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. Author manuscript; available in PMC: 2019 Jul 3.
Published in final edited form as: Cell Metab. 2018 May 24;28(1):118–129.e5. doi: 10.1016/j.cmet.2018.04.021

Figure 6.

Figure 6

Dual HO-receptor antagonism attenuates tumor-induced impairments in glucose processing and improves sleep quality without affecting peripheral inflammation. (a) Blood glucose (ZT 6 2-way ANOVA main effect of tumor: F1,33 = 8.903, p = 0.0053; interaction: F1,33 = 4.381, p = 0.0441)(ZT 18 2-way ANOVA main effect of tumor: F1,35 = 5.149, p = 0.03), (b) liver ldha expression (ZT 6 2-way ANOVA main effect of tumor: F1,32 = 9.194, p = 0.0048), (c) liver gck expression (ZT 6 main effect of tumor: F1,30 = 19.25, p = 0.0001), and (d) liver slc2a4 expression (ZT 6 main effect of tumor: F1,31 = 8.089, p = 0.0078) were altered by tumor-status and attenuated by administration of ALX. (e) Experimental design for ALX administration. Changes in hepatic inflammatory gene expression were not observed in response to ALX treatment. (f) Liver stat3 (ZT 6 main effect of tumor: F1,32 = 24.41, p < 0.0001; ZT 18 main effect of tumor: F1,33 = 22.79, p < 0.0001), (g) liver il6 (ZT 6 main effect of tumor: F1,32 = 21.43, p < 0.0001), and (h) liver socs3 (ZT 6 main effect of tumor: F1,30 = 17.37, p = 0.0002; ZT 18 main effect of tumor: F1,34 = 17.4, p = 0.0002; main effect of ALX F1,34 = 4.778, p = 0.0358; interaction F1,34 = 7.874, p = 0.0082) showed enhanced expression in tumor-bearing mice regardless of ALX treatment (n = 8-10/group/timepoint). (i) ALX treatment (V = vehicle, A = ALX) increased NREM sleep time during the first 6 hours following injections (day 22 ZT 14 t = 3.755, p = 0.0032; ZT 16 t = 3.126, p = 0.0096; ZT 18 t = 2.925, p = 0.014; day 25 ZT 14 t = 3.574, p = 0.0044; ZT 16 t = 3.995, p = 0.0021; ZT 18 t = 2.301, p = 0.042). This sleep was characterized by more restorative delta (0.5-4 Hz) frequencies in the EEG on day 25 normalized to the same time-frame (ZT14-20) on a non-treatment day (day 24) (1.5 Hz t = 3.361, p = 0.0063; 2 Hz t = 2.825, p = 0.0165, 20.5 Hz t = 2.354, p = 0.0382). (j) ALX had negligible effects on REM sleep time (day 20 ZT 12 t = 2.234, p =0.047, day 21 ZT 18 t = 3.464, p = 0.00529; ZT 0 t = 2.889, p = 0.015; day 22 ZT 14 t = 3.973, p = 0.0022, ZT 8 t = 3.177, p = 0.0088; day 23 ZT 18 t = 3.141, p = 0.0094; day 24 ZT 12 t = 3.095, p = 0.01; day 25 ZT 14 t = 2.685, p = 0.021). No effects of ALX on normalized REM EEG spectra were observed. (k) ALX treatment decreased wakefulness during the first 6 hours following injections (day 22 ZT 14 t = 4.139, p = 0.0016; ZT 16 t = 2.974, p = 0.013; ZT 18 t = 2.831, p = 0.016; day 23 ZT 22 t = 2.213, p = 0.049; day 25 ZT 14 t = 3.625, p = 0.004; ZT 16 t = 3.828, p = 0.003; ZT 18 t = 2.421, p = 0.034). ALX decreased wakefulness theta/alpha EEG frequencies following treatment (7.5 Hz: t = 2.298, p = 0.042; 8 Hz: t = 2.888, p = 0.015; 8.5 Hz: t = 2.799, p = 0.017; 9 Hz: t = 2.737, p = 0.019; 9.5 Hz: t = 3.335, p = 0.0067; 10 Hz: t = 3.129, p = 0.0096; 10.5 Hz: t = 2.612, p = 0.024; 11 Hz: t = 2.346, p = 0.039). (n = 6 tumor + veh, 7 tumor + alx). Error bars represent S.E.M, † = main effect of tumor, * = interaction, § = main effect of ALX treatment; different letter headings represent multiple comparisons at p < 0.05, 2-way ANOVA; Tukey’s multiple comparisons test).