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J. Biol. Chem., Vol. 279, Issue 44, 45803-45809, October 29, 2004

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Modulation of the JNK Pathway in Liver Affects Insulin Resistance Status^*

Yoshihisa Nakatani, Hideaki Kaneto, Dan Kawamori, Masahiro Hatazaki, Takeshi Miyatsuka, Taka-aki Matsuoka, Yoshitaka Kajimoto, Munehide Matsuhisa, Yoshimitsu Yamasaki, and Masatsugu Hori

From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Received for publication, June 22, 2004 , and in revised form, August 17, 2004.

	ABSTRACT

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The c-Jun N-terminal kinase (JNK) pathway is known to be activated under diabetic conditions and to possibly be involved in the progression of insulin resistance. In this study, we examined the effects of modulation of the JNK pathway in liver on insulin resistance and glucose tolerance. Overexpression of dominant-negative type JNK in the liver of obese diabetic mice dramatically improved insulin resistance and markedly decreased blood glucose levels. Conversely, expression of wild type JNK in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of crucial molecules for insulin signaling was altered upon modification of the JNK pathway. Furthermore, suppression of the JNK pathway resulted in a dramatic decrease in the expression levels of the key gluconeogenic enzymes, and endogenous hepatic glucose production was also greatly reduced. Similar effects were observed in high fat, high sucrose diet-induced diabetic mice. Taken together, these findings suggest that suppression of the JNK pathway in liver exerts greatly beneficial effects on insulin resistance status and glucose tolerance in both genetic and dietary models of diabetes.

	INTRODUCTION

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The hallmark of type 2 diabetes is insulin resistance and pancreatic -cell dysfunction (1, 2). Normal -cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, insulin sensitivity is further reduced, and -cell function progressively deteriorates (3). Various studies have demonstrated that hyperglycemia is the direct cause of these phenomena, collectively called "glucose toxicity" (4–8).

It has been reported that the activity of c-Jun N-terminal kinase (JNK)¹ (9–13), which is known to be activated by various stress signals such as cytokines or oxidative stress, is abnormally elevated in various tissues under diabetic conditions (14–16) and that activation of the JNK pathway interferes with insulin action (14, 17). Indeed, it was shown that insulin resistance is substantially decreased in mice homozygous for a targeted mutation in the JNK gene (14). Furthermore, we reported recently that JNK activation is involved in the reduction of insulin gene expression by oxidative stress and that suppression of the JNK pathway can protect -cells from glucose toxicity (18). Thus, it is likely that JNK is a crucial mediator of the progression of insulin resistance as well as -cell dysfunction found in type 2 diabetes. Here we report that suppression of the JNK pathway in the liver improves insulin resistance in the whole body and markedly ameliorates glucose intolerance in diabetic mice.

	MATERIALS AND METHODS

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Preparation of Recombinant Adenoviruses—Recombinant adenoviruses expressing wild type (WT) and dominant-negative type (DN) JNK were prepared using the AdEasy system (kindly provided by Dr. Bert Vogelstein, the Johns Hopkins Oncology Center) (33). In brief, the encoding region of WT- and DN-JNK (K55R) was cloned into a shuttle vector pAdTrack-CMV, and to allow for homologous recombination, the linearized plasmid containing WT- or DN-JNK and the adenoviral backbone plasmid, pAdEasy-1, were introduced into electrocompetent Escherichia coli BJ5183 cells. The linearized plasmids were transfected into the adenovirus packaging cell line 293 using LipofectAMINE (Invitrogen), and the adenovirus titers were increased up to 1 x 10⁸ plaque-forming units (PFU)/ml in the 293 cells. Control adenovirus expressing green fluorescent protein (Ad-GFP) was prepared in the same manner. Adenovirus titers were further increased up to 1 x 10¹⁰ PFU/ml using the Adeno-X^TM virus purification kit (Clontech). Virus titers were estimated using the Adeno-X^TM titer kit (Clontech).

Animals and Administration of Recombinant Adenoviruses—Male C57BL6 and C57BL/KsJ-db/db mice were purchased from Japan SLC (Hamamatsu, Japan). Mice (8 weeks old) were injected with Ad-WT-JNK, Ad-DN-JNK, or Ad-GFP (1 x 10¹⁰ PFU/ml for Ad-WT-JNK and 2 x 10⁹ PFU/ml for Ad-DN-JNK) from the cervical vein. After adenovirus injection, blood glucose levels were measured regularly with a portable glucose meter (Glu-test Sensor, Sanwa, Japan) after tail snipping. For measurement of serum insulin levels, blood samples of mice after a 6-h fast were collected into heparinized capillary tubes, and serum insulin levels were determined with the Insulin-EIA test kit (Glazyme).

