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Cited by 211Regulation of Appetite and ObesityGDF15 and Related BiomarkersAdipokines, Inflammation, and Metabolic Diseases

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Macrophage Inhibitory Cytokine 1 (MIC-1/GDF15) Decreases Food Intake, Body Weight and Improves Glucose Tolerance in Mice on Normal & Obesogenic Diets

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Macia, Laurence, Tsai, Vicky Wang-Wei, Nguyen, Amy D., Johnen, Heiko, Kuffner, Tamara, Shi, Yan-Chuan, Lin, Shu, Herzog, Herbert, Brown, David A., Breit, Samuel N., Sainsbury, Amanda·2012·PLoS ONE
DOI 10.1371/journal.pone.0034868PMC PMC3325923
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Abstract

Food intake and body weight are controlled by a variety of central and peripheral factors, but the exact mechanisms behind these processes are still not fully understood. Here we show that that macrophage inhibitory cytokine-1 (MIC-1/GDF15), known to have anorexigenic effects particularly in cancer, provides protection against the development of obesity. Both under a normal chow diet and an obesogenic diet, the transgenic overexpression of MIC-1/GDF15 in mice leads to decreased body weight and fat mass. This lean phenotype was associated with decreased spontaneous but not fasting-induced food intake, on a background of unaltered energy expenditure and reduced physical activity. Importantly, the overexpression of MIC-1/GDF15 improved glucose tolerance, both under normal and high fat-fed conditions. Altogether, this work shows that the molecule MIC-1/GDF15 might be beneficial for the treatment of obesity as well as perturbations in glucose homeostasis.

