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. 2018 Aug 2;13(8):e0201584.
doi: 10.1371/journal.pone.0201584. eCollection 2018.

GDF15 deficiency promotes high fat diet-induced obesity in mice

Thanhvien Tran  1 , Jingping Yang  1 , Jonitha Gardner  1 , Yumei Xiong  1
Affiliations

GDF15 deficiency promotes high fat diet-induced obesity in mice

Thanhvien Tran et al. PLoS One. .

Abstract

Pharmacological treatment of recombinant growth differentiation factor 15 (GDF15) proteins reduces body weight in obese rodents and primates. Paradoxically, circulating GDF15 levels are increased in obesity. To investigate the role of endogenous GDF15 in obesity development, we put GDF15 knockout mice and wildtype controls on high fat diet for the mice to develop diet-induced obesity. Compared to wildtype animals, GDF15 knockout mice were more prone to high fat diet-induced obesity. Male knockout mice showed worse glucose tolerance, lower locomotor activity and lower metabolic rate than wildtype mice. Additionally, GDF15 deficiency increased occurrences of high fat diet-induced skin lesions. Our data suggests that endogenous GDF15 has a protective role in obesity development and lack of GDF15 aggravates the progression of obesity and associated pathological conditions. Elevated GDF15 levels in obesity may have resulted from a response to overcome GDF15 resistance.

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Conflict of interest statement

The authors’ affiliation with Amgen does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Male GDF15 were more prone to high fat diet-induced obesity.
(A) Body weight of male mice. (B) Body weight of female mice. (C) Average daily food intake. (D) Body composition of male mice. n = 12–21 for male mice. n = 11–22 for female mice. Data are shown as mean±SEM. *p<0.05, ***p<0.001 between WT and KO by ANOVA.
Fig 2
Fig 2. Male GDF15 knockout DIO mice had higher glucose levels, insulin levels and worsened glucose tolerance.
(A) 4hr fasting blood glucose levels of male mice. (B) 4hr fasting blood glucose levels of female mice. (C) 4hr fasting serum insulin levels of male mice. (D) 4hr fasting serum insulin levels of female mice. (E) Blood glucose levels of male mice during oral glucose tolerance test. (F) Blood glucose levels of female mice during oral glucose tolerance test. n = 12–21 for male mice. n = 11–22 for female mice. Data are shown as mean±SEM. *p<0.05, **p<0.01, ***p<0.001 between WT and KO by 2-Way ANOVA.
Fig 3
Fig 3. GDF15 knockout DIO mice had higher body weight and higher incidences of skin lesions.
(A) Body weight of male GDF15 mice (n = 6–14). (B) Body weight of female mice (n = 8–13). (C) Skin lesion incidence count and age of first observation. Body weight data are shown as mean±SEM. *p<0.05, **p<0.01, ***p<0.001 between WT and KO by 2-way ANOVA.
Fig 4
Fig 4. Male GDF15 knockout DIO mice had lower locomotor activity.
(A) X-axis activity of male DIO mice: continuous 3-d recording and average value of each light cycle. (B) Z-axis activity of male DIO mice: continuous 3-d recording and average value of each light cycle. (C) Continuous 3-d recording of food intake of male DIO mice. (D) Cumulative food intake of male DIO mice. n = 6. Raw CLAMS recorded data are shown as mean. Analyzed average values are shown as mean±SEM. *p<0.05, **p<0.01 between WT and KO by 2-way ANOVA.
Fig 5
Fig 5. Locomotor activity and food intake of female mice.
(A) X-axis activity of female DIO mice: continuous 3-d recording and average value of each light cycle. (B) Z-axis activity of female DIO mice: continuous 3-d recording and average value of each light cycle. (C) Continuous 3-d recording of food intake of female DIO mice. (D) Cumulative food intake of female DIO mice. n = 5–7. Raw CLAMS recorded data are shown as mean. Analyzed average values are shown as mean±SEM.
Fig 6
Fig 6. Male GDF15 knockout DIO mice had lower metabolic rate than wildtype mice.
(A) Oxygen consumption of male DIO mice: continuous 3-d recording and average value of each light cycle. (B) RER of male DIO mice: continuous 3-d recording and average value of each light cycle. (C) Heat production of male DIO mice: continuous 3-d recording and average value of each light cycle. n = 6. CLAMS recorded data are shown as mean. Analyzed average values are shown as mean±SEM. *p<0.05 between WT and KO by unpaired t-test.
Fig 7
Fig 7. Metabolic rate and RER of female mice.
(A) Oxygen consumption of female DIO mice: continuous 3-d recording and average value of each light cycle. (B) RER of female DIO mice: continuous 3-d recording and average value of each light cycle. (C) Heat production of female DIO mice: continuous 3-d recording and average value of each light cycle. n = 5–7. CLAMS recorded data are shown as mean. Analyzed average values are shown as mean±SEM.
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