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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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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.
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pone-0055174-g005: 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.

Mentions: To further investigate possible mechanisms underlying the increases in body weight and adiposity of male and female MIC-1−/− versus MIC-1+/+ mice, we compared their respiratory exchange ratio (RER), energy expenditure and physical activity (Figs 4 and 5). The increased body weight and adiposity of MIC-1−/− animals does not appear to result from differential use of lipids versus carbohydrate as oxidative fuel sources as there was no difference in RER between genotypes (Fig. 4A, 5A). Female mice, MIC-1−/− animals exhibit significantly lower energy expenditure normalized to bodyweight compared to the age matched control MIC-1+/+ mice (p<0.01, Fig. 5B, 5D). This difference may be partially attributed to a decrease in physical activity, since physical activity was significantly decreased during the dark phase in female MIC-1−/− versus control mice (p = 0.03, Fig. 5C, 5E). No such differences in energy expenditure or physical activity were observed between MIC-1−/− and MIC-1+/+ male mice (Fig. 4B, 4C, 4D, 4E).


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−/− 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.
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Related In: Results  -  Collection

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pone-0055174-g005: 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.
Mentions: To further investigate possible mechanisms underlying the increases in body weight and adiposity of male and female MIC-1−/− versus MIC-1+/+ mice, we compared their respiratory exchange ratio (RER), energy expenditure and physical activity (Figs 4 and 5). The increased body weight and adiposity of MIC-1−/− animals does not appear to result from differential use of lipids versus carbohydrate as oxidative fuel sources as there was no difference in RER between genotypes (Fig. 4A, 5A). Female mice, MIC-1−/− animals exhibit significantly lower energy expenditure normalized to bodyweight compared to the age matched control MIC-1+/+ mice (p<0.01, Fig. 5B, 5D). This difference may be partially attributed to a decrease in physical activity, since physical activity was significantly decreased during the dark phase in female MIC-1−/− versus control mice (p = 0.03, Fig. 5C, 5E). No such differences in energy expenditure or physical activity were observed between MIC-1−/− and MIC-1+/+ male mice (Fig. 4B, 4C, 4D, 4E).

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