Figure 3. Liver-derived GDF15 mediates... | Rockefeller University Press

Liver-derived GDF15 mediates chemotherapy-induced anorexia and body weight loss. (A) Volcano plot showing DEGs (FDR < 0.05 and |Log2(Foldchange)| > 2) between the liver samples from Vehicle- and Cis-treated mice. Significantly changed genes are colored in red (upregulated, Up) and blue (downregulated, Down), while non-significantly changed genes (Not sig) are in gray. (B) Heatmap of 26 genes encoding secreted factors among 135 overlapping upregulated genes (compared to Vehicle treatment) in liver samples from both DOX- and Cis-treated mice. (C and D) mRNA levels of Gdf15 in livers (C) and circulating GDF15 protein levels (D) from mice treated with the indicated chemotherapy drugs (DOX, 10 mg per kg body weight, i.p.; Cis, 10 mg per kg body weight, i.p.; or PTX, 10 mg per kg body weight, i.p.) for 0 (n = 4), 1 (n = 6), 3 (n = 6), and 7 days (n = 6). (E) Circulating GDF15 protein levels in healthy volunteers (non-tumor) and in individuals with colon or breast cancer before and after receiving chemotherapy for the first time (healthy volunteer, n = 15; colon cancer patients, n = 12; breast cancer patients, n = 10). (F) mRNA levels of Gdf15 in various tissues isolated from mice treated with Vehicle (n = 6), DOX (n = 6), or Cis (n = 6). Tissues were collected 1 day after injection. gWAT, gonadal white adipose tissue; iWAT, inguinal white adipose tissue; TA, tibialis anterior; Gas, gastrocnemius. (G–J) C57BL/6 male mice were injected with AAV-shNC (n = 12) or AAV-shGdf15-1 (n = 12) for 4 wk before i.p. injection of Cis (10 mg per kg body weight) or Vehicle. (G and H) Liver Gdf15 mRNA abundance (G) and circulating GDF15 protein levels (H) were quantified in liver samples collected 1 day after injection and serum samples harvested at the indicated time points following Cis treatment, respectively. AAV-shNC+Veh., n = 6; AAV-shGdf15+Veh., n = 6; AAV-shNC+Cis, n = 6; AAV-shGdf15+Cis, n = 6. (I and J) Daily food intake (I) and body weight changes (J) of AAV-shNC- and AAV-shGdf15-injected mice following Vehicle or Cis treatment. The arrow indicates the time point of Cis injection. Data are representative of two independent (except A, B, and E) experiments and presented as mean ± SEM. *P < 0.05, **P < 0.01, or ***P < 0.001 by one-way ANOVA (C, D, and F), two-way ANOVA (G), unpaired two-tailed Student’s t test (H–J), or paired Student’s t test (E).

Figure 3.

Liver-derived GDF15 mediates chemotherapy-induced anorexia and body weight loss. (A) Volcano plot showing DEGs (FDR < 0.05 and |Log₂(Foldchange)| > 2) between the liver samples from Vehicle- and Cis-treated mice. Significantly changed genes are colored in red (upregulated, Up) and blue (downregulated, Down), while non-significantly changed genes (Not sig) are in gray. (B) Heatmap of 26 genes encoding secreted factors among 135 overlapping upregulated genes (compared to Vehicle treatment) in liver samples from both DOX- and Cis-treated mice. (C and D) mRNA levels of Gdf15 in livers (C) and circulating GDF15 protein levels (D) from mice treated with the indicated chemotherapy drugs (DOX, 10 mg per kg body weight, i.p.; Cis, 10 mg per kg body weight, i.p.; or PTX, 10 mg per kg body weight, i.p.) for 0 (n = 4), 1 (n = 6), 3 (n = 6), and 7 days (n = 6). (E) Circulating GDF15 protein levels in healthy volunteers (non-tumor) and in individuals with colon or breast cancer before and after receiving chemotherapy for the first time (healthy volunteer, n = 15; colon cancer patients, n = 12; breast cancer patients, n = 10). (F) mRNA levels of Gdf15 in various tissues isolated from mice treated with Vehicle (n = 6), DOX (n = 6), or Cis (n = 6). Tissues were collected 1 day after injection. gWAT, gonadal white adipose tissue; iWAT, inguinal white adipose tissue; TA, tibialis anterior; Gas, gastrocnemius. (G–J) C57BL/6 male mice were injected with AAV-shNC (n = 12) or AAV-shGdf15-1 (n = 12) for 4 wk before i.p. injection of Cis (10 mg per kg body weight) or Vehicle. (G and H) Liver Gdf15 mRNA abundance (G) and circulating GDF15 protein levels (H) were quantified in liver samples collected 1 day after injection and serum samples harvested at the indicated time points following Cis treatment, respectively. AAV-shNC+Veh., n = 6; AAV-shGdf15+Veh., n = 6; AAV-shNC+Cis, n = 6; AAV-shGdf15+Cis, n = 6. (I and J) Daily food intake (I) and body weight changes (J) of AAV-shNC- and AAV-shGdf15-injected mice following Vehicle or Cis treatment. The arrow indicates the time point of Cis injection. Data are representative of two independent (except A, B, and E) experiments and presented as mean ± SEM. *P < 0.05, **P < 0.01, or ***P < 0.001 by one-way ANOVA (C, D, and F), two-way ANOVA (G), unpaired two-tailed Student’s t test (H–J), or paired Student’s t test (E).

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