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TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator.

Tsai VW, Macia L, Johnen H, Kuffner T, Manadhar R, Jørgensen SB, Lee-Ng KK, Zhang HP, Wu L, Marquis CP, Jiang L, Husaini Y, Lin S, Herzog H, Brown DA, Sainsbury A, Breit SN - PLoS ONE (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales, Sydney, New South Wales, Australia.

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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Related in: MedlinePlus

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.
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pone-0055174-g003: 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.

Mentions: To examine possible causes for the increased body weight and fat mass in the MIC-1−/− mice, we first studied their spontaneous food intake. Female but not male MIC-1−/− had significant increased food intake compared to the age and sex-matched control mice, both in absolute terms (15.59±0.67 versus 12.77±0.88 g/gBW/d in female knockout and control mice, respectively) and when normalized to body weight (p = 0.05 for female mice (Fig. 3A). This data suggested that the increased body weight in female MIC-1−/− is at least partly due to increased food intake. Whilst the 3.7% difference in food intake between male MIC-1−/− and MIC-1+/+ was not statistically significant, this may reflect the capacity of our method to detect small differences in food intake. Power analysis indicates that to determine with 95% certainty whether this 3.7% difference in food intake was significant would require 126 mice of each genotype. As, over a more prolonged period, a difference in 3 days-accumulated food intake of as little as 3.7% is likely to be able alter body weight and composition [23], in this study, we cannot exclude such a small difference being present.


TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator.

Tsai VW, Macia L, Johnen H, Kuffner T, Manadhar R, Jørgensen SB, Lee-Ng KK, Zhang HP, Wu L, Marquis CP, Jiang L, Husaini Y, Lin S, Herzog H, Brown DA, Sainsbury A, Breit SN - PLoS ONE (2013)

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.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585300&req=5

pone-0055174-g003: 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.
Mentions: To examine possible causes for the increased body weight and fat mass in the MIC-1−/− mice, we first studied their spontaneous food intake. Female but not male MIC-1−/− had significant increased food intake compared to the age and sex-matched control mice, both in absolute terms (15.59±0.67 versus 12.77±0.88 g/gBW/d in female knockout and control mice, respectively) and when normalized to body weight (p = 0.05 for female mice (Fig. 3A). This data suggested that the increased body weight in female MIC-1−/− is at least partly due to increased food intake. Whilst the 3.7% difference in food intake between male MIC-1−/− and MIC-1+/+ was not statistically significant, this may reflect the capacity of our method to detect small differences in food intake. Power analysis indicates that to determine with 95% certainty whether this 3.7% difference in food intake was significant would require 126 mice of each genotype. As, over a more prolonged period, a difference in 3 days-accumulated food intake of as little as 3.7% is likely to be able alter body weight and composition [23], in this study, we cannot exclude such a small difference being present.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales, Sydney, New South Wales, Australia.

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.

Show MeSH
Related in: MedlinePlus