ABSTRACT BACKGROUND Elevated circulating levels of the divergent transforming growth factor-beta (TGFb) family cytokine, growth differentiation factor 15 (GDF15), acting through its CNS

receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), can cause anorexia and weight loss leading to anorexia/cachexia syndrome of cancer and other diseases. Preclinical

studies suggest that administration of drugs based on recombinant GDF15 might be used to treat severe obesity. However, the role of the GDF15–GFRAL pathway in the physiological regulation of

body weight and metabolism is unclear. The critical site of action of GFRAL in the CNS has also not been proven beyond doubt. To investigate these two aspects, we have inhibited the actions

solitary tract (NTS). Metabolic measurements were determined during both experiments. CONCLUSIONS Treating mice with monoclonal antibody to GDF15 shortly after commencing HFD results in more

rapid gain of body weight, adiposity and hepatic lipid deposition than the control groups. This is accompanied by reduced glucose and insulin tolerance and greater expression of

pro-inflammatory cytokines in adipose tissue. Localised AP and NTS shRNA-GFRAL knockdown in mice commencing HFD similarly caused an increase in body weight and adiposity. This effect was in

proportion to the effectiveness of GFRAL knockdown, indicated by quantitative analysis of hindbrain GFRAL staining. We conclude that the GDF15–GFRAL axis plays an important role in

resistance to obesity in HFD-fed mice and that the major site of action of GDF15 in the CNS is GFRAL-expressing neurons in the AP and NTS. Access through your institution Buy or subscribe

This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access

$259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are

calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS

DOUBLECORTIN-LIKE KNOCKDOWN IN MICE ATTENUATES OBESITY BY STIMULATING ENERGY EXPENDITURE IN ADIPOSE TISSUE Article Open access 22 August 2024 GDF15: EMERGING BIOLOGY AND THERAPEUTIC

APPLICATIONS FOR OBESITY AND CARDIOMETABOLIC DISEASE Article 11 August 2021 GDF15 PROMOTES WEIGHT LOSS BY ENHANCING ENERGY EXPENDITURE IN MUSCLE Article Open access 28 June 2023 REFERENCES *

Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci

USA. 1997;94:11514–9. Article  CAS  Google Scholar  * Tsai VWW, Husaini Y, Sainsbury A, Brown DA, Breit SN. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity,

cachexia, and other associated diseases. Cell Metab. 2018;28:353–68. Article  CAS  Google Scholar  * Mullican SE, Rangwala SM. Uniting GDF15 and GFRAL: therapeutic opportunities in obesity

and beyond. Trends Endocrinol Metab. 2018;29:560–70. Article  CAS  Google Scholar  * Brown DA, Ward RL, Buckhaults P, Liu T, Romans KE, Hawkins NJ, et al. MIC-1 serum level and genotype:

associations with progress and prognosis of colorectal carcinoma. Clin Cancer Res. 2003;9:2642–50. CAS  PubMed  Google Scholar  * Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW, Bauskin AR,

et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med. 2007;13:1333–40. Article  CAS  Google Scholar  * Li Z, Wang B, Wu X, Cheng SY,

Paraoan L, Zhou J. Identification, expression and functional characterization of the GRAL gene. J Neurochem. 2005;95:361–76. Article  CAS  Google Scholar  * Mullican SE, Lin-Schmidt X, Chin

CN, Chavez JA, Furman JL, Armstrong AA, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017;23:1150–7. Article  CAS 

Google Scholar  * Emmerson PJ, Wang F, Du Y, Liu Q, Pickard RT, Gonciarz MD, et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med. 2017;23:1215–9. Article

  CAS  Google Scholar  * Yang L, Chang CC, Sun Z, Madsen D, Zhu H, Padkjær SB, et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med.

2017;23:1158–66. Article  CAS  Google Scholar  * Hsu JY, Crawley S, Chen M, Ayupova DA, Lindhout DA, Higbee J, et al. Non-homeostatic body weight regulation through a brainstem-restricted

receptor for GDF15. Nature. 2017;550:255–9. Article  Google Scholar  * Tsai VW, Zhang HP, Manandhar R, Lee-Ng KKM, Lebhar H, Marquis CP, 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 (Lond). 2018;42:561–71. Article  CAS  Google Scholar  * Lerner L, Tao

J, Liu Q, Nicoletti R, Feng B, Krieger B, et al. MAP3K11/GDF15 axis is a critical driver of cancer cachexia. J Cachexia Sarcopenia Muscle. 2016;7:467–82. Article  Google Scholar  * Breit SN,

Tsai VW, Brown DA. Targeting Obesity and Cachexia: Identification of the GFRAL Receptor-MIC-1/GDF15 Pathway. Trends Mol Med. 2017;23:1065–7. Article  CAS  Google Scholar  * Tsai VW, Lin S,

Brown DA, Salis A, Breit SN. Anorexia-cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15. Int J Obes (Lond). 2016;40:193–7.

Article  CAS  Google Scholar  * Macia L, Tsai VW, Nguyen AD, Johnen H, Kuffner T, Shi YC, et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and

improves glucose tolerance in mice on normal & obesogenic diets. PLoS ONE. 2012;7:e34868. Article  CAS  Google Scholar  * Xiong Y, Walker K, Min X, Hale C, Tran T, Komorowski R, et al.

Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci Transl Med. 2017;9:eaav1069. Article  Google Scholar  * Tsai VW, Macia L, Johnen H, Kuffner T, Manadhar

R, Jørgensen SB, et al. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS ONE. 2013;8:e55174. Article  CAS  Google Scholar  * Fairlie WD,

Russell PK, Wu WM, Moore AG, Zhang HP, Brown PK, et al. Epitope mapping of the transforming growth factor-beta superfamily protein, macrophage inhibitory cytokine-1 (MIC-1): identification

of at least five distinct epitope specificities. Biochemistry. 2001;40:65–73. Article  CAS  Google Scholar  * Tsai VW, Manandhar R, Jorgensen SB, Lee-Ng KK, Zhang HP, Marquis CP, et al. The

anorectic actions of the TGFbeta cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLoS ONE. 2014;9:e100370. Article  Google Scholar  *

Kaiyala KJ, Morton GJ, Leroux BG, Ogimoto K, Wisse B, Schwartz MW. Identification of body fat mass as a major determinant of metabolic rate in mice. Diabetes. 2010;59:1657–66. Article  CAS 

Google Scholar  * Tsai VW, Macia L, Feinle-Bisset C, Manandhar R, Astrup A, Raben A, et al. Serum levels of human MIC-1/GDF15 vary in a diurnal pattern, do not display a profile suggestive

of a satiety factor and are related to BMI. PLoS ONE. 2015;10:e0133362. Article  Google Scholar  * Xu J, Bartolome CL, Low CS, Yi X, Chien CH, Wang P, et al. Genetic identification of leptin

neural