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. 2016 Feb 3:7:10626.
doi: 10.1038/ncomms10626.

PKR is not obligatory for high-fat diet-induced obesity and its associated metabolic and inflammatory complications

G I Lancaster  1 , H L Kammoun  1 , M J Kraakman  1 , G M Kowalski  1   2 , C R Bruce  1   2 , M A Febbraio  1   3
Affiliations

PKR is not obligatory for high-fat diet-induced obesity and its associated metabolic and inflammatory complications

G I Lancaster et al. Nat Commun. .

Abstract

Protein kinase R (PKR) has previously been suggested to mediate many of the deleterious consequences of a high-fat diet (HFD). However, previous studies have observed substantial phenotypic variability when examining the metabolic consequences of PKR deletion. Accordingly, herein, we have re-examined the role of PKR in the development of obesity and its associated metabolic complications in vivo as well as its putative lipid-sensing role in vitro. Here we show that the deletion of PKR does not affect HFD-induced obesity, hepatic steatosis or glucose metabolism, and only modestly affects adipose tissue inflammation. Treatment with the saturated fatty acid palmitate in vitro induced comparable levels of inflammation in WT and PKR KO macrophages, demonstrating that PKR is not necessary for the sensing of pro-inflammatory lipids. These results challenge the proposed role for PKR in obesity, its associated metabolic complications and its role in lipid-induced inflammation.

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Figures

Figure 1
Figure 1. Loss of PKR does not prevent the development of obesity.
Total body mass (a), fat mass (b), lean mean (c) and epididymal adipose tissue mass (d) in WT and PKR KO mice fed either a HFD or SCD for 16 weeks. Ns are 9, 8, 12 and 18 for WT SCD, PKR KO SCD, WT HFD and PKR KO HFD, respectively. Data are presented as the mean±standard deviation (s.d.). *P<0.001, two-way ANOVA, main effect of diet between SCD and HFD.
Figure 2
Figure 2. Loss of PKR does not improve glucose metabolism in HF-fed mice.
Glucose tolerance as assessed by OGTT (a,c,e,g) and plasma insulin during the OGTT (b,d,f,h), in WT and PKR KO mice after 6 (a–d) and 16 (e–h) weeks of either a SCD (a,b,e,f) or HFD (c,d,g,h). The area under the curve for the OGTT in all groups at 6 (i) and 16 weeks (j). Fasting plasma insulin concentrations in all groups at 6 (k) and 16 weeks (l). Except for plasma insulin following 16 weeks of HFD in PKR KO mice where N=17, Ns are 9, 8, 12 and 18 for WT SCD, PKR KO SCD, WT HFD and PKR KO HFD, respectively. Data are presented as the mean±standard deviation (s.d.). *P<0.001, two-way ANOVA, main effect for time between 0 and 15 min. **P<0.01, two-way ANOVA, main effect for time between 0 and 15 min. †P=0.018, two-way ANOVA, main effect for genotype between WT and PKR KO. ‡P<0.001, two-way ANOVA, main effect of diet between SCD and HFD. ‡‡P=0.01, two-way ANOVA, main effect of diet between SCD and HFD.
Figure 3
Figure 3. Loss of PKR does not improve hepatic steatosis in HF-fed mice but decreases plasma TAG.
Liver TAG (a), plasma NEFA (b), plasma cholesterol (c) and plasma TAG (d) in WT and PKR KO mice fed either a HFD or SCD for 16 weeks. Ns are 9, 8, 12 and 18 for WT SCD, PKR KO SCD, WT HFD and PKR KO HFD, respectively. Data are presented as the mean±standard deviation (s.d.). *P<0.001, two-way ANOVA, main effect for diet between SCD and HFD. †P=0.034, two-way ANOVA, main effect for genotype between WT and PKR KO.
Figure 4
Figure 4. Loss of PKR does not prevent HFD-induced adipose tissue macrophage recruitment, but ameliorates T-cell recruitment.
Inflammatory gene expression (a,c), percentages of specific immune cell populations (b,d,e), circulating monocyte and neutrophil numbers (f), phosphorylation of JNK (g) and the phosphorylation of eIF2α (h) within WAT in WT and PKR KO mice fed either a HFD (c–h) or SCD (a,b,f–h) for 16 weeks. Ns for WT SCD, PKR KO SCD, WT HFD and PKR KO HFD, respectively, for each figure are as follows: (a) 8–9 and 7; (b) 4 and 4; (c) 11–12 and 13–15; (d) 5 and 8; (e) 5 and 4; (f) 9, 8, 12 and 18; (g) 9, 8, 12 and 18; (h) 9, 8, 12 and 18. Data are presented as the mean±standard deviation (s.d.). *P<0.05, independent samples t-test. **P<0.001, two-way ANOVA, main effect for diet between SCD and HFD. ‡P<0.05, two-way ANOVA, main effect of diet between SCD and HFD.
Figure 5
Figure 5. Loss of PKR in vitro does not prevent saturated fatty acid-induced inflammation or inflammasome activation.
Phosphorylation of JNK (a), eIF2α (b), secretion of TNFα (c) and the secretion of IL-1β (d) in BMDM from WT and PKR KO mice treated with 1 mM palmitate or vehicle for 4 h (a,b) or 8 h (c,d). (e,f) The secretion of IL-1β in WT and PKR KO BMDM following treatment with either Nigericin (Nig; e) or ATP (f). All the data represent three independent mice per genotype with BMDM from each mouse comprised of three technical replicates. Data are presented as the mean±standard deviation (s.d.).
Figure 6
Figure 6. Injection of Poly(I:C) does not impair glucose metabolism.
Glucose tolerance as assessed by OGTT in C57Bl6/J mice administered with either sterile saline or 10 mg kg−1 Poly(I:C) 6 h before OGTT (a–c). Ns are 8 for both groups. Data are presented as the mean±standard deviation (s.d.). An independent samples t-test was used to compare the area under the curve between the two groups.
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References

    1. McNelis J. C. & Olefsky J. M. Macrophages, immunity, and metabolic disease. Immunity 41, 36–48 (2014). - PubMed
    1. Osborn O. & Olefsky J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nature Med. 18, 363–374 (2012). - PubMed
    1. Hotamisligil G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006). - PubMed
    1. Park E. J. et al.. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010). - PMC - PubMed
    1. Libby P., Lichtman A. H. & Hansson G. K. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 38, 1092–1104 (2013). - PMC - PubMed

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