Tumour necrosis factor alpha: a key regulator of adipose tissue mass

Warne, James P.

doi:10.1677/joe.0.1770351

Cited by 157 publications

(115 citation statements)

References 29 publications

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“…Prediabetes and type 2 diabetes mellitus are characterized by sub-acute chronic inflammation where individuals show elevated serum levels of acute phase proteins such as C-reactive protein and fibrinogen (70) and cytokines such as TNF-␣ (71) and IL-6 (70,72). Although TNF-␣ is produced mainly by adipose tissue in obese prediabetic and diabetic individuals (71,73), a critical source for the proinflammatory cytokines IL-6 and IL-1␤ is activated macrophages (74). Furthermore, these macrophagegenerated cytokines are potent inducers of liver-produced C-reactive protein and fibrinogen.…”

Section: Discussionmentioning

confidence: 99%

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Hartman

O’Connor

Godbout

et al. 2004

Journal of Biological Chemistry

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We have shown previously that hyperinsulinemia inhibits interferon-␣-dependent activation of phosphatidylinositol 3-kinase (PI3-kinase) through mammalian target of rapamycin (mTOR)-induced serine phosphorylation of insulin receptor substrate (IRS)-1. Here we report that chronic insulin and high glucose synergistically inhibit interleukin (IL)-4-dependent activation of PI3-kinase in macrophages via the mTOR pathway. Resident peritoneal macrophages (PerM⌽s) from diabetic (db/db) mice showed a 44% reduction in IRS-2-associated PI3-kinase activity stimulated by IL-4 compared with PerM⌽s from heterozygote (db/؉) control mice. IRS-2 from db/db mouse PerM⌽s also showed a 78% increase in Ser/Thr-Pro motif phosphorylation without a difference in IRS-2 mass. To investigate the mechanism of this PI3-kinase inhibition, 12-O-tetradecanoylphorbol-13-acetate-matured U937 cells were treated chronically with insulin (1 nM, 18 h) and high glucose (4.5 g/liter, 48 h). In these cells, IL-4-stimulated IRS-2-associated PI3-kinase activity was reduced by 37.5%. Importantly, chronic insulin or high glucose alone did not impact IL-4-activated IRS-2-associated PI3-kinase. Chronic insulin ؉ high glucose did reduce IL-4-dependent IRS-2 tyrosine phosphorylation and p85 association by 54 and 37%, respectively, but did not effect IL-4-activated JAK/STAT signaling. When IRS-2 Ser/Thr-Pro motif phosphorylation was examined, chronic insulin ؉ high glucose resulted in a 92% increase in IRS-2 Ser/Thr-Pro motif phosphorylation without a change in IRS-2 mass. Pretreatment of matured U937 cells with rapamycin blocked chronic insulin ؉ high glucose-dependent IRS-2 Ser/Thr-Pro motif phosphorylation and restored IL-4-dependent IRS-2-associated PI3-kinase activity. Taken together these results indicate that IRS-2-dependent IL-4 signaling in macrophages is impaired in models of type 2 diabetes mellitus through a mechanism that relies on insulin/ glucose-dependent Ser/Thr-Pro motif serine phosphorylation mediated by the mTOR pathway.The first member of the insulin receptor substrate (IRS) 1 family, IRS-1, was initially discovered in Fao hepatoma cells as a tyrosine-phosphorylated substrate of the insulin receptor (1). In addition to insulin signaling, IRS proteins are integrally linked to intracellular signaling pathways initiated by IGF-I and the cytokines IL-2, 3, 4, 7, 9, 10, 13, 15 and IFN-␣ and IFN-␥ (2-10). Importantly, serine phosphorylation of IRS-1 blocks insulin, IGF-I, and cytokine signaling through IRS-1 (11-15) and appears critical to the initiation of proteasomedependent IRS-1 degradation (16,17). We have shown that chronic insulin in the presence of high glucose leads to serine phosphorylation of IRS-1 through an mTOR-dependent mechanism and that this renders IRS-1 a poorer substrate for JAK1 (18). In addition, we have shown that serine phosphorylation targets IRS-1 for proteasome-dependent degradation in L6 muscle cells (19). However, these same mechanisms have not been investigated in relation to IRS-2-dependent cytokine signaling.IRS-2 is...

