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Cited by 190Regulation of Appetite and ObesityGDF15 and Related BiomarkersFibroblast Growth Factor Research

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TGF-b Superfamily Cytokine MIC-1/GDF15 Is a Physiological Appetite and Body Weight Regulator

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Tsai, Vicky Wang-Wei, Macia, Laurence, Johnen, Heiko, Kuffner, Tamara, Manadhar, Rakesh, Jørgensen, Sebastian Beck, Lee-Ng, Ka Ki Michelle, Zhang, Hong Ping, Wu, Liyun, Marquis, Christopher Peter, Jiang, Lele, Husaini, Yasmin, Lin, Shu, Herzog, Herbert, Brown, David A., Sainsbury, Amanda, Breit, Samuel N.·2013·PLoS ONE
DOI 10.1371/journal.pone.0055174PMC PMC3585300
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Abstract

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1(-/-)) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1(-/-) mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1(-/-) mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.

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Figure 1 MIC-1−/− are heavier than MIC-1+/+ mice. (A) Male and (B) female MIC-1−/− mice and syngeneic control MIC-1+/+ mice were weighed once every four weeks from age of 4 weeks to 1 year. Both male and female MIC-1−/− mice were on average 6–10% heavier than the MIC-1+/+ mice (male n = 13/group, p = 0.04; female n = 13/group, p = 0.01 repeated measures ANOVA). The weight difference between genotypes appeared from the age of 4 weeks with increased weight differences with ageing in both (C) male and (D) female mice (male n = 13/group, p = 0.044, r2 = 0.32; female n = 13/group p<0.001, r2 = 0.55, linear regression). Data expressed as mean ± SE.
Figure 1 MIC-1−/− are heavier than MIC-1+/+ mice. (A) Male and (B) female MIC-1−/− mice and syngeneic control MIC-1+/+ mice were weighed once every four weeks from age of 4 weeks to 1 year. Both male and female MIC-1−/− mice were on average 6–10% heavier than the MIC-1+/+ mice (male n = 13/group, p = 0.04; female n = 13/group, p = 0.01 repeated measures ANOVA). The weight difference between genotypes appeared from the age of 4 weeks with increased weight differences with ageing in both (C) male and (D) female mice (male n = 13/group, p = 0.044, r2 = 0.32; female n = 13/group p<0.001, r2 = 0.55, linear regression). Data expressed as mean ± SE.CC BY · PubMed Central
Figure 2 Lack of MIC-1 signaling alters the regulation of body fat depots. (A) Whole body lean mass and (B) fat mass was determined by dual energy X-ray absorptiometry (DXA) in 15 mice per group at 12–14 weeks of age. Female MIC-1−/− mice had lower lean mass relative to control mice (p<0.01, n = 15/group, t-test), Both male and female MIC-1−/− mice had significantly higher fat depot mases compared to synergic control (male p<0.01, female p = 0.04, n = 15/group, t-test). Mass of individual white adipose tissue depots were measured in (C) male and (D) female mice (n = 9/group) aged between 14–16 weeks. Fat masses, namely inguinal, epididymal (Epididy), mesenteric (Mesent), retroperitoneal (Retrop), and total white adipose tissue (WATt) were normalized to body weight. In both male and female MIC-1−/− mice, WATt depots were significantly higher than the synergic control (male p<0.01, female p = 0.02, n = 9/group, t-test). Data are means ± SE. Significance indicated as () for p<0.05 or ( ) for p<0.01.
Figure 2 Lack of MIC-1 signaling alters the regulation of body fat depots. (A) Whole body lean mass and (B) fat mass was determined by dual energy X-ray absorptiometry (DXA) in 15 mice per group at 12–14 weeks of age. Female MIC-1−/− mice had lower lean mass relative to control mice (p<0.01, n = 15/group, t-test), Both male and female MIC-1−/− mice had significantly higher fat depot mases compared to synergic control (male p<0.01, female p = 0.04, n = 15/group, t-test). Mass of individual white adipose tissue depots were measured in (C) male and (D) female mice (n = 9/group) aged between 14–16 weeks. Fat masses, namely inguinal, epididymal (Epididy), mesenteric (Mesent), retroperitoneal (Retrop), and total white adipose tissue (WATt) were normalized to body weight. In both male and female MIC-1−/− mice, WATt depots were significantly higher than the synergic control (male p<0.01, female p = 0.02, n = 9/group, t-test). Data are means ± SE. Significance indicated as () for p<0.05 or ( ) for p<0.01.CC BY · PubMed Central
