Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-α

Ruan, Hong; Lodish, Harvey F.

doi:10.1016/s1359-6101(03)00052-2

Cited by 473 publications

(339 citation statements)

References 107 publications

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“…TNFα and rosiglitazone regulate autotaxin expression in 3T3F442A adipocytes In order to test whether autotaxin expression could be directly dependent on adipocyte glucose homeostasis and insulin sensitivity, mouse 3T3F442A adipocytes were treated with TNFα (a diabetogenic cytokine known to impair glucose utilisation and insulin sensitivity in adipocytes) or rosiglitazone (a peroxisome proliferator-activated receptor [PPAR]-γ agonist known to improve adipocyte glucose utilisation and insulin sensitivity in adipocytes) [11]. Compared with untreated cells, 24 h of treatment with 10 ng/ml TNFα led to a significant increase (1.5-fold) in autotaxin mRNA levels, whereas treatment with 1 μmol/l rosiglitazone led to a strong and significant reduction (80% reduction) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Since insulin resistance is known to greatly influence gene expression in adipocytes [11], it is likely that insulin resistance of db/db adipocytes could play a role in the up-regulation of autotaxin gene expression. This hypothesis was supported by the direct positive effect of TNFα (a cytokine that promotes insulin resistance), and the negative regulatory effect of rosiglitazone (a PPARγ agonist well known for its ability to improve insulin sensitivity) on autotaxin expression in 3T3F442A adipocytes.…”

Section: Discussionmentioning

confidence: 99%

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Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

et al. 2005

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Aims/hypothesis: Autotaxin is a lysophospholipase D that is secreted by adipocytes and whose expression is substantially up-regulated in obese, diabetic db/db mice. The aim of the present study was to depict the physiopathological and cellular mechanisms involved in regulation of adipocyte autotaxin expression. Methods: Autotaxin mRNAs were quantified in adipose tissue from db/db mice (obese and highly diabetic type 2), gold-thioglucose-treated (GTG) mice (highly obese and moderately diabetic type 2), high-fat diet-fed (HFD) mice (obese and moderately diabetic type 2), streptozotocin-treated mice (thin and diabetic type 1), and massively obese humans with glucose intolerance. Results: When compared to non-obese controls, autotaxin expression in db/db mice was significantly increased, but not in GTG, HFD, or streptozotocin-treated mice. During db/db mice development, up-regulation of autotaxin occurred only 3 weeks after the emergence of hyperinsulinaemia, and simultaneously with the emergence of hyperglycaaemia. Adipocytes from db/db mice exhibited a stronger impairment of insulin-stimulated glucose uptake than non-obese and HFD-induced obese mice. Autotaxin expression was up-regulated by treatment with TNFα (insulin resistance-promoting cytokine), and down-regulated by rosiglitazone treatment (insulin-sensitising compound) in 3T3F442A adipocytes. Finally, adipose tissue autotaxin expression was significantly up-regulated in patients exhibiting both insulin resistance and impaired glucose tolerance. Conclusions/interpretation: The present work demonstrates the existence of a db/db-specific upregulation of adipocyte autotaxin expression, which could be related to the severe type 2 diabetes phenotype and adipocyte insulin resistance, rather than excess adiposity in itself. It also showed that type 2 diabetes in humans is also associated with up-regulation of adipocyte autotaxin expression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

et al. 2005

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“…Many studies have analysed this question, and these will only be summarised here. Immune mediators such as TNF-α and IL-6 can directly interfere with insulin signalling [99][100][101][102][103], and the binding of these cytokines to their cognate receptor on muscle cells or hepatocytes has been shown to induce an intracellular response that interferes with the ability of the insulin receptor to phosphorylate its intracellular targets. The cellular response to insulin is dampened in consequence.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

An immune origin of type 2 diabetes?

2005

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Subclinical, low-grade systemic inflammation has been observed in patients with type 2 diabetes and in those at increased risk of the disease. This may be more than an epiphenomenon. Alleles of genes encoding immune/ inflammatory mediators are associated with the disease, and the two major environmental factors the contribute to the risk of type 2 diabetes-diet and physical activity-have a direct impact on levels of systemic immune mediators. In animal models, targeting of immune genes enhanced or suppressed the development of obesity or diabetes. Obesity is associated with the infiltration and proinflammatory activity of macrophages in adipose tissue, and immune mediators may be important regulators of insulin resistance, mitochondrial function, ectopic lipid storage and beta cell dysfunction or death. Intervention studies targeting these pathways would help to determine the contribution of an activated innate immune system to the development of type 2 diabetes.

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“…As expected, a rapid and robust downregulation of PPARγ, ATGL, resistin, and SCD1 is noted within 12 h of TNFα exposure. Given the large proportion of adipocyte-abundant transcripts that DNA oligonucleotide microarray studies have indicated are TNFα-responsive in 3T3-L1 adipocytes [60][61][62], we were rather surprised to find that Adhfe1 transcript level was refractory to alteration by TNFα treatment. Exposure of 3T3-L1 adipocytes to nanomolar through micromolar concentrations of TNFα for 24 h ( Figure 4B) was consistent with data in Figure 4A in that while ATGL, resistin, and SCD1 were responsive to TNFα, Adhfe1 transcript level was not altered by either low or high concentrations of TNFα.…”

Section: Adhfe1 Transcript Expression In 3t3-l1 Adipocytes Is Refractmentioning

confidence: 98%

“…To begin to investigate the signals that might regulate Adhfe1 transcript level in adipocytes, we treated 3T3-L1 adipocytes with an agent closely tied to adipocyte function and phenotype, TNFα [22,52,61,62]. Treatment of preadipocytes with TNFα inhibits adipogenic conversion [71,81] and treatment of adipocytes results in what has been termed "dedifferentiation" [70,71,75].…”

Section: Adhfe1 Transcript Expression In 3t3-l1 Adipocytes Is Refractmentioning

confidence: 99%

Differentiation-dependent expression of Adhfe1 in adipogenesis

Kim¹,

Tillison²,

Zhou³

et al. 2007

Archives of Biochemistry and Biophysics

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We have determined that adipocytes are a major site of expression of the transcript for the novel alcohol dehydrogenase (ADH), Adhfe1. Adhfe1 is unique in that the sequence of its encoded protein places it among the iron-activated ADHs. Western blot analysis reveals Adhfe1 encodes a 50 kDa cytoplasmic protein and immunocytochemical staining indicates mitochondrial localization. Adhfe1 transcript exhibits differentiation-dependent expression during in vitro brown and white adipogenesis. Unlike many adipocyte-enriched genes, however, Adhfe1 transcript expression in adipocytes is refractory to TNFα-mediated downregulation. However, use of pharmacological inhibitors reveals PI 3-kinase-mediated signals maintain the basal level of Adhfe1 transcript in 3T3-L1 adipocytes. Tissue profiling studies show Adhfe1 transcript is restricted to white and brown adipose tissues, liver, and kidney. In comparison to C57BL/6 mice, Adhfe1 transcript is downregulated 40% in white adipose tissue of ob/ob obese mice. Further characterization of Adhfe1 should yield new insights into adipocyte function and energy metabolism.

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Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-α

Cited by 473 publications

References 107 publications

Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

An immune origin of type 2 diabetes?

Differentiation-dependent expression of Adhfe1 in adipogenesis

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