A central role for JNK in obesity and insulin resistance

Hirosumi, Jiro; Tuncman, Gürol; Chang, Louise; Görgün, Cem Z.; Uysal, K. Teoman; Maeda, Kazuhisa; Karin, Michael; Hotamışlıgil, Gökhan S.

doi:10.1038/nature01137

Cited by 2,878 publications

(2,514 citation statements)

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“…There is a striking increase in JNK activity at crucial metabolic sites such as adipose and liver tissue in mouse models of obesity 86 . Most importantly, JNK deficiency protects mice from insulin resistance, fatty liver and diabetes 86 , which implies that JNK inhibition might be a promising therapeutic avenue for diabetes [87][88][89] .…”

Section: Nature Reviews | Molecular Cell Biologymentioning

confidence: 99%

“…JNK deficiency has been reported to protect mice from insulin resistance, fatty liver and diabetes 86 , and inhibition of JNK is considered to be a promising therapeutic avenue [87][88][89] . Similarly, mouse models harbouring null mutations in IKK have validated that this kinase impacts insulin signalling, and inhibition of IKK by high-dose salicylates improves insulin action in experimental models and humans 90 .…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

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Lipid signalling in disease

Wymann

Schneiter

2008

Nat Rev Mol Cell Biol

1,101

877

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Section: Nature Reviews | Molecular Cell Biologymentioning

confidence: 99%

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Lipid signalling in disease

Wymann

Schneiter

2008

Nat Rev Mol Cell Biol

1,101

877

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“…Excess fat has been shown to cause peripheral insulin resistance via multiple mechanisms which include among others, excess supply of non-esterified fatty acids [9], increased intracellular accumulation of muscle triglycerides and long chain acyl CoAs (LCACoAs) [9], excessive production of tumor necrosis factor-α [10], reduction in the concentration of adiponectin [11] and increased c-Jun amino-terminal kinase (JNK) activity [12].…”

mentioning

confidence: 99%

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

et al. 2003

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Aims/hypothesis. To study the secondary consequences of impaired suppression of endogenous glucose production (EGP) we have created a transgenic rat overexpressing the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in the kidney. The aim of this study was to determine whether peripheral insulin resistance develops in these transgenic rats. Methods. Whole body rate of glucose disappearance (R d ) and endogenous glucose production were measured basally and during a euglycaemic/hyperinsulinaemic clamp in phosphoenolpyruvate carboxykinase transgenic and control rats using [6-3 H]-glucose. Glucose uptake into individual tissues was measured in vivo using 2-[1-14 C]-deoxyglucose. Results. Phosphoenolpyruvate carboxykinase transgenic rats were heavier and had increased gonadal and infrarenal fat pad weights. Under basal conditions, endogenous glucose production was similar in phosphoenolpyruvate carboxykinase transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min). Moderate hyperinsulinaemia (810 pmol/l) completely suppressed EGP in control rats (−0.6±5.5 µmol/kg/min, p<0.05) while there was no suppression in phosphoenolpyruvate carboxykinase rats (45.2±7.9 µmol/kg/min). Basal R d was comparable between PEPCK transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min) but under insulin-stimulated conditions the increase in R d was greater in control compared to phosphoenolpyruvate carboxykinase transgenic rats indicative of insulin resistance (73.4±11.2 vs 112.0±8.0 µmol/kg/min, p<0.05). Basal glucose uptake was reduced in white and brown adipose tissue, heart and soleus while insulin-stimulated transport was reduced in white and brown adipose tissue, white quadriceps, white gastrocnemius and soleus in phosphoenolpyruvate carboxykinase transgenic compared to control rats. The impairment in both white and brown adipose tissue glucose uptake in phosphoenolpyruvate carboxykinase transgenic rats was associated with a decrease in GLUT4 protein content. In contrast, muscle GLUT4 protein, triglyceride and long-chain acylCoA levels were comparable between PEPCK transgenic and control rats. Conclusions/interpretation. A primary defect in suppression of EGP caused adipose tissue and muscle insulin resistance. [Diabetologia (2003[Diabetologia ( ) 46:1338[Diabetologia ( -1347

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“…Interesting links have been made between insulin insensitivity, obesity, ER stress and chronic inflammation in the pathogenesis of T2D [77][78][79][80]. T2D is a multifactorial disease characterized by insensitivity of target organs such as skeletal muscle, liver and adipose tissue, to the effects of insulin.…”

Section: Proteotoxic Stress In the Pathogenesis Of Diseases Not Formementioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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A central role for JNK in obesity and insulin resistance

Cited by 2,878 publications

References 25 publications

Lipid signalling in disease

Lipid signalling in disease

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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