Figure 3 Female MIC-1−/− mice eat more. (A) Spontaneous 3 day cumulated food intake was measured in male and female MIC-1−/− and control mice at 13 weeks of age. All mice were fed with standard chow diet ad libitum. Similar food intake was observed between male genotypes (p = 0.3, n = 8/group, t-test), female MIC-1−/− mice had higher food intake relatively to the control mice (p = 0.05, n = 8/group). (B) Cumulated 24-hour fasting-induced food intake of was performed with the same group of mice at age of 14 weeks. MIC-1−/− and control mice were fasted for 24 hours before re-introduction of food and spillage were collected at indicated time points, no genotypic difference were observed both male and female mice. Food intake at (C) light and (D) dark phase was also measured in the same group of mice at age of 12 weeks. No significant changes were observed between MIC-1−/− and control mice in both sexes. Data are normalized to body weight plotted as means ± SE. Significance indicated as () for p≤0.05.
Figure 3 Female MIC-1−/− mice eat more. (A) Spontaneous 3 day cumulated food intake was measured in male and female MIC-1−/− and control mice at 13 weeks of age. All mice were fed with standard chow diet ad libitum. Similar food intake was observed between male genotypes (p = 0.3, n = 8/group, t-test), female MIC-1−/− mice had higher food intake relatively to the control mice (p = 0.05, n = 8/group). (B) Cumulated 24-hour fasting-induced food intake of was performed with the same group of mice at age of 14 weeks. MIC-1−/− and control mice were fasted for 24 hours before re-introduction of food and spillage were collected at indicated time points, no genotypic difference were observed both male and female mice. Food intake at (C) light and (D) dark phase was also measured in the same group of mice at age of 12 weeks. No significant changes were observed between MIC-1−/− and control mice in both sexes. Data are normalized to body weight plotted as means ± SE. Significance indicated as () for p≤0.05.CC BY · PubMed Central
Figure 4 Male MIC−/− mice exhibit similar metabolic activity to their synergic control mice. Metabolic activity of male MIC-1−/− and control mice with groups of 16 at age between 14–16 weeks was determined by time course of (A) respiratory exchange rate (RER), (B) energy expenditure and (C) ambulatory activity. Energy expenditure was adjusted for lean mass via ANCOVA (common lean mass = 25.65 g). (D) Energy expenditure and (E) ambulatory activity were also presented as total for 24 hour, light phase and dark phase. Data are normalized to body weight and plotted as means ± SE.
Figure 4 Male MIC−/− mice exhibit similar metabolic activity to their synergic control mice. Metabolic activity of male MIC-1−/− and control mice with groups of 16 at age between 14–16 weeks was determined by time course of (A) respiratory exchange rate (RER), (B) energy expenditure and (C) ambulatory activity. Energy expenditure was adjusted for lean mass via ANCOVA (common lean mass = 25.65 g). (D) Energy expenditure and (E) ambulatory activity were also presented as total for 24 hour, light phase and dark phase. Data are normalized to body weight and plotted as means ± SE.CC BY · PubMed Central
Figure 5 Female MIC−/− mice exhibit lower metabolic activity than their synergic controls. Metabolic activity of female MIC-1−/− and control mice with groups of 9 at age between 14–16 weeks was determined by time course of (A) respiratory exchange rate (RER), (B) energy expenditure and (C) ambulatory activity. Energy expenditure (EE) was adjusted for lean mass via ANCOVA (common lean mass = 18.72 g), EE were significantly lower measured over 24 hour in MIC-1−/− mice (p = 0.001, n = 9/group, repeated measures ANOVA). (D) MIC-1−/− also displayed lower total EE in time courses over 24 hour, light phase and dark phase (p = 0.001. p = 0.005 and p<0.001, respectively, n = 9/group, t-test). (E) Physical activity in dark phase were significantly lower in MIC-1−/− mice (p = 0.03, n = 9, t-test). Data are normalized to body weight and plotted as means ± SE. Significance indicated as () for p<0.05 or ( ) for p<0.01, or ( ) for p<0.001.
Figure 5 Female MIC−/− mice exhibit lower metabolic activity than their synergic controls. Metabolic activity of female MIC-1−/− and control mice with groups of 9 at age between 14–16 weeks was determined by time course of (A) respiratory exchange rate (RER), (B) energy expenditure and (C) ambulatory activity. Energy expenditure (EE) was adjusted for lean mass via ANCOVA (common lean mass = 18.72 g), EE were significantly lower measured over 24 hour in MIC-1−/− mice (p = 0.001, n = 9/group, repeated measures ANOVA). (D) MIC-1−/− also displayed lower total EE in time courses over 24 hour, light phase and dark phase (p = 0.001. p = 0.005 and p<0.001, respectively, n = 9/group, t-test). (E) Physical activity in dark phase were significantly lower in MIC-1−/− mice (p = 0.03, n = 9, t-test). Data are normalized to body weight and plotted as means ± SE. Significance indicated as () for p<0.05 or ( ) for p<0.01, or ( ) for p<0.001.CC BY · PubMed Central
