMA-IR were assessed in 110 overweight/obese children (10·6 (sd 1·1) years old). Linear regression analyses were used to examine the association of dietary intake with hepatic fat and HOMA-IR adjusted for potential confounders (sex, age, energy intake, maternal educational level, total and abdominal adiposity and sugar intake). The results showed that there was a negative association between cereal intake and hepatic fat (β=–0·197, P<0·05). In contrast, both SSB consumption (β=0·217; P=0·028) and sugar in SSB (β=0·210, P=0·035), but not DDS or sugar in DDS or other dietary components, were positively associated with hepatic fat regardless of potential confounders including total sugar intake. In conclusion, cereal intake might decrease hepatic fat, whereas SSB consumption and its sugar content may increase the likelihood of having hepatic steatosis. Although these observations need to be confirmed using experimental evidence, these results suggest that healthy lifestyle intervention programs are needed to improve dietary habits as well as to increase the awareness of the detrimental effects of SSB consumption early in life.

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Metabolic Profiles in Obese Children and Adolescents with Insulin Resistance

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2018.097 ◽

2018 ◽

Vol 6 (3) ◽

pp. 511-518 ◽

Cited By ~ 2

Author(s):

Marko Kostovski ◽

Viktor Simeonovski ◽

Kristina Mironska ◽

Velibor Tasic ◽

Zoran Gucev

Keyword(s):

Insulin Resistance ◽

Children And Adolescents ◽

Plasma Glucose ◽

Metabolic Profile ◽

Total Serum ◽

Model Assessment ◽

Fasting Insulin ◽

Obese Children ◽

Insulin Resistant ◽

Study Results

BACKGROUND: In the past several decades, the increasing frequency of overweight and obese children and adolescents in the world has become a public health problem. It has contributed significantly to the already high tide of diabetes, cardiovascular and cerebrovascular diseases.AIM: To investigate the frequency of insulin resistance and to evaluate the metabolic profile of insulin resistant and non-insulin resistant obese children and adolescents.SUBJECTS AND METHODS: The study included 96 (45 boys, 51 girls) obese children and adolescents aged 4-17 years old (10.50 ± 2.87 years). Only participants with Body Mass Index ≥ 95 percentile were included. We analysed sera for fasting insulin levels (FI), fasting serum triglycerides (TG), total serum cholesterol (TC), fasting plasma glucose (FPG) and plasma glucose 2 hours after the performance of the oral glucose tolerance test (2-h G). Homeostatic model assessment for insulin resistance (HOMA-IR) index was calculated as fasting insulin concentration (microunits per millilitre) x fasting glucose concentration (millimolar)/22.5. The value of HOMA-IR above 3.16 was used as a cut-off value for both genders.RESULTS: Insulin resistance was determined in 58.33% of study participants. Insulin resistant participants had significantly higher level of 2-h G (p = 0.02), FI level (p = 0.000) as well as TG levels (p = 0.01), compared to non-insulin resistant group. Strikingly, 70.73% of the pubertal adolescents were insulin resistant in comparison to 49.09% of the preadolescents (p = 0.03). Significantly higher percentage of insulin-resistant participants were girls (p = 0.009). Moreover, a higher percentage of the girls (70.59%) than boys (44.44%) had HOMA-IR above 3.16 and had elevated FI levels (70.59% vs 48.89%). The difference in the frequency of insulin resistance among obese versus severely obese children and adolescents was not significant (p = 0.73, p > 0.05). Our study results also showed positive, but weak, correlation of HOMA-IR with age, FPG, TG and BMI of the participants (p < 0.05).CONCLUSION: Higher percentage of insulin-resistant participants was of female gender and was adolescents. In general, insulin resistant obese children and adolescents tend to have a worse metabolic profile in comparison to individuals without insulin resistance. It is of note that the highest insulin resistance was also linked with the highest concentrations of triglycerides.

