Overexpression of the dual-specificity phosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance

Emanuelli, Brice; Eberlé, Delphine; Suzuki, Ryo; Kahn, C. Ronald

doi:10.1073/pnas.0712275105

Cited by 94 publications

(90 citation statements)

References 35 publications

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“…In contrast to CENTD2, where there is no reported biological data to support an effect on beta cell function, DUSP9 (which codes for mitogen-activated dual specificity protein kinase phosphastase-4) has been identified as a gene involved in insulin signalling and in the pathogenesis of insulin resistance [8][9][10].…”

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release

Nielsen

Sparsø²,

Grarup

et al. 2011

Diabetologia

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Aims/hypothesis By combining multiple genome-wide association (GWA) studies and comprehensive replication efforts, 12 novel type 2 diabetes associated loci have recently been discovered. Here we evaluate the effect of lead variants of these loci on estimates of insulin release and insulin resistance derived from an oral glucose tolerance test. Methods We examined 12 lead variants in or near HMGA2, CENTD2 (also known as ARAP1), KLF14, PRC1, TP53INP1, ZBED3, ZFAND6, CHCHD9, DUSP9, KCNQ1, BCL11A and HNF1A in 5,722 middle-aged people from the population-based Inter99 sample.Results Carriers of the major diabetogenic allele of rs1552224 in CENTD2 had increased 30-min plasma glucose values (2.0%, p=2×10 ) as well as 4.2% reduced insulin release 30 min after an oral glucose load (p=0.001). Risk allele carriers also had decreased BIGTT-acute insulin release (AIR), which is a surrogate measure of insulin release where sex, BMI, plasma glucose and serum insulin are integrated (5.3%, p=8×10 −7 ). In addition, a decreased corrected insulin response (CIR; 9.9%, p = 3 × 10 −8 ) was observed. For rs5945326 near DUSP9 on the X-chromosome we stratified according to sex. Diabetologia (2011) 54:1052-1056 DOI 10.1007/s00125-011-2054 bolic traits were found in women. For the remaining ten lead variants no consistent associations were demonstrated. Conclusions/interpretation Of the lead variants from 12 novel type 2 diabetes associated loci, CENTD2 significantly associated with increased plasma glucose values and decreased glucose-stimulated insulin release, suggesting that the diabetogenic effect of this locus is mediated through an impaired pancreatic beta cell function.

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Section: Discussionmentioning

confidence: 99%

Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release

Nielsen

Sparsø²,

Grarup

et al. 2011

Diabetologia

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“…However, those experiments demonstrated that p38 MAPK positively, rather than negatively, regulated PPAR␥ mRNA in the liver of high fat diet-fed mice (7). Moreover, overexpression of MKP-4 in the liver, which inhibits JNK and ERK1/2, was shown to prevent hepatic steatosis (40). Because ERK1/2 and JNK inhibit PPAR␥ activity by phosphorylation on Ser 112 (22,32,33,41) we speculated that MKP-1 might be exerting its effects on PPAR␥ activity by negatively regulating MAPK-dependent phosphorylation at this site.…”

Section: Discussionmentioning

confidence: 99%

Loss of Mitogen-activated Protein Kinase Phosphatase-1 Protects from Hepatic Steatosis by Repression of Cell Death-inducing DNA Fragmentation Factor A (DFFA)-like Effector C (CIDEC)/Fat-specific Protein 27