Glucose Tolerance Tests—After a 6-h fast, mice were injected intraperitoneally with glucose (2.0 g/kg of body weight). Blood samples were taken at various time points (0–120 min), and blood glucose levels and serum insulin levels were determined as described above.

Insulin Tolerance Tests—After a 6-h fast, mice were injected intraperitoneally with insulin (2.0 units/kg for C57BL/KsJ-db/db mice). Blood samples were taken at various time points (0–90 min), and blood glucose levels were measured as described above.

Euglycemic Hyperinsulinemic Clamp—Fourteen days before the clamp study, Ad-WT-JNK (1 x 10¹⁰ PFU/ml) or Ad-DN-JNK (2 x 10⁹ PFU/ml) was injected from the left jugular vein. Three days before the clamp study, a silicon catheter (Phicon Tube, Fuji-Systems, Tokyo, Japan) was inserted into the right jugular vein under general anesthesia with sodium pentobarbital. The catheter, which is required for infusion in the clamp study, was exteriorized at the back of the neck through a subcutaneous tunnel and filled with heparinized saline (200 units/ml). Clamp studies were performed on mice under conscious and unstressed conditions after a 6-h fast. A euglycemic hyperinsulinemic clamp with a tracer dilution method was applied to determine peripheral glucose uptake and endogenous glucose production. Experiments consisted of a 120-min euglycemic hyperinsulinemic clamp period (15 pmol of regular human insulin/kg/min for C57BL6 mice and 27 pmol/kg/min for C57BL/KsJ-db/db mice during the 120-min clamp period). During this period, blood glucose levels were monitored every 5 min, and the rate of 50% glucose containing 10% [6,6-²H₂]glucose infusion into the jugular vein was adjusted to maintain blood glucose concentrations at 120 ± 10 mg/dl.

Measurement of Endogenous Hepatic Glucose Production (HGP) by Stable Isotope-labeled Glucose Enrichment—To estimate HGP, stable isotope-labeled glucose enrichment was determined. Blood samples were taken at 90, 105, and 120 min, and 20 µl of each plasma sample were deproteinized with 60 µl of 99.5% ethanol. The supernatant was evaporated, and the residue was derivatized by the following procedure. First, 7.5 µl of N-methyl-bis(trifluoroacetamide) (MBTFA, Pierce) and 7.5 µl of pyridine were added to the residue, and the mixture was heated for 1 h at 60 °C. The reaction product (1 µl) containing trifluoroacetylated glucose was then analyzed by gas chromatography and mass spectrometry (model TSQ-700, Finningan-MAT, San Jose, CA) with a silicon SE-30 capillary column (30 m x 0.25 mm inner diameter, Gasukuro Kogyo, Tokyo, Japan). The trifluoroacetyl derivative of glucose was separated from the other compounds by gas chromatography and was analyzed by electron impact mass spectrometry at 70 eV. The fragment ion peaks of unlabeled glucose and [6,6-²H₂]glucose were measured at a mass/electrical charge (m/e) of 319 and 321, respectively.

Western Blot Analysis—Whole cell extracts obtained from liver were fractionated by 10% SDS-PAGE and transferred to a reinforced cellulose nitrate membrane (Optitran BA-S85, Schleicher & Schuell). After blocking, the membranes were incubated at 4 °C overnight in TBS buffer (50 mM Tris-HCl, 150 mM NaCl) containing a 1:1000 dilution of rabbit anti-IRS-1, anti-IRS-1-Ser(P)-307 antibody (Upstate Biotechnology), anti-Akt, or anti-Akt-Ser(P)-473 antibody (Cell Signaling, Beverly, MA) and then incubated for 1 h at room temperature in TBS containing a 1:1000 dilution of anti-rabbit IgG antibody coupled to horseradish peroxidase (Bio-Rad). Immunoreactive bands were visualized by incubation with LumiGLO (Cell Signaling) and exposed to light-sensitive film.

Northern Blot Analysis—Ten µg of total RNA isolated from freeze-clamped liver tissues were electrophoresed on 1.0% formaldehyde-denatured agarose gel in 1x MOPS running buffer and then transferred overnight to a Hybond-N⁺ membrane (Amersham Biosciences). The phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (Glc-6-Pase) cDNA probes were labeled with [-³²P]dCTP using the Rediprime labeling system kit (Amersham Biosciences). After overnight hybridization with a ³²P-labeled probe at 42 °C, the membranes were washed in 2x saline/sodium phosphate/EDTA (SSPE), 0.1% SDS at 42 °C. The probed membranes were exposed to an imaging plate, BAS-MS 2040 (Fujifilm, Tokyo, Japan), and the hybridization intensity was quantified using a BAS2500 system (Fujifilm).

