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. 2013 Jan 11;339(6116):218-22.
doi: 10.1126/science.1227568. Epub 2012 Dec 6.

JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation

Myoung Sook Han  1 , Dae Young Jung, Caroline Morel, Saquib A Lakhani, Jason K Kim, Richard A Flavell, Roger J Davis
Affiliations

JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation

Myoung Sook Han et al. Science. .

Abstract

The cJun NH(2)-terminal kinase (JNK) signaling pathway contributes to inflammation and plays a key role in the metabolic response to obesity, including insulin resistance. Macrophages are implicated in this process. To test the role of JNK, we established mice with selective JNK deficiency in macrophages. We report that feeding a high-fat diet to control and JNK-deficient mice caused similar obesity, but only mice with JNK-deficient macrophages remained insulin-sensitive. The protection of mice with macrophage-specific JNK deficiency against insulin resistance was associated with reduced tissue infiltration by macrophages. Immunophenotyping demonstrated that JNK was required for pro-inflammatory macrophage polarization. These studies demonstrate that JNK in macrophages is required for the establishment of obesity-induced insulin resistance and inflammation.

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Figures

Fig. 1
Fig. 1
Macrophage JNK promotes the establishment of obesity-induced insulin resistance. (A) Insulin tolerance tests (ITT) were performed on chow diet and HFD-fed ΦWT and ΦKO mice (4 wk.) by intraperitoneal (i.p.) injection of insulin (0.75 U/kg) and measurement of blood glucose concentration (mean ± S.E.M.; n = 7 ~ 10 mice). (B) Glucose tolerance tests (GTT) were performed by i.p. injection of glucose (1 g/kg) and measurement of blood glucose concentration (mean ± S.E.M.; n = 7 ~ 10 mice). (C–E) The blood concentration of glucose and insulin in overnight fasted mice and the blood glucose concentration in fed mice were measured (mean ± S.E.M.; n = 10 mice). (F–J) Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp in conscious mice. The steady-state glucose infusion rate (GIR), hepatic insulin action (HIA), clamp hepatic glucose production (HGP), whole body glucose turnover, and whole body glycogen plus lipid synthesis are presented (mean ± S.E.M.; n = 8 ~ 10 mice). (K) Chow-fed (ND) and HFD-fed mice (4 wk.) were fasted overnight and then treated by i.p. injection with 1 U/kg insulin (15 min). Multiplexed ELISA was used to detect AKT and activated (pSer473) AKT in the liver, epididymal adipose tissue (WAT), and gastrocnemius muscle (mean ± S.E.M.; n = 3 ~ 5 mice). Representative tissue samples were also examined by immunoblot analysis by probing with antibodies to phospho-AKT, AKT, and αTubulin (Tub.). Data (A–E) are representative of three experiments. Data were pooled from (F–J) eight to ten and (K) three to five experiments. *P < 0.05, **P < 0.01, ***P < 0.001 as determined by Student's t test (A,B) or ANOVA with Bonferroni's posttest correction for multiple comparisons (C–K).
Fig. 2
Fig. 2
Macrophage JNK promotes pancreatic islet dysfunction. (A,B) The morphology of pancreatic islets was examined using chow-fed (ND) and HFD-fed mice (4 wk.) fasted overnight. Sections were stained with antibodies to insulin, glucagon, or F4/80. DNA was stained with DAPI (blue). Scale bar, 75 μm. No significant differences between ΦWT and ΦKO islet infiltration by F4/80+ macrophages were detected (fig. S19). (C) The islet area per section is presented (mean ± S.E.M.; n = 7 ~ 10 mice). (D) The number of β cells per islet that stained with an antibody to the proliferation marker PCNA is presented (mean ± S.E.M.; n = 5 ~ 7 mice). (E) Glucose-induced insulin release measurements were performed by i.p. injection of glucose (2 g/kg) and measurement of blood insulin concentration (mean ± S.E.M.; n = 8 ~ 10 mice). (F) Glucose-induced insulin secretion in vitro. Isolated islets were incubated (1 hr) with low glucose (3.3 mM) or high glucose (16.7 mM). Insulin secretion was measured (mean ± S.E.M.; n = 5 mice). Data (A,B) are representative of (A,B) five to ten, (E) three, and (F) two experiments. Data (C,D) were pooled from five to ten experiments. *P < 0.05, **P < 0.01, ***P < 0.001 as determined by Student's t test (E) or ANOVA with Bonferroni's posttest correction for multiple comparisons (C,D,F).
Fig. 3
Fig. 3
JNK promotes M1 polarization of adipose tissue macrophages. (A–C) The stromal vascular fraction (SVF) of epididymal adipose tissue was isolated from chow-fed and HFD-fed (4 wk.) mice and examined by flow cytomtery to detect the total number of F4/80+ adipose tissue macrophages (ATM), the number of F4/80+ CD11c+ CD206− (M1 ATM), and the number of F4/80+ CD11c− CD206+ (M2 ATM) (mean ± S.E.M.; n = 5 mice). (D) Total RNA was isolated from epididymal adipose tissue from chow-fed and HFD-fed ΦWT and ΦKO mice. The relative expression of mRNA associated with M1-polarized macrophages and M2-polarized macrophages was measured by quantitative RT-PCR assays (mean ± S.E.M.; n = 8 ~ 10 mice). Data (A–C) are representative of three experiments. Data (D) were pooled from eight to ten experiments. *P < 0.05, **P < 0.01, ***P < 0.001 as determined by ANOVA with Bonferroni's posttest correction for multiple comparisons.
Fig. 4
Fig. 4
JNK promotes M1 polarization of macrophages in vitro. (A) Bone marrow-derived macrophages (BMDM) from ΦWT and ΦKO mice were incubated without or with 100 ng/ml IFN-γ (36 hr). F4/80+ cells were stained with an antibody to the M1 marker CD11c and examined by flow cytometry (mean relative fluorescence intensity ± S.E.M.; n = 3). (B) Total RNA was isolated from BMDM incubated (8 hr) with 100 ng/ml IFN-γ. The relative expression of the indicated M1 marker genes was measured by quantitative RT-PCR assays (mean ± S.E.M.; n = 5 mice). (C) Chow-fed ΦWT and ΦKO mice were fasted overnight. Blood was collected from the mice 2.5 hr after i.p. injection of LPS (20 mg/kg) or solvent (Control). The blood concentration of CCL2, CCL5, IL1β, IL6, and TNFα was measured (mean ± S.E.M.; n = 10 mice). Data are representative of (A) three and (C) two experiments. Data (B) were pooled from five experiments. *P < 0.05, **P < 0.01, ***P < 0.001 as determined by ANOVA with Bonferroni's posttest correction for multiple comparisons.
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