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Figure 1 MIC-1/GDF15 overexpression reduces body weight, adiposity and food intake without altering metabolism. A. Body weight of mice overexpressing MIC-1/GDF15 (MIC-1fms) and control mice (MIC-1+/+) from 11 to 24 weeks of age, represented as 0–13 weeks on the normal chow diet. B–E. Absolute and relative (as a percent of body weight) fat and lean mass as determined by dual energy X-ray absorptiometry (DXA) in normal chow-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. F–I Mass of white adipose tissue (WAT) and interscaptular brown adipose tissue depots as absolute weight (F, H) or normalized to body weight (G, I) in normal chow-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. i, inguinal; p, periovarian; r, retroperitoneal and m, mesenteric WAT depots. J–K. Spontaneous (J) and cumulative 24-hour fasting-induced food intake (K), normalized to body weight, measured over 24 hours in normal chow-fed MIC-1fms and MIC-1+/+ control mice at 25 weeks of age. L. Body weight of 25 week-old normal chow-fed MIC-1fms and MIC-1+/+ control mice before 24 hour fasting and at the indicated time points after re-introduction of food, with 100% representing pre-fasting body weight. M–O. Respiratory exchange ratio (RER, M), energy expenditure normalized to lean mass as determined by DXA (N) and ambulatory activity (O) of normal chow-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. Data are means ± SEM of 5 female mice per group. *p<0.05, **p<0.01 and ***p<0.001 for the difference between genotypes.
Figure 1 MIC-1/GDF15 overexpression reduces body weight, adiposity and food intake without altering metabolism. A. Body weight of mice overexpressing MIC-1/GDF15 (MIC-1fms) and control mice (MIC-1+/+) from 11 to 24 weeks of age, represented as 0–13 weeks on the normal chow diet. B–E. Absolute and relative (as a percent of body weight) fat and lean mass as determined by dual energy X-ray absorptiometry (DXA) in normal chow-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. F–I Mass of white adipose tissue (WAT) and interscaptular brown adipose tissue depots as absolute weight (F, H) or normalized to body weight (G, I) in normal chow-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. i, inguinal; p, periovarian; r, retroperitoneal and m, mesenteric WAT depots. J–K. Spontaneous (J) and cumulative 24-hour fasting-induced food intake (K), normalized to body weight, measured over 24 hours in normal chow-fed MIC-1fms and MIC-1+/+ control mice at 25 weeks of age. L. Body weight of 25 week-old normal chow-fed MIC-1fms and MIC-1+/+ control mice before 24 hour fasting and at the indicated time points after re-introduction of food, with 100% representing pre-fasting body weight. M–O. Respiratory exchange ratio (RER, M), energy expenditure normalized to lean mass as determined by DXA (N) and ambulatory activity (O) of normal chow-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. Data are means ± SEM of 5 female mice per group. *p<0.05, **p<0.01 and ***p<0.001 for the difference between genotypes.CC BY · PubMed Central
Figure 2 MIC-1/GDF15 overexpression improves glucose tolerance and response to insulin. A. Blood glucose concentrations in response to i.p. glucose injection (1 g/kg) in normal chow-fed mice overexpressing MIC-1/GDF15 (MIC-1fms) and control mice (MIC-1+/+) at 23 weeks of age. B. Area under the curve calculated from the glucose tolerance test in (A). C. Blood glucose concentrations in response to i.p. insulin injection (1 U/kg) in normal chow-fed MIC-1fms and MIC-1+/+ mice at 24 weeks of age. Data are means ± SEM of 5 female mice per group. *p<0.05, **p<0.01 and ***p<0.001 for the difference between genotypes.
Figure 2 MIC-1/GDF15 overexpression improves glucose tolerance and response to insulin. A. Blood glucose concentrations in response to i.p. glucose injection (1 g/kg) in normal chow-fed mice overexpressing MIC-1/GDF15 (MIC-1fms) and control mice (MIC-1+/+) at 23 weeks of age. B. Area under the curve calculated from the glucose tolerance test in (A). C. Blood glucose concentrations in response to i.p. insulin injection (1 U/kg) in normal chow-fed MIC-1fms and MIC-1+/+ mice at 24 weeks of age. Data are means ± SEM of 5 female mice per group. *p<0.05, **p<0.01 and ***p<0.001 for the difference between genotypes.CC BY · PubMed Central
Figure 3 MIC-1/GDF15 overexpression reduces body weight, adiposity and food intake in high fat-fed mice. A. Body weight of mice overexpressing MIC-1/GDF15 (MIC-1fms) and control mice (MIC-1+/+) from 11 to 24 weeks of age, at 0–13 weeks on a high fat diet. B–E. Absolute and relative (as a percent of body weight) fat and lean mass as determined by dual energy X-ray absorptiometry (DXA) in MIC-1fms and MIC-1+/+ control mice at 26 weeks of age, after 15 weeks on the high fat diet. F–I Mass of white adipose tissue (WAT) and interscapular brown adipose tissue depots as absolute weight (F, H) or normalized to body weight (G, I) in high fat-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. i, inguinal; p, periovarian; r, retroperitoneal and m, mesenteric WAT depots. J–K. Spontaneous (J) and cumulative 24-hour fasting-induced food intake (K), normalized to body weight, measured over 24 hours in high fat-fed MIC-1fms and MIC-1+/+ control mice at 25 weeks of age. L. Body weight of 25 week-old high fat-fed MIC-1fms and MIC-1+/+ control mice before 24 hour fasting and at the indicated time points after re-introduction of food, with 100% representing pre-fasting body weight. M–O. Respiratory exchange ratio (RER, M), energy expenditure normalized to lean mass as determined by DXA (N) and ambulatory activity (O) of high fat-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. Data are means ± SEM of 5 female mice per group. *p<0.05, **p<0.01 and ***p<0.001 for the difference between genotypes.
Figure 3 MIC-1/GDF15 overexpression reduces body weight, adiposity and food intake in high fat-fed mice. A. Body weight of mice overexpressing MIC-1/GDF15 (MIC-1fms) and control mice (MIC-1+/+) from 11 to 24 weeks of age, at 0–13 weeks on a high fat diet. B–E. Absolute and relative (as a percent of body weight) fat and lean mass as determined by dual energy X-ray absorptiometry (DXA) in MIC-1fms and MIC-1+/+ control mice at 26 weeks of age, after 15 weeks on the high fat diet. F–I Mass of white adipose tissue (WAT) and interscapular brown adipose tissue depots as absolute weight (F, H) or normalized to body weight (G, I) in high fat-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. i, inguinal; p, periovarian; r, retroperitoneal and m, mesenteric WAT depots. J–K. Spontaneous (J) and cumulative 24-hour fasting-induced food intake (K), normalized to body weight, measured over 24 hours in high fat-fed MIC-1fms and MIC-1+/+ control mice at 25 weeks of age. L. Body weight of 25 week-old high fat-fed MIC-1fms and MIC-1+/+ control mice before 24 hour fasting and at the indicated time points after re-introduction of food, with 100% representing pre-fasting body weight. M–O. Respiratory exchange ratio (RER, M), energy expenditure normalized to lean mass as determined by DXA (N) and ambulatory activity (O) of high fat-fed MIC-1fms and MIC-1+/+ control mice at 26 weeks of age. Data are means ± SEM of 5 female mice per group. *p<0.05, **p<0.01 and ***p<0.001 for the difference between genotypes.CC BY · PubMed Central
Figure 4 MIC-1/GDF15 overexpression improves glucose tolerance in mice on a high fat diet. A. Blood glucose concentrations in response to i.p. glucose injection (1 g/kg) in mice overexpressing MIC-1/GDF15 (MIC-1fms) and control mice (MIC-1+/+) at 23 weeks of age, after 13 weeks on a high fat diet. B. Area under the curve calculated from the glucose tolerance test in (A). C. Blood glucose concentrations in response to i.p. insulin injection (1 U/kg) in MIC-1fms and MIC-1+/+ mice at 24 weeks of age, after 14 weeks on a high fat diet. Data are means ± SEM of 5 female mice per group. *p<0.05, **p<0.01 and ***p<0.001 for the difference between genotypes.
Figure 4 MIC-1/GDF15 overexpression improves glucose tolerance in mice on a high fat diet. A. Blood glucose concentrations in response to i.p. glucose injection (1 g/kg) in mice overexpressing MIC-1/GDF15 (MIC-1fms) and control mice (MIC-1+/+) at 23 weeks of age, after 13 weeks on a high fat diet. B. Area under the curve calculated from the glucose tolerance test in (A). C. Blood glucose concentrations in response to i.p. insulin injection (1 U/kg) in MIC-1fms and MIC-1+/+ mice at 24 weeks of age, after 14 weeks on a high fat diet. Data are means ± SEM of 5 female mice per group. *p<0.05, **p<0.01 and ***p<0.001 for the difference between genotypes.CC BY · PubMed Central

