JNK and Tumor Necrosis Factor-α Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes

Nguyen, Matthew; Satoh, Hiroaki; Favelyukis, Svetlana; Babendure, Jennie L.; Imamura, Teruhiko; Sbodio, Juan I.; Zalevsky, Jonathan; Dahiyat, Bassil I.; Wen, Nai; Olefsky, Jerrold M.

doi:10.1074/jbc.m504611200

Cited by 371 publications

(298 citation statements)

References 49 publications

(59 reference statements)

Supporting

Mentioning

263

Contrasting

Unclassified

Order By: Relevance

“…In agreement with the present data, obesity in rats induced by a high-fat diet led to increased iron requirements in association with greater accretion of body mass and vulnerability to iron deficiency [34]. The negative effects of palmitate in adipogenesis are mediated in part by the induction of inflammatory pathways and concomitant insulin resistance [35,36]. Moreover, we found that intracellular iron deficiency induced gene expression of inflammatory cytokines, leading us to suggest that iron deficiency might exacerbate the proinflammatory effects of saturated fatty acids.…”

Section: Intracellular Iron Deficiency Impairs Adipogenesissupporting

confidence: 78%

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

et al. 2014

View full text Add to dashboard Cite

Aims/hypothesis Adipose tissue from obese and insulinresistant individuals showed altered expression of several iron-related genes in a recent study, suggesting that iron might have an important role in adipogenesis. To investigate this possible role, we aimed to characterise the effects of iron on adipocyte differentiation. Methods Intracellular iron deficiency was achieved using two independent approaches: deferoxamine administration (20 and 100 μmol/l) and transferrin knockdown (TF KD). The effects of added FeSO 4 , holo-transferrin and palmitate were studied during human and 3T3-L1 adipocyte differentiation. Finally, the relationship between iron-related and mitochondrialrelated genes was investigated in human adipose tissue. Results Most adipose tissue iron-related genes were predominantly expressed in adipocytes compared with stromal vascular cells. Of note, transferrin gene and protein expression increased significantly during adipocyte differentiation. Both deferoxamine and TF KD severely blunted adipocyte differentiation in parallel with increased inflammatory mRNAs. These effects were reversed in a dose-dependent manner after iron supplementation. Palmitate administration also led to a state of functional intracellular iron deficiency, with decreased Tf gene expression and iron uptake during adipocyte differentiation, which was reversed with transferrin co-treatment. On the other hand, iron in excess impaired differentiation, but this antiadipogenic effect was less pronounced than under iron chelation. Of interest, expression of several genes involved in mitochondrial biogenesis occurred in parallel with expression of iron-related genes both during adipogenesis and in human adipose tissue. Conclusions/interpretation Precise and fine-tuned iron availability is essential to achieve optimal adipocyte differentiation, possibly modulating adipocyte mitochondrial biogenesis.

show abstract

Section: Intracellular Iron Deficiency Impairs Adipogenesissupporting

confidence: 78%

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Particularly, palmitic and stearic acids are known to be major fatty acids acylated in the lipoprotein or lipopeptide to activate TLR2 [31,32]. NEFA possess the capacity to induce stress/inflammatory signals not only in immune cells but also other cell types and tissues [13,14,33]. This phenomenon is of particular importance in conditions of nutrient excess such as obesity and diabetes or after ingestion of a fatty meal.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse

Kuo¹,

Tsai

Jiang³

et al. 2010

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Substantial evidence suggests a link between elevated inflammation and development of insulin resistance. Toll-like receptor 2 (TLR2) recognises a large number of lipid-containing molecules and transduces inflammatory signalling in a variety of cell types, including insulin-responsive cells. Considering the contribution of the fatty acid composition in TLR2-depedent signalling, we hypothesised that the inflammatory signals transduced by TLR2 contribute to insulin resistance.Methods Mice deficient in TLR2 were used to investigate the in vivo roles of TLR2 in initiating and maintaining inflammation-associated insulin resistance and energy homeostasis.Results We first recapitulated the observation with elevated expression of TLR2 and inflammatory cytokines in white adipose tissue and liver of ob/ob mice. Aged or high-fat-fed TLR2-deficient mice were protected from obesity and adipocyte hypertrophy compared with wild-type mice. Moreover, mice lacking TLR2 exhibited improved glucose tolerance and insulin sensitivity regardless of feeding them regular chow or a high-fat diet. This is accompanied by reductions in expression of inflammatory cytokines and activation of extracellular signal-regulated kinase (ERK) in a liver-specific manner. The attenuated hepatic inflammatory cytokine expression and related signalling are correlated with increased insulin action specifically in the liver in TLR2-deficient mice, reflected by increased insulinstimulated protein kinase B (Akt) phosphorylation and IRS1 tyrosine phosphorylation and increased insulinsuppressed hepatocyte glucose production. Conclusions/interpretation The absence of TLR2 attenuates local inflammatory cytokine expression and related signalling and increases insulin action specifically in the liver. Thus, our work has identified TLR2 as a key mediator of hepatic inflammation-related signalling and insulin resistance.

show abstract

“…Those FFAs that escape reesterification play a critical role in several organs as a primary energy source during prolonged fasting (32). However, FFAs can also serve as ligands for the TLR4 complex (33), thereby activating the classical inflammatory response in the context of increased local extracellular lipid concentrations, which ultimately drives ATMΦ accumulation (34,35). Even though we do not consider AT as a conventional tissue suffering from lipotoxic side effects, either high rates of lipolysis or an influx of saturated FFAs into adipocytes do cause temporary inflammation within the tissue (33).…”

Section: Macrophages Major Constituents Of At and Mediators Of Remodmentioning

confidence: 99%

Adipose tissue remodeling and obesity

Sun¹,

Kusminski²,

Scherer³

2011

J. Clin. Invest.

1,498

1,323

View full text Add to dashboard Cite

To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth. IntroductionAdipose tissue (AT) can respond rapidly and dynamically to alterations in nutrient deprivation and excess through adipocyte hypertrophy and hyperplasia, thereby fulfilling its major role in wholebody energy homeostasis. AT remodeling is an ongoing process that is pathologically accelerated in the obese state, and thus, features such as reduced angiogenic remodeling, ECM overproduction, a heightened state of immune cell infiltration and subsequent proinflammatory responses prevail in many obese fat-pads (1). However, not all AT expansion is necessarily associated with pathological changes. The concept of the "metabolically healthy obese" state (2) suggests that some individuals can preserve systemic insulin sensitivity on the basis of "healthy" AT expansion, bypassing all of the aforementioned pathological consequences associated with obesity (3), thereby also avoiding the obesity-associated lipotoxic side effects. Many physiologically relevant processes important for human AT remodeling can be studied in rodent models, with the added advantage that processes related to AT expansion and reduction can occur at an extremely rapid rate. A 24-hour fast in a mouse is associated with a dramatic loss of AT mass and an acute remodeling process that involves rapid infiltration of macrophages; moreover, merely 24 to 48 hours of exposure to a high-fat diet (HFD) can cause a prompt increase in adipocyte size (4). AT is therefore an ideal model system to study rapid alterations in tissue expansion and reduction, as it adapts to a differential nutrient supply. Here, we will focus on key aspects of the intricate dynamics of AT remodeling and subsequent inflammatory consequences that arise from obesity.

show abstract

JNK and Tumor Necrosis Factor-α Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes

Cited by 371 publications

References 49 publications

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

Fine-tuned iron availability is essential to achieve optimal adipocyte differentiation and mitochondrial biogenesis

Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse

Adipose tissue remodeling and obesity

Contact Info

Product

Resources

About