Figure 6 Major contribution to genotypic difference in total EE was basal metabolism. Correlation between physical activity and EE was based on average values collected over 24 h. Each point represents data collected in 1-h intervals from the (A) male MIC-1−/− and control mice (Trend line equation: MIC-1−/− y = 12932x –4375 R2 = 0.8705, control y = 18893x –6637 R2 = 0.8813) and (B) female MIC-1−/− and control mice (Trend line equation: MIC-1−/− y = 18517x –6851 R2 = 0.8796, control y = 12326x –3628 R2 = 0.8261). Basal metabolic rate is determined using the function from the trend line and extrapolating to set the physical activity to zero. No significant difference in basal metabolic rate between the male genotypes (0.35±0.01 vs 0.34±0.02, respectively, p = 0.23, n = 15/group). Basal metabolic rate was significantly lower in the female MIC-1−/− mice compared to control (0.37±0.02 vs 0.29±0.01, respectively, p<0.01, n = 9/group). Data are means ± SE.
Figure 6 Major contribution to genotypic difference in total EE was basal metabolism. Correlation between physical activity and EE was based on average values collected over 24 h. Each point represents data collected in 1-h intervals from the (A) male MIC-1−/− and control mice (Trend line equation: MIC-1−/− y = 12932x –4375 R2 = 0.8705, control y = 18893x –6637 R2 = 0.8813) and (B) female MIC-1−/− and control mice (Trend line equation: MIC-1−/− y = 18517x –6851 R2 = 0.8796, control y = 12326x –3628 R2 = 0.8261). Basal metabolic rate is determined using the function from the trend line and extrapolating to set the physical activity to zero. No significant difference in basal metabolic rate between the male genotypes (0.35±0.01 vs 0.34±0.02, respectively, p = 0.23, n = 15/group). Basal metabolic rate was significantly lower in the female MIC-1−/− mice compared to control (0.37±0.02 vs 0.29±0.01, respectively, p<0.01, n = 9/group). Data are means ± SE.CC BY · PubMed Central
Figure 7 Physiological levels of human MIC-1/GDF15 reduce weight and food intake in mice. Male MIC-1−/− and MIC-1+/+ mice were infused with human MIC-1/GDF15 (1ug/20gBW/d) or vehicle via osmotic mini-pump. Food intake, body weight and serum levels of human MIC-1/GDF15 were measured on day 5 of infusion. (A) MIC-1/GDF15-treated MIC-1−/− mice had an average serum MIC-1/GDF15 level of 643±67 pg/ml and weighed 95.86±0.77% of their starting body weight whilst vehicle-treated mice weighed 102.3±0.75% of their starting weight (n = 6/group, p<0.01 unpaired t-test). (B) MIC-1/GDF15-treated MIC-1+/+ mice had an average serum MIC-1/GDF15 level of 576±45 pg/ml and weighed 99.86±0.47% of their starting weight whilst vehicle-treated mice weighed 102±0.52% (n = 14, p = 0.01 unpaired t-test). This decreased body weight in both genotypes was associated with reduced food intake. (C) MIC-1/GDF15-treated MIC-1−/− and (D) MIC-1/GDF15-treated MIC-1+/+ consumed significantly less food than the matched vehicle-treated mice of same genotype (MIC-1−/− n = 6/group, p = 0.04; MIC-1+/+ n = 14/group, p<0.01 unpaired t-test). Data expressed as mean ± SE.
Figure 7 Physiological levels of human MIC-1/GDF15 reduce weight and food intake in mice. Male MIC-1−/− and MIC-1+/+ mice were infused with human MIC-1/GDF15 (1ug/20gBW/d) or vehicle via osmotic mini-pump. Food intake, body weight and serum levels of human MIC-1/GDF15 were measured on day 5 of infusion. (A) MIC-1/GDF15-treated MIC-1−/− mice had an average serum MIC-1/GDF15 level of 643±67 pg/ml and weighed 95.86±0.77% of their starting body weight whilst vehicle-treated mice weighed 102.3±0.75% of their starting weight (n = 6/group, p<0.01 unpaired t-test). (B) MIC-1/GDF15-treated MIC-1+/+ mice had an average serum MIC-1/GDF15 level of 576±45 pg/ml and weighed 99.86±0.47% of their starting weight whilst vehicle-treated mice weighed 102±0.52% (n = 14, p = 0.01 unpaired t-test). This decreased body weight in both genotypes was associated with reduced food intake. (C) MIC-1/GDF15-treated MIC-1−/− and (D) MIC-1/GDF15-treated MIC-1+/+ consumed significantly less food than the matched vehicle-treated mice of same genotype (MIC-1−/− n = 6/group, p = 0.04; MIC-1+/+ n = 14/group, p<0.01 unpaired t-test). Data expressed as mean ± SE.CC BY · PubMed Central

