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. 2008 Dec 5;322(5907):1539-43.
doi: 10.1126/science.1160794.

A stress signaling pathway in adipose tissue regulates hepatic insulin resistance

Guadalupe Sabio  1 , Madhumita Das, Alfonso Mora, Zhiyou Zhang, John Y Jun, Hwi Jin Ko, Tamera Barrett, Jason K Kim, Roger J Davis
Affiliations

A stress signaling pathway in adipose tissue regulates hepatic insulin resistance

Guadalupe Sabio et al. Science. .

Abstract

A high-fat diet causes activation of the regulatory protein c-Jun NH2-terminal kinase 1 (JNK1) and triggers development of insulin resistance. JNK1 is therefore a potential target for therapeutic treatment of metabolic syndrome. We explored the mechanism of JNK1 signaling by engineering mice in which the Jnk1 gene was ablated selectively in adipose tissue. JNK1 deficiency in adipose tissue suppressed high-fat diet-induced insulin resistance in the liver. JNK1-dependent secretion of the inflammatory cytokine interleukin-6 by adipose tissue caused increased expression of liver SOCS3, a protein that induces hepatic insulin resistance. Thus, JNK1 activation in adipose tissue can cause insulin resistance in the liver.

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Figures

Fig. 1
Fig. 1
Creation of mice with adipose tissue-specific deficiency of JNK1. (A) The expression of Jnk1 mRNA in adipose tissue was examined by quantitative RT-PCR analysis (Taqman©) and is presented as relative mRNA expression (mean ± SD; n = 5). The data are normalized for the amount of Gapdh mRNA in each sample. The amount of Jnk1 mRNA was significantly reduced in the adipose tissue of FKO mice compared to FWT mice (*, P < 0.01). (B) JNK1 expression in adipose tissue, liver, muscle (quadriceps), and macrophages isolated from FWT, FKO, and Jnk1-/- mice was examined by immunoblot analysis using an antibody to JNK1. Control immunoblots were performed using antibodies to Actin and Tubulin. (C) FKO and FWT mice were maintained on a standard chow diet (ND) or on a high fat diet (HF) for 16 wk. Protein extracts were prepared from epididymal fat, muscle (quadriceps), and liver. Equal amounts of cell extract prepared from FWT and FKO mice, confirmed by immunoblot analysis using an antibody to Tubulin, were used to measure JNK activity in a kinase assay (KA) using ATP[γ-32P] and cJun as substrates.
Fig. 2
Fig. 2
JNK1-deficient adipose tissue prevents diet-induced insulin resistance. (A-C) FKO and FWT mice were maintained on a standard chow diet (ND) or on a high fat diet (HF) for 16 wk. (A) Glucose tolerance test (GTT). Mice fasted overnight were injected intraperitoneally with glucose (1 mg/g). Blood glucose concentration was measured at the indicated times (mean ± SD; n = 14). (B) Insulin tolerance test (ITT). Mice fed ad libitum were injected intraperitoneally with insulin (0.75 mU/g). Blood glucose concentration was measured at the indicated times (mean ± SD; n = 14). (C) Glucose-induced insulin release. Mice fasted overnight were injected intraperitoneally with glucose (2 mg/g). Blood insulin concentration was measured at the indicated times (mean ± SD; n = 14). No statistically significant differences between FKO and FWT mice were detected (P > 0.05). (D-J) FKO and FWT mice were maintained on a standard chow diet or on a high fat (HF) diet for 3 wk. (D) Steady-state glucose infusion rates to maintain euglycemia during the hyperinsulinemic-euglycemic clamps. (E) Insulin-stimulated whole body glucose turnover. (F) Whole body glycolysis. (G) Basal hepatic glucose production (HGP). (H) Insulin-stimulated rates of HGP during clamps. (I) Hepatic insulin action, expressed as insulin-mediated percent suppression of basal HGP. (J) Glycogen synthesis. The data presented are the mean ± SE for 6 to 8 experiments. Statistically significant differences are indicated (*, P < 0.05; **, P < 0.01; ***, P < 0.001). (K-L) Resting blood insulin and glucose were examined in mice that were fasted overnight (mean ± SD, n =10). Statistically significant differences between FKO mice and FWT mice are indicated (*, P < 0.01).
Fig. 3
Fig. 3
JNK1-deficient adipose tissue causes reduced diet-induced expression of IL6. (A) The expression of IL6 and TNFα mRNA in adipose tissue was examined by quantitative RT-PCR analysis (Taqman©) and is presented as relative mRNA expression (mean ± SD; n = 6). Statistically significant differences between FKO mice and FWT mice are indicated (*, P < 0.01). (B) FWT and FKO mice were fasted overnight and treated with insulin (1.5 U/kg body mass) by intraperitoneal injection. The epididymal fat pads were isolated after 30 min and examined by immunoblot analysis using antibodies to AKT and phospho-AKT. (C) Mice were fasted overnight and the amount of IL6, TNFα, Leptin and Resistin in plasma were measured (mean ± SD; n=10). Statistically significant differences between FKO mice and FWT mice are indicated (*, P < 0.05).
Fig. 4
Fig. 4
JNK1-deficiency in adipose tissue causes increased hepatic insulin sensitivity. (A) Fabp4-Cre+ Jnk1+/- (FWT) and Fabp4-Cre+ Jnk1f/- (FKO) mice were fed a standard chow diet or a high fat diet for 16 wk. Representative histological sections of liver stained with H&E or Oil Red-O are presented. (B) Mice were fasted overnight and treated with insulin (1.5 U/kg body mass) by intraperitoneal injection. Livers were isolated after 30 min and examined by immunoblot analysis to detect AKT, phospho-AKT, JNK1/2, and Tubulin. (C) The expression of SOCS3 in the liver was examined by immunoblot analysis. Control immunoblots were performed using an antibody to Tubulin. (D) The tyrosine phosphorylation and expression of the insulin receptor (IR) and IRS1 in the liver were examined by immunoblot analysis. (E) FWT and FKO mice were fed a HFD (16 wks). FKO mice were treated with IL6 (1μg/kg) by sub-cutaneous injection. At 90 mins post-injection, the blood IL6 concentration was 44 ± 9.1 pg/ml (mean ± SD; n = 8), the liver was isolated, and the expression of SOCS3 and Tubulin were examined by immunoblot analysis. (F) Insulin tolerance test (ITT). Mice were treated by sub-cutaneous injection with IL6 (1μg/kg) and then treated (after 90 mins) with insulin (0.75 mU/g) by intraperitoneal injection. Blood glucose concentration was measured at the indicated times. Statistically significant differences between FKO and FWT mice are indicated (*, P < 0.05; **, P < 0.01). (G,H) HFD-fed FKO mice were treated by sub-cutaneous injection with IL6 (1μg/kg) and then treated (after 90 mins) with insulin (0.3 mU/g) by intravenous injection. The liver (G) and epididymal fat pads (H) were isolated after 5 mins and examined by immunoblot analysis to detect AKT, phospho-AKT, and Tubulin.
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References

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