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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

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.
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pone-0055174-g007: 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.

Mentions: To investigate whether the increased body weight of MIC-1−/− mice was specifically due to germline gene deletion of MIC-1/GDF15 and not resulting from any unrecognized compensatory or developmental changes in MIC-1−/− mice, we continuously infused male MIC-1−/− and MIC+/+ mice with MIC-1/GDF15 (1–2 µg/d) via osmotic minipumps. Infusion of MIC-1/GDF15 over 5 days resulted in increased circulating human MIC-1/GDF15 levels from zero to 643±67 pg/ml and 576±45 pg/ml in MIC-1−/− and MIC-1+/+ mice, respectively. As discussed below, this would have the effect of increasing total MIC-1/GDF15 levels in MIC-1−/− mice to about the middle of the human normal range and in MIC-1+/+ mice to the top of the human normal range. This infusion of MIC-1/GDF15 resulted in reduced body weight gain relative to syngeneic vehicle-infused controls (Fig. 7A and 7B, MIC-1−/−p<0.01; MIC-1+/+p = 0.01), coupled with a significant reduction in food intake (Fig. 7C and 7D, MIC-1−/−p = 0.04; MIC-1+/+p<0.01).


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)

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.
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pone-0055174-g007: 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.
Mentions: To investigate whether the increased body weight of MIC-1−/− mice was specifically due to germline gene deletion of MIC-1/GDF15 and not resulting from any unrecognized compensatory or developmental changes in MIC-1−/− mice, we continuously infused male MIC-1−/− and MIC+/+ mice with MIC-1/GDF15 (1–2 µg/d) via osmotic minipumps. Infusion of MIC-1/GDF15 over 5 days resulted in increased circulating human MIC-1/GDF15 levels from zero to 643±67 pg/ml and 576±45 pg/ml in MIC-1−/− and MIC-1+/+ mice, respectively. As discussed below, this would have the effect of increasing total MIC-1/GDF15 levels in MIC-1−/− mice to about the middle of the human normal range and in MIC-1+/+ mice to the top of the human normal range. This infusion of MIC-1/GDF15 resulted in reduced body weight gain relative to syngeneic vehicle-infused controls (Fig. 7A and 7B, MIC-1−/−p<0.01; MIC-1+/+p = 0.01), coupled with a significant reduction in food intake (Fig. 7C and 7D, MIC-1−/−p = 0.04; MIC-1+/+p<0.01).

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