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Section: Discussionmentioning

confidence: 99%

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Hartman

O’Connor

Godbout

et al. 2004

Journal of Biological Chemistry

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“…21 In addition, it is also possible that insulin resistance per se might involve the development of obesity. 22,23 Aberrant production of TNF-a in adipose tissue may inhibit insulin from promoting adipocyte triglyceride stores or adipocyte differentiation. Indeed, gene polymorphisms of TNF have been associated with obesity by many investigators.…”

Section: Discussionmentioning

confidence: 99%

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity

et al. 2005

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Objective: To explore the association of promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene with obesity. Subjects: In total, 213 nondiabetic Japanese subjects. They were divided into three groups according to World Health Organization definitions: lean (body mass index (BMI) o25 kg/m 2 ), overweight (25pBMIo30 kg/m 2 ) and obese (BMIX30 kg/m 2 ). Methods: We examined two polymorphic loci in the MIF gene in the subjects: a single-nucleotide polymorphism at position À173 (G/C) and a CATT-tetranucleotide repeat polymorphism at position À794, which both can affect promoter activity in different cells. Results: We detected four alleles: 5-, 6-, 7-and 8-CATT at position À794. Genotypes without the 5-CATT allele (X/X, X refers to 6-, 7-or 8-CATT alleles) were more common in obese subjects than in lean or overweight groups (P ¼ 0.013). The X-CATT allele was more frequent in obese subjects than in lean or overweight subjects (P ¼ 0.030). In contrast, À173G/C was not associated with obesity. Among the haplotypes of the two promoter polymorphisms, G/5-CATT ((À173G/C)/(À794[CATT] 5-8 )) was associated with a decreased risk of obesity (P ¼ 0.025) and G/6-CATT with an increased risk of overweight (P ¼ 0.028). Conclusion: Promoter polymorphism in the MIF gene is linked with obesity.

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“…Indivíduos obesos têm excesso de tecido adiposo, o qual é metabolicamente ativo, secretando citocinas e adiponectinas capazes de modular reações imunes (22)(23)(24)(25)(26)(27).…”

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“…A expressão e a secreção de TNF-alfa encontram--se elevadas no tecido adiposo e a neutralização de sua secreção melhora a resistência à insulina (25,26). Vá-rios estudos sugerem um papel para o TNF-alfa com resistência à insulina encontrada na obesidade (25)(26)(27).…”

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Avaliação do peso corporal em pacientes com doença de Graves durante o tratamento com metimazol

Moretto¹,

Pedro²,

Leite³

et al. 2012

Arq Bras Endocrinol Metab

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RESUMOObjetivo: Avaliar a alteração de peso durante o tratamento do hipertiroidismo e correlacioná--la com IL-6 e TNF-alfa. Sujeitos e métodos: Quarenta e dois pacientes foram incluídos. Peso corporal (PC), índice de massa corpórea (IMC), características clínicas e laboratoriais foram registrados. IL-6 e TNF-alfa foram determinados antes do tratamento com metimazol (MMI) e no estado de eutiroidismo. Resultados: O PC foi de 59,62 ± 11,5 kg no estado de hipertiroidismo e de 69,91 ± 14,4 kg no estado de eutiroidismo (p < 0,001 Descritores Hipertiroidismo; fator de necrose tumoral alfa; interleucina-6; metimazol; hormônio tiroidiano; peso corporal ABSTRACT Objective: To evaluate weight change during hyperthyroidism treatment, and to correlate it with IL-6 and TNF-alpha concentrations. Subjects and methods: Forty two patients were included. Body weight (BW), body mass index (BMI), clinical and laboratory characteristics were recorded. IL-6 and TNF-alpha were determined before treatment with methimazole (MMI) and in euthyroidism. Results: BW was 59.62 ± 11.5 kg in hyperthyroidism, and 69.91 ± 14.4 kg in euthyroidism (p < 0.001). BMI increased from 23.1 ± 3.8 kg/m 2 to 27 kg/m 2 ± 4.7 during treatment (p < 0.0001). Before treatment, 66.6% subjects had BMI < 25 kg/m 2 and 33.3%, BMI ≥ 25 kg/m 2 . In euthyroidism, 38% of patients had BMI < 25 kg/m 2 and 62%, BMI ≥ 25 kg/m 2 (p = 0.01). In euthyroidism, we found a significant reduction in IL-6 and TNF-alpha concentrations, but no correlation between IL-6 and TNF-alpha, and BW or BMI. Conclusion: An important increase in BW and BMI was observed during hyperthyroidism treatment, and IL-6 and TNF-alpha alterations were only related with return to euthyroidism. Arq Bras Endocrinol Metab. 2012;56(6):364-9

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Tumour necrosis factor alpha: a key regulator of adipose tissue mass

Cited by 157 publications

References 29 publications

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity

Avaliação do peso corporal em pacientes com doença de Graves durante o tratamento com metimazol

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