Flach¹,

Hui

Zhang

et al. 2011

Journal of Biological Chemistry

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The integration of metabolic signals required for the regulation of hepatic lipid homeostasis is complex. Previously, we showed that mice lacking expression of the mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) have increased fatty acid oxidation and are protected from the development of hepatic steatosis. Here, we show that leptin receptor-deficient (db/db) mice lacking MKP-1 are also resistant to the development of hepatic steatosis. Microarray analyses of livers from db/db mice lacking MKP-1 showed suppression of peroxisome proliferator-activated receptor ␥ (PPAR␥) target genes. We identified the fat-specific protein 27 (Fsp27), which promotes PPAR␥-mediated hepatic steatosis, as repressed in livers of both db/db and high fat diet-fed mice lacking MKP-1. Hepatocytes from MKP-1-deficient mice exhibited reduced PPAR␥-induced lipid droplet formation. Mechanistically, loss of MKP-1 inhibited PPAR␥ function by increasing MAPK-dependent phosphorylation on PPAR␥ at its inhibitory residue of serine 112. These results demonstrate that in addition to inhibiting hepatic fatty acid oxidation, MKP-1 promotes hepatic lipogenic gene expression through PPAR␥. Hence, MKP-1 plays an important role in MAPK-mediated control of hepatic lipid homeostasis.The liver represents a tissue in which multiple signals are sensed and subsequently integrated to maintain metabolic homeostasis. An imbalance in how these metabolic cues are relayed through signaling pathways that lead to the expression of genes involved in hepatic metabolism can result in excess accumulation of fat in the liver (steatosis). A steatotic liver can progress to steatohepatitis, cirrhosis, fibrosis, and ultimately, either liver failure or hepatocellular carcinoma. Therefore, defining the molecular events surrounding the regulation of hepatic lipid homeostasis is of paramount importance, and elucidating the contributing facets of hepatic lipid regulation will provide insight in to both physiological and pathophysiological aspects of liver function (1).The mitogen-activated protein kinase (MAPK) family includes the growth factor-responsive extracellular signal-regulated kinases 1 and 2 (ERK1/2), and the stress-responsive MAPKs, p38 MAPK and c-jun NH 2 -terminal kinase (JNK) (2, 3). MAPK activation is mediated by phosphorylation on a threonine and tyrosine residue in the activation loop by upstream MAP kinase kinases in response to diverse stimuli (2, 3). The MAPKs have been implicated in the regulation of hepatic lipid deposition. Mice lacking expression of JNK1, but not JNK2, have an improved steatotic phenotype in a model of methionine and choline deficiency (4), whereas mice lacking JNK1 specifically in the liver are insulin-resistant and develop hepatic steatosis (5). p38 MAPK promotes fatty acid ␤-oxidation by direct phosphorylation of the nuclear receptor, peroxisome proliferator-activated receptor (PPAR) 3 ␣, which plays an important role in hepatic lipid metabolism (6), and in cultured hepatocytes p38 MAPK activity has been linked to decreased he...

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“…In support of our proposed mechanism in which AICAR inhibits the phosphorylation of ERK and subsequently the serine phosphorylation of IRS-1 at 636/639 and 307, it has been proposed that DUSP6/ MKP-3, which has a high sequence homology to DUSP9/ MKP-4, specifically within its catalytic domain, can form a complex with ERK, leading to enhanced DUSP6/ MKP-3 activity (29). Moreover, it has been reported that overexpression of an adenovirus encoding DUSP9/ MKP-4 protects against stress-induced insulin resistance in 3T3L1 adipocytes (30). On the other hand, we demonstrated that the PP2A inhibitor okadaic acid did not restore ERK phosphorylation levels suppressed by AICAR stimulation, indicating that AICAR does not increase PP2A activity.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the TNF-α^|^ndash;Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR

et al. 2013

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Abstract. AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. However, the mechanism by which AMPK regulates insulin signaling remains unclear. Serine phosphorylation of insulin receptor substrate (IRS)-1 negatively regulates insulin signaling. Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)- in 3T3L1 adipocytes. We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF--induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal-regulated kinase (ERK) phosphorylation but not c-Jun-NH 2 -terminal kinase (JNK) phosphorylation. In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. In conclusion, we propose a new mechanism in which AICAR suppresses TNF--induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. Taken together, these findings provide evidence that AMPK plays a crucial role in improving of type 2 diabetes.

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Overexpression of the dual-specificity phosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance

Cited by 94 publications

References 35 publications

Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release

Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release

Loss of Mitogen-activated Protein Kinase Phosphatase-1 Protects from Hepatic Steatosis by Repression of Cell Death-inducing DNA Fragmentation Factor A (DFFA)-like Effector C (CIDEC)/Fat-specific Protein 27

Inhibition of the TNF-α^|^ndash;Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR

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