Diet Study—Six-week-old male mice (C57BL6) were divided at random into two groups. One group was fed a high fat, high sucrose diet (AIN93G, Oriental Yeast, Suita, Japan), and the other was fed standard laboratory mouse chow (Clea Japan, Tokyo, Japan) for 4 weeks.

Statistical Analysis—Results are expressed as mean ± S.E. Differences between groups were examined for statistical significance using the Student's t test or analysis of variance (ANOVA) with the Fisher's test.

	RESULTS

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Activation of the JNK Pathway in the Liver Decreases Insulin Sensitivity in C57BL6 Mice—To examine the effects of JNK overexpression in the liver on insulin sensitivity and glucose tolerance in non-diabetic animals, we prepared WT-JNK-expressing adenovirus (Ad-WT-JNK) and control adenovirus (Ad-GFP) and delivered each adenovirus to 8-week-old C57BL6 mice from the cervical vein. It is noted that this Ad-WT-JNK expressed GFP as well as WT-JNK. As shown in Fig. 1A, a marked increase in JNK expression was observed in the liver, but not in other tissues such as muscle and adipose tissue. The left panel of Fig. 1A shows a representative liver after exposure to Ad-WT-JNK. As seen by the GFP fluorescence, many cells in the liver were infected with the adenovirus. There was no difference in body weight and food intake between the two groups (data not shown), and nonfasting blood glucose concentrations in Ad-WT-JNK-treated mice were also comparable with those in Ad-GFP-treated mice (Fig. 1B). Next, to examine the effect of WT-JNK overexpression in the liver on glucose tolerance, we performed the intraperitoneal glucose tolerance test (IPGTT). As shown in Fig. 1C, there was no difference in glucose tolerance between Ad-GFP-treated and Ad-WT-JNK-treated mice. Fasting serum insulin concentrations in Ad-WT-JNK-treated mice were higher than those in Ad-GFP-treated mice at the compatible fasting blood glucose levels (Fig. 1D), indicating that JNK overexpression increases insulin resistance. To investigate this point further, we performed the euglycemic hyperinsulinemic clamp test. As shown in the left panel of Fig. 1E, in the clamp study, the steady-state glucose infusion rate (GIR) in Ad-WT-JNK-treated C57BL6 mice was significantly lower than that in Ad-GFP-treated mice (58.0 ± 6.8 versus 73.7 ± 3.2 mg/kg/min, p < 0.05, n = 6), indicating that activation of the JNK pathway in the liver reduces insulin sensitivity in C57BL6 mice. Furthermore, we evaluated endogenous HGP in Ad-WT-JNK-treated mice using tracer methods. As shown in the right panel of Fig. 1E, HGP in Ad-WT-JNK-treated mice was significantly greater than that in Ad-GFP-treated mice (18.2 ± 3.1 versus 6.4 ± 3.3 µmol/kg/min, p < 0.05, n = 6). In contrast, there was no difference in glucose disappearance rate between the two groups, which reflects glucose utilization in the peripheral tissues (data not shown). These results indicate that overexpression of JNK decreases insulin sensitivity mainly by increasing HGP in control mice. On the other hand, although JNK is well known to be involved in the immune response and regulation of apoptosis, hematoxylin and eosin staining revealed no morphological changes in the liver after WT-JNK overexpression (data not shown), indicating that the increase in insulin resistance induced by WT-JNK overexpression is not because of the induction of apoptosis in the liver.

View larger version (29K): [in this window] [in a new window]   FIG. 1. Effects of adenoviral WT-JNK overexpression in the liver on insulin resistance and glucose tolerance in C57BL6 mice. A, Ad-WT-JNK or Ad-GFP (1 x 1010 PFU/ml) was injected into the cervical vein of male C57BL6 mice. After injection with the adenovirus, total protein was obtained from the liver, and Western blot analysis was performed with an antibody for JNK. Induction of JNK expression is clearly observed in the liver, but not in muscle or adipose tissue (left panel). In addition, the GFP fluorescence in the right panel shows that many cells in the liver are infected with the adenovirus after treatment with Ad-JNK. B, nonfasting blood glucose levels in C57BL6 mice treated with Ad-WT-JNK or Ad-GFP. After infection with the adenovirus, nonfasting blood glucose levels were measured for 25 days. C, glucose tolerance in C57BL6 mice treated with Ad-WT-JNK or Ad-GFP. Two weeks after infection with Ad-WT-JNK or Ad-GFP, IPGTTs were performed. After a 6-h fast, glucose was injected intraperitoneally at a dose of 2.0 g/kg of body weight, and blood glucose levels were measured. D, fasting blood glucose and serum insulin levels 2 weeks after infection with Ad-WT-JNK or Ad-GFP. E, GIR and endogenous HGP in C57BL6 mice treated with Ad-WT-JNK or Ad-GFP. Two weeks after the adenovirus infection, GIR and HGP were estimated with an euglycemic hyperinsulinemic clamp. *, p < 0.05, n = 6.

