Pharmacologic blocking of IRE1α activity alleviates chemotherapy-induced anorexia and body weight loss via suppression of hepatic GDF15. (A and B)XBP1 mRNA splicing and GDF15 mRNA levels in Huh7 cells treated with (A) Vehicle, 4μ8C (1 μM), DOX (0.01 μg/ml), or DOX+4μ8C or (B) Vehicle, 4μ8C (1 μM), Cis (10 μM), or Cis+4u8C for 24 h. n = 3 per group. (C–H) Male C57BL/6 mice were treated with Vehicle, 4μ8C (3.3 mg per kg body weight, i.p.), DOX (5 mg per kg body weight, i.p.), or the combination of DOX and 4μ8C at the indicated time points (black arrows) for three doses of treatment. (C and D)Xbp1 mRNA splicing (C) and Gdf15 mRNA levels (D) in liver samples from mice after the treatments. Veh., n = 5; 4μ8C, n = 5; DOX, n = 5; DOX+4μ8C, n = 5. (E) Circulating GDF15 protein levels in mice after the treatments. Veh., n = 6; 4μ8C, n = 6; DOX, n = 6; DOX+4μ8C, n = 6. (F) Representative images of immunofluorescence staining against c-Fos and GFRAL at the area AP and NTS of the murine brainstem (left). GFRAL+ c-Fos+ cells (indicated by arrowheads, left) per HPF were quantified (right). The frozen brainstem slides were from mice at 1 day after the final treatments. Scale bar, 100 μm. (G and H) Daily food intake (G, Veh., n = 4; 4μ8C, n = 4; DOX, n = 4; DOX+4μ8C, n = 4) and body weight changes (H, Veh., n = 6; 4μ8C, n = 6; DOX, n = 6; DOX+4μ8C, n = 6) of mice following the indicated treatments. (I–N) C57BL/6 male mice were treated with three doses of Vehicle, 4μ8C (3.3 mg per kg body weight, i.p.), Cis (5 mg per kg body weight, i.p.), or the combination of Cis and 4μ8C at the indicated time points (black arrows). (I and J)Xbp1 mRNA splicing (I, Veh., n = 7; 4μ8C, n = 8; Cis, n = 8; Cis+4μ8C, n = 8) and Gdf15 mRNA levels (J, Veh., n = 6; 4μ8C, n = 6; Cis, n = 6; Cis+4μ8C, n = 6) in liver samples from mice after the treatments. (K) Circulating GDF15 protein levels in mice after the treatments. Veh., n = 6; 4μ8C, n = 6; Cis, n = 6; Cis+4μ8C, n = 6. (L) Representative images of immunofluorescence staining against c-Fos and GFRAL at the area AP and NTS of the murine brainstem (left). GFRAL+ c-Fos+ cells (indicated by arrowheads, left) per HPF were quantified (right). The frozen brainstem slides were from mice at 1 day after the final treatments. Scale bar, 100 μm. (M and N) Daily food intake (M, Veh., n = 3; 4μ8C, n = 3; Cis, n = 4; Cis+4μ8C, n = 4) and body weight changes (N, Veh., n = 6; 4μ8C, n = 6; Cis, n = 6; Cis+4μ8C, n = 6) of mice following the treatments. (O) Proposed model: Hepatic IRE1α-XBP1 signaling activated by chemo drugs regulates hepatic GDF15 expression and promotes chemotherapy-induced anorexia and body weight Loss. Data are representative of three independent experiments (A and B) or two independent experiments (C–M) and presented as mean ± SEM. *P < 0.05, **P < 0.01, or ***P < 0.001 by two-way ANOVA (A–E and I–K) or unpaired two-tailed Student’s t test (F–H and L–N).
Figure 5.

Pharmacologic blocking of IRE1α activity alleviates chemotherapy-induced anorexia and body weight loss via suppression of hepatic GDF15. (A and B) XBP1 mRNA splicing and GDF15 mRNA levels in Huh7 cells treated with (A) Vehicle, 4μ8C (1 μM), DOX (0.01 μg/ml), or DOX+4μ8C or (B) Vehicle, 4μ8C (1 μM), Cis (10 μM), or Cis+4u8C for 24 h. n = 3 per group. (C–H) Male C57BL/6 mice were treated with Vehicle, 4μ8C (3.3 mg per kg body weight, i.p.), DOX (5 mg per kg body weight, i.p.), or the combination of DOX and 4μ8C at the indicated time points (black arrows) for three doses of treatment. (C and D)Xbp1 mRNA splicing (C) and Gdf15 mRNA levels (D) in liver samples from mice after the treatments. Veh., n = 5; 4μ8C, n = 5; DOX, n = 5; DOX+4μ8C, n = 5. (E) Circulating GDF15 protein levels in mice after the treatments. Veh., n = 6; 4μ8C, n = 6; DOX, n = 6; DOX+4μ8C, n = 6. (F) Representative images of immunofluorescence staining against c-Fos and GFRAL at the area AP and NTS of the murine brainstem (left). GFRAL+ c-Fos+ cells (indicated by arrowheads, left) per HPF were quantified (right). The frozen brainstem slides were from mice at 1 day after the final treatments. Scale bar, 100 μm. (G and H) Daily food intake (G, Veh., n = 4; 4μ8C, n = 4; DOX, n = 4; DOX+4μ8C, n = 4) and body weight changes (H, Veh., n = 6; 4μ8C, n = 6; DOX, n = 6; DOX+4μ8C, n = 6) of mice following the indicated treatments. (I–N) C57BL/6 male mice were treated with three doses of Vehicle, 4μ8C (3.3 mg per kg body weight, i.p.), Cis (5 mg per kg body weight, i.p.), or the combination of Cis and 4μ8C at the indicated time points (black arrows). (I and J)Xbp1 mRNA splicing (I, Veh., n = 7; 4μ8C, n = 8; Cis, n = 8; Cis+4μ8C, n = 8) and Gdf15 mRNA levels (J, Veh., n = 6; 4μ8C, n = 6; Cis, n = 6; Cis+4μ8C, n = 6) in liver samples from mice after the treatments. (K) Circulating GDF15 protein levels in mice after the treatments. Veh., n = 6; 4μ8C, n = 6; Cis, n = 6; Cis+4μ8C, n = 6. (L) Representative images of immunofluorescence staining against c-Fos and GFRAL at the area AP and NTS of the murine brainstem (left). GFRAL+ c-Fos+ cells (indicated by arrowheads, left) per HPF were quantified (right). The frozen brainstem slides were from mice at 1 day after the final treatments. Scale bar, 100 μm. (M and N) Daily food intake (M, Veh., n = 3; 4μ8C, n = 3; Cis, n = 4; Cis+4μ8C, n = 4) and body weight changes (N, Veh., n = 6; 4μ8C, n = 6; Cis, n = 6; Cis+4μ8C, n = 6) of mice following the treatments. (O) Proposed model: Hepatic IRE1α-XBP1 signaling activated by chemo drugs regulates hepatic GDF15 expression and promotes chemotherapy-induced anorexia and body weight Loss. Data are representative of three independent experiments (A and B) or two independent experiments (C–M) and presented as mean ± SEM. *P < 0.05, **P < 0.01, or ***P < 0.001 by two-way ANOVA (A–E and I–K) or unpaired two-tailed Student’s t test (F–H and L–N).

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