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Animal Models

Treatment with the TGF-b superfamily cytokine MIC-1/GDF15 reduces the adiposity and corrects the metabolic dysfunction of mice with diet-induced obesity

International Journal of Obesity volume 42, pages 561–571 (2018)Cite this article

Subjects

Abstract

Objectives:

To test the potential efficacy of recombinant macrophage inhibitory cytokine-1 (MIC-1/GDF15) as an obesity therapeutic.

Methods:

Male C57BL/6 J mice, either fed on normal chow or high-fat diet for 16 weeks to induce diet-induced obesity, were infused with either recombinant MIC-1/GDF15 or vehicle for 34 days by osmotic minipump. During the experimental period metabolic parameters were measured. Blood and tissue were collected for analysis of inflammatory markers.

Results:

MIC-1/GDF15 decreased food intake and body weight of high-fat-fed and chow-fed mice compared with their vehicle-treated control mice. MIC-1/GDF15 reduced body weight, accompanied by greater reduction in fat mass in high-fat-fed mice compared to its effect on chow-fed mice. Further, whilst MIC-1/GDF15-treated chow-fed mice lost lean as well as fat mass, MIC-1/GDF15-treated high-fat-fed mice lost fat mass alone. This reduction in body weight and adiposity was due largely to reduced food intake, but MIC-1/GDF15-treated high-fat-fed mice also displayed increased energy expenditure that may be due to increased thermogenesis. MIC-1/GDF15-treated high-fat-fed mice also had higher circulating level of adiponectin and lower tissue expression, and circulating levels of leptin and inflammatory mediators associated with insulin resistance. Peripheral insulin and glucose intolerance were improved in both MIC-1/GDF15-treated high-fat-fed and chow-fed mice compared to that of their vehicle-treated control mice.

Conclusions:

MIC-1/GDF15 is highly effective in reducing adiposity and correcting the metabolic dysfunction of mice with high-fat fed. These studies suggest that MIC-1/GDF15 may be a candidate anti-obesity therapeutic.

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Acknowledgements

This project was supported in part by grants from the National Health and Medical Research Council (NHMRC) of Australia, Diabetes Australia and Thelma Greig Grant of the St Vincent’s Clinic Foundation. AS and DAB are recipients of NHMRC Career Development Awards or Fellowships.

Author contributions

SNB and VWT conceived the experiments. VWT, HPZ, RM, KKML-N, HL, CPM and YH generated the research data. VWT and SNB wrote the manuscript. VWT, SNB, AS and DAB contributed to discussion and reviewed and edited the manuscript.

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Authors and Affiliations

  1. St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, New South Wales, Australia

    V W Tsai, H P Zhang, R Manandhar, K K M Lee-Ng, Y Husaini, D A Brown & S N Breit

  2. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia

    H Lebhar & C P Marquis

  3. The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Charles Perkins Centre, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia

    A Sainsbury

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  1. V W Tsai
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Correspondence to S N Breit.

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Competing interests

DAB and SNB are inventors on patents owned by St Vincent’s Hospital that pertain to the clinical use of MIC-1/GDF15. The remaining authors declare no conflict of interest.

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Tsai, V., Zhang, H., Manandhar, R. et al. Treatment with the TGF-b superfamily cytokine MIC-1/GDF15 reduces the adiposity and corrects the metabolic dysfunction of mice with diet-induced obesity. Int J Obes 42, 561–571 (2018). https://doi.org/10.1038/ijo.2017.258

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