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Serum uric acid and its association with metabolic syndrome and carotid atherosclerosis in obese children

Acta Endocrinologica ◽

10.1530/eje-08-0618 ◽

2009 ◽

Vol 160 (1) ◽

pp. 45-52 ◽

Cited By ~ 71

Author(s):

Lucia Pacifico ◽

Vito Cantisani ◽

Caterina Anania ◽

Elisabetta Bonaiuto ◽

Francesco Martino ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Uric Acid ◽

Carotid Atherosclerosis ◽

Resistance Index ◽

Model Assessment ◽

Obese Children ◽

Pubertal Stage ◽

Carotid Imt

ObjectiveThe association between hyperuricemia, metabolic syndrome (MS), and atherosclerotic vascular disease has been reported in adults, but very little is known about this association in children. The aims of our study were to ascertain the correlates of uric acid (UA) in a sample of obese children, and to investigate whether UA is associated with carotid intima-media thickness (IMT) independently from classical risk factors including MS.MethodsWe analyzed carotid IMT along with serum triglycerides, total and high-density lipoprotein cholesterol, glucose, insulin, insulin resistance index (as homeostasis model assessment of insulin resistance), alanine aminotransferase, γ-glutamyltransferase, creatinine, and UA in 120 obese children and 50 healthy control children.ResultsUA concentrations were significantly higher in obese children compared with controls; moreover, they correlated with the most established cardiovascular risk factors. In the group of obese children, after adjustment for age, sex, pubertal stage, and creatinine, an independent association between UA levels and the presence of MS syndrome was observed (unstandardized coefficient, 0.044 (95% confidence intervals (CI) 0.015–0.072); P<0.01). Carotid IMT significantly increased in the fourth quartile of UA compared with that in the first, second, and third quartile (0.49 (0.46–0.53), 0.53 (0.49–0.56), and 0.55 (0.52–0.59) vs 0.61 (95% CI, 0.58–0.64); P<0.01). When multivariate analysis was performed after adjusting for age, gender, pubertal stage, creatinine, and MS (considered as a single clinical entity), or the individual components of MS simultaneously included, the association between UA and carotid IMT was significant (P<0.01).ConclusionsIn obese children and adolescents, increased UA levels are associated with carotid atherosclerosis.

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Relation of insulin resistance to neurocognitive function and electroencephalography in obese children

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2017-0186 ◽

2017 ◽

Vol 30 (10) ◽

Cited By ~ 3

Author(s):

Onur Akın ◽

İbrahim Eker ◽

Mutluay Arslan ◽

Süleyman Tolga Yavuz ◽

Sevil Akman ◽

...

Keyword(s):

Insulin Resistance ◽

Central Nervous System ◽

Nervous System ◽

Healthy Children ◽

Model Assessment ◽

Obese Children ◽

Neurocognitive Functions ◽

The Central Nervous System ◽

Biochemical Indices ◽

The Impact

AbstractBackground:Childhood obesity may lead to neuronal impairment in both the peripheral and the central nervous system. This study aimed to investigate the impact of obesity and insulin resistance (IR) on the central nervous system and neurocognitive functions in children.Methods:Seventy-three obese children (38 male and 35 female) and 42 healthy children (21 male and 21 female) were recruited. Standard biochemical indices and IR were evaluated. The Wechsler Intelligence Scale for Children-Revised (WISC-R) and electroencephalography (EEG) were administered to all participants. The obese participants were divided into two groups based on the presence or absence of IR, and the data were compared between the subgroups.Results:Only verbal scores on the WISC-R in the IR+ group were significantly lower than those of the control and IR– groups. There were no differences between the groups with respect to other parameters of the WISC-R or the EEG. Verbal scores of the WISC-R were negatively correlated with obesity duration and homeostatic model assessment-insulin resistance (HOMA-IR) values. EEGs showed significantly more frequent ‘slowing during hyperventilation’ (SDHs) in obese children than non-obese children.Conclusions:Neurocognitive functions, particularly verbal abilities, were impaired in obese children with IR. An early examination of cognitive functions may help identify and correct such abnormalities in obese children.

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Insulin resistance and lung function in obese asthmatic pre-pubertal children

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2017-0182 ◽

2018 ◽

Vol 31 (1) ◽

pp. 45-51 ◽

Cited By ~ 4

Author(s):

Paola Di Filippo ◽

Alessandra Scaparrotta ◽

Daniele Rapino ◽

Tommaso de Giorgis ◽

Marianna Immacolata Petrosino ◽

...

Keyword(s):

