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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

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.
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pone-0055174-g006: 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.

Mentions: To determine the likely contribution of changes in physical activity to changes in energy expenditure, correlation analysis was performed using hourly data from individual mice. There was a positive correlation between energy expenditure and physical activity within all the groups (p<0.02 by Pearson correlation for all groups, Fig. 6A and 6B). In both males and females, the difference in the slope of the regression line is significantly different for MIC-1−/− and MIC-1+/+ mice (p<0.01 in all group, Fig. 6), indicating that the energy cost of activity was different between genotypes. Further, to estimate basal metabolic rate, the function from the trend line was used to extrapolate physical activity to zero, with the point at which the line crosses the X-axis signifying basal metabolic rate. While there was no genotypic difference in basal metabolic rate between males (Fig. 6A), female MIC-1−/− displayed a significantly lower basal metabolic rate compared to wild type controls (p<0.01) (Fig. 6B). These data indicate that there is a fundamental metabolic difference between the male and female MIC-1−/− mice relatively to their matched controls, suggesting MIC-1/GDF15 exerts its effects differentially on male and female mice. The difference in total energy expenditure between the female genotypic groups may have been more affected by changes in basal metabolic rate and less by the physical activity. Both of these are likely to contribute to the body weight difference displayed in female MIC-1−/− versus control mice.


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)

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.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585300&req=5

pone-0055174-g006: 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.
Mentions: To determine the likely contribution of changes in physical activity to changes in energy expenditure, correlation analysis was performed using hourly data from individual mice. There was a positive correlation between energy expenditure and physical activity within all the groups (p<0.02 by Pearson correlation for all groups, Fig. 6A and 6B). In both males and females, the difference in the slope of the regression line is significantly different for MIC-1−/− and MIC-1+/+ mice (p<0.01 in all group, Fig. 6), indicating that the energy cost of activity was different between genotypes. Further, to estimate basal metabolic rate, the function from the trend line was used to extrapolate physical activity to zero, with the point at which the line crosses the X-axis signifying basal metabolic rate. While there was no genotypic difference in basal metabolic rate between males (Fig. 6A), female MIC-1−/− displayed a significantly lower basal metabolic rate compared to wild type controls (p<0.01) (Fig. 6B). These data indicate that there is a fundamental metabolic difference between the male and female MIC-1−/− mice relatively to their matched controls, suggesting MIC-1/GDF15 exerts its effects differentially on male and female mice. The difference in total energy expenditure between the female genotypic groups may have been more affected by changes in basal metabolic rate and less by the physical activity. Both of these are likely to contribute to the body weight difference displayed in female MIC-1−/− versus control mice.

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