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Metadata

Authors
Tsai, V. W.-W., Macia, L., Johnen, H., Kuffner, T., Manadhar, R., Jørgensen, S. B., Lee-Ng, K. K. M., Zhang, H. P., Wu, L., Marquis, C. P., Jiang, L., Husaini, Y., Lin, S., Herzog, H., Brown, D. A., Sainsbury, A., & Breit, S. N.
Affiliations
  • UNSW Sydney (AU)
  • Garvan Institute of Medical Research (AU)
  • Novo Nordisk (Denmark) (DK)
Corresponding author
Breit, Samuel N.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-02-28
Volume
8
Issue
2
Pages
e55174
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0055174
PMC
PMC3585300
OpenAlex
W1983011875
Cited by
188
References
42
Citations by year
2026: 7 · 2025: 11 · 2024: 20 · 2023: 20 · 2022: 17 · 2021: 18 · 2020: 24 · 2019: 24 · 2018: 9 · 2017: 12 · 2016: 10 · 2015: 7 · 2014: 8 · 2013: 1
FWCI
4.67
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Monash University Research Portal (Monash University) (acceptedVersion, cc-by)
  • The Sydney eScholarship Repository (The University of Sydney) (submittedVersion)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
  • UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Medical Research Council
  • National Health and Medical Research Council
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Keywords
appetite regulation, body weight regulation, basal metabolic rate, energy expenditure, dietary intake, adiposity, lean body mass, knockout mice, energy storage
MeSH terms
Adipose Tissue, Animals, Appetite, Body Weight, Eating, Energy Metabolism, Female, Genotype, Humans, Male, Organ Size, Sex Factors, Signal Transduction, Weight Gain, Mice, Knockout, Mice, Growth Differentiation Factor 15

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