Insulin Resistance ◽

Lung Function ◽

Statistical Significance ◽

Serum Levels ◽

Forced Expiratory Volume ◽

Normal Weight ◽

Model Assessment ◽

Obese Children ◽

Asthmatic Children ◽

Insulin Resistant

AbstractBackground:Recent findings have supposed that the underlying association between the increased prevalence of both asthma and obesity may be insulin resistance (IR).Methods:Insulin and glucose serum levels were analyzed to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) for IR in 98 pre-pubertal children. Lung function and allergy status evaluation were performed. The study population was divided into four groups: (1) obese asthmatic children (ObA); (2) normal-weight asthmatic children (NwA); (3) normal-weight non-asthmatic children (Nw) and (4) obese non-asthmatic children (Ob).Results:Forced expiratory volume in 1 s (FEV1) was slightly lower in obese subjects compared with normal-weight subjects and forced vital capacity (FVC) appeared lower in asthmatics, whereas between non-asthmatics subjects, it was lower in the obese group than in the normal-weight one. The post hoc analysis revealed a statistically significant reduction in FEV1, peak expiratory flow (PEF), forced expiratory flows (FEF) between 50% and 25% of the FVC (FEF50and FEF25) between ObA and Nw and in FEV1, FVC, PEF, FEF50and FEF25between NwA and Nw, but no statistically significant differences of lung function parameters were observed between ObA and NwA. We found an inverse relationship between HOMA-IR and all spirometric parameters, although without any statistical significance. We also observed a significantly lower FVC in insulin-resistant children (HOMA-IR>95th percentile) (p=0.03).Conclusions:This study suggests that lung function could be early altered in obese children, already in pre-pubertal age. Although IR should not manifest its effects on lungs in pre-pubertal obese children, the prevention or treatment of obesity in the pre-pubertal period may prevent definitive negative effects on lungs.

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Selective Expression and Functions of Interleukin 18 Receptor on T Helper (Th) Type 1 but not Th2 Cells

Journal of Experimental Medicine ◽

10.1084/jem.188.8.1485 ◽

1998 ◽

Vol 188 (8) ◽

pp. 1485-1492 ◽

Cited By ~ 257

Author(s):

Damo Xu ◽

Woon Ling Chan ◽

Bernard P. Leung ◽

David Hunter ◽

Kerstin Schulz ◽

...

Keyword(s):

Th2 Cells ◽

Interleukin 18 ◽

T Helper ◽

Th2 Cell ◽

A Cell ◽

Ifn Γ

Interleukin (IL)-18 induces interferon (IFN)-γ synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rβ2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R–derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin–T cell antigen receptor-αβ transgenic mice (D011.10). Anti–IL-18R antibody inhibited IL-18– induced IFN-γ production by Th1 clones in vitro. In vivo, anti–IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-γ and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

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Subsets and Function Changes of Th Cells in the Bone Marrow of Patients with Immune Related Pancytopenia.

Blood ◽

10.1182/blood.v106.11.3762.3762 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3762-3762

Author(s):

Guangsheng He ◽

Xiuli Wang ◽

De Pei Wu ◽

Aining Sun ◽

Zhengming Jin

Keyword(s):

Bone Marrow ◽

Mononuclear Cells ◽

Th2 Cells ◽

Th1 Cells ◽

T Helper ◽

Ifn Γ ◽

Polymerase Chain ◽

And Function ◽

Normal Controls ◽

Th Lymphocytes

Abstract Objectives To explore the subsets and function of T helper (Th) in bone marrow of the patients with immune related pancytopenia(IRP). Methods The CD4+ cells producing IFN-γ or IL-4 in cytoplasm were defined as Th1 or Th2 cells respectively. All these cells in bone marrow were measured from 16 normal controls, 25 untreated IRP patients; The mRNA expressions of IL-4, IL-10, IFN-γ and IL-2 genes in unstimulated bone marrow mononuclear cells(BMMNC)from 25 untreated IRP patients, 10 normal controls were measured by reverse transcription polymerase chain reaction (RT-PCR). Results The percentage of Th1 cells, Th2 cells and ratio of Th1/Th2 in bone marrow of normal controls was: 0.42%, 0.24%, 1.57 respectively, and the percentage of Th1 cells in untreated patients with IRP was 0.58%, which was not markedly different from the that of normal controls(t=0.903, P>0.05). But the percentage of Th2 cells of the patients with IRP was significantly higher than that of normal controls(t=4.673, P<0.01), and the balance of Th1/Th2 shifted to Th2 more significantly by comparing to that of normal controls (t=4.880, P<0.01). The mRNA expressions of IL-4 and IL-10 in the Th2 cells of the untreated IRP patients were significantly higher than those of the normal controls, however difference of the expressions of IFN-γ and IL-2 in the Th1 cells were not significantly. Conclusions The percentage of Th2 cells increased in the patients with IRP, and the balance of Th1/Th2 shifted to Th2. And the expression of Th2 type cytokines was more frequent in IRP. The imbalance of subtypes of Th lymphocytes and hyperfunction of Th2 lymphocytes might play important roles in the pathogenic mechanism of IRP, which lead to more B lymphocytes and producing autoantibodies consistenly.

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