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Metadata

Authors
Macia, L., Tsai, V. W.-W., Nguyen, A. D., Johnen, H., Kuffner, T., Shi, Y.-C., Lin, S., Herzog, H., Brown, D. A., Breit, S. N., & Sainsbury, A.
Affiliations
  • Garvan Institute of Medical Research (AU)
  • UNSW Sydney (AU)
  • The University of Sydney (AU)
Corresponding author
Sainsbury, Amanda
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-04-13
Volume
7
Issue
4
Pages
e34868
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0034868
PMC
PMC3325923
OpenAlex
W2057219729
Cited by
211
References
26
Citations by year
2026: 10 · 2025: 20 · 2024: 20 · 2023: 21 · 2022: 21 · 2021: 18 · 2020: 32 · 2019: 19 · 2018: 12 · 2017: 11 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 2
FWCI
2.97
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) (submittedVersion, cc-by)
  • 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, cc-by-sa)
  • The Sydney eScholarship Repository (The University of Sydney) (submittedVersion)
Funders
  • Medical Research Council
  • National Health and Medical Research Council (455291)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
MIC-1, GDF15, obesity, dietary intake, body weight, glucose tolerance, glucose homeostasis, high-fat diet, fat mass, energy expenditure, transgenic overexpression, anorectic effect
MeSH terms
Animals, Body Weight, Eating, Female, Glucose, Mice, Transgenic, Obesity, Mice, Growth Differentiation Factor 15

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