View larger version (20K): [in this window] [in a new window]   FIG. 2. Effects of adenoviral DN-JNK overexpression in the liver on insulin resistance and glucose tolerance in C57BL/KsJ-db/db mice. A, nonfasting blood glucose levels in C57BL/KsJ-db/db mice treated with Ad-DN-JNK or Ad-GFP (2 x 109 PFU/ml). After infection with the adenovirus, nonfasting blood glucose levels were measured for 25 days. B, fasting blood glucose and serum insulin levels 2 weeks after infection with Ad-DN-JNK or Ad-GFP. C, insulin resistance in C57BL6 mice treated with Ad-DN-JNK or Ad-GFP. Two weeks after Ad-DN-JNK or Ad-GFP treatment, intraperitoneal insulin tolerance tests were performed. After a 6-h fast, insulin was injected intraperitoneally at a dose of 2.0 units/kg of body weight, and blood glucose levels were measured. D, GIR and endogenous HGP in C57BL6 mice treated with Ad-DN-JNK or Ad-GFP. Two weeks after the adenovirus infection, GIR and HGP were estimated with an euglycemic hyperinsulinemic clamp. *, p < 0.05, n = 6.

Alteration of Insulin Action in the Liver via the JNK Pathway Is Associated with the Phosphorylation Status of Insulin Signaling Molecules and Expression of Gluconeogenic Enzymes—It has been reported that serine phosphorylation of insulin receptor substrate-1 inhibits insulin-stimulated tyrosine phosphorylation of IRS-1, leading to an increase in insulin resistance (14, 17). To explore the molecular mechanisms involved in the alteration of insulin actions via the JNK pathway, we evaluated IRS-1 serine 307 phosphorylation in the liver of Ad-WT-JNK-treated C57BL6 mice. As shown in Fig. 3A, IRS-1 serine 307 phosphorylation was increased in Ad-WT-JNK-treated mice compared with Ad-GFP-treated mice. We also found a decrease in IRS-1 tyrosine phosphorylation in Ad-WT-JNK-treated mice compared with Ad-GFP-treated mice. Furthermore, a decrease in Akt serine 473 phosphorylation was observed in Ad-WT-JNK-treated C57BL6 mice compared with Ad-GFP-treated mice. Similarly, we examined the molecular mechanisms involved in the reduction of insulin resistance by DN-JNK overexpression in the liver. As shown in Fig. 3A, IRS-1 serine 307 phosphorylation was markedly decreased in Ad-DN-JNK-treated mice compared with Ad-GFP-treated mice. We also found an increase in IRS-1 tyrosine phosphorylation in Ad-DN-JNK-treated mice compared with control mice. Reduction of Akt serine 473 phosphorylation was observed in Ad-DN-JNK-treated C57BL/KsJ-db/db mice compared with Ad-GFP-treated mice. Therefore, an increase in IRS-1 serine phosphorylation may be closely associated with the development of insulin resistance induced by JNK overexpression.

View larger version (41K): [in this window] [in a new window]   FIG. 3. Effects of WT- and DN-JNK overexpression on insulin signaling and gluconeogenesis in the liver. A, Ad-WT-JNK or Ad-GFP was injected into C57BL6 mice, and Ad-DN-JNK or Ad-GFP was injected into C57BL6 mice. Two weeks after the adenovirus infection, expressions of total and serine-phosphorylated forms (Ser-307) of IRS-1 were examined with Western blot analysis, and the tyrosine-phosphorylated form of IRS-1 was examined with immunoprecipitation. Expressions of total and serine-phosphorylated forms of Akt (Ser-473) were also examined with Western blot analysis. Similar results were obtained with at least three independent experiments. B, two weeks after the adenovirus infection, mRNA levels of the key gluconeogenic enzymes, PEPCK and Glc-6-Pase, were examined by Northern blot analysis. *, p < 0.05, n = 3.

Suppression of the JNK Pathway in the Liver Improves High Fat, High Sucrose Diet-induced Insulin Resistance and Glucose Tolerance—Because it is well known that a high fat and high sucrose diet induces insulin resistance, we fed C57BL6 mice a high fat, high sucrose diet and examined whether suppression of the JNK pathway has any effect on high fat, high sucrose diet-induced insulin resistance. There was no difference in body weight and food intake between the two groups (data not shown). As shown in Fig. 4A, nonfasting blood glucose gradually became lower 2–3 weeks after the challenge in the DN-JNK-treated mice. Four weeks after starting the high fat, high sucrose diet, nonfasting blood glucose and insulin concentrations were significantly lower in Ad-DN-JNK-treated mice compared with Ad-GFP-treated mice (nonfasting blood glucose of 115 ± 12 versus 157 ± 7 mg/dl, p < 0.05; insulin concentration of 8.2 ± 1.5 versus 10.0 ± 1.2 ng/ml) (Fig. 4B). To further investigate this point, we performed the IPGTT. As shown in Fig. 4C, blood glucose levels in Ad-DN-JNK-treated mice were significantly lower compared with those of Ad-GFP-treated mice. These results indicate that suppression of the JNK pathway in the liver improves insulin resistance and glucose tolerance induced by a high fat, high sucrose diet. Taken together, our results show that suppression of the JNK pathway in the liver improves insulin resistance and ameliorates glucose tolerance in two different diabetic animal models with insulin resistance, C57BL/KsJ-db/db diabetic mice (Fig. 2) and high fat, high sucrose diet-induced diabetic mice (Fig. 4).

View larger version (23K): [in this window] [in a new window]   FIG. 4. Effects of adenoviral DN-JNK overexpression in liver on insulin resistance and glucose tolerance in C57BL6 mice treated with a high fat, high sucrose diet. A, nonfasting blood glucose levels in C57BL/KsJ-db/db mice treated with Ad-DN-JNK or Ad-GFP (2 x 109 PFU/ml). After infection with the adenovirus, nonfasting blood glucose levels were measured for 4 weeks. B, fasting blood glucose and serum insulin levels 4 weeks after infection with Ad-DN-JNK or Ad-GFP. C, glucose tolerance in C57BL6 mice treated with Ad-DN-JNK or Ad-GFP. Four weeks after Ad-DN-JNK or Ad-GFP treatment, IPGTTs were performed. After a 6-h fast, glucose was injected intraperitoneally at a dose of 2.0 g/kg of body weight, and blood glucose levels were measured. *, p < 0.05, n = 6.

	DISCUSSION

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View larger version (21K): [in this window] [in a new window]   FIG. 5. Possible mechanism for JNK-mediated insulin resistance and glucose tolerance.

Here we report the dramatic improvement of insulin resistance by suppression of the JNK pathway, indicating the novel important role of the JNK pathway in insulin resistance. So far, the importance of the IB kinase (IKK) pathway in insulin resistance has been reported (34, 35); salicylate, which inhibits the IKK pathway, improves insulin resistance in skeletal muscle and decreases blood glucose levels in type 2 diabetic patients. Our present data suggest that specific inhibitors of the JNK pathway for the liver are potential therapeutic agents for insulin resistance in diabetic patients (36).

In conclusion, activation of the JNK pathway as seen under diabetic conditions increases insulin resistance, and in contrast, suppression of the JNK pathway decreases insulin resistance and markedly improves glucose tolerance in diabetic animal models.

	FOOTNOTES

 
^* This work was supported in part by grants from the Ministry of Education of Japan (to Y. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 81-6-6879-3633; Fax: 81-6-6879-3639; E-mail: kaneto{at}medone.med.osaka-u.ac.jp.

¹ The abbreviations used are: JNK, c-Jun N-terminal kinase; WT, wild type; DN, dominant-negative type; Ad, adenovirus; GFP, green fluorescent protein; PFU, plaque-forming unit; GIR, glucose infusion rate; HGP, hepatic glucose production; IRS-1, insulin receptor substrate-1; PEPCK, phosphoenolpyruvate carboxykinase; FFA, free fatty acid; TNF-, tumor necrosis factor-; IPGTT, intraperitoneal glucose tolerance test; MOPS, 4-morpholinepropanesulfonic acid.

	ACKNOWLEDGMENTS

 
We thank Dr. Bert Vogelstein (Johns Hopkins Oncology Center) for kindly providing the AdEasy system. We also thank Yuko Sasaki for excellent technical assistance and Chikayo Yokogawa for efficient secretarial assistance. We also thank Dr. Helena Akiko Popiel for valuable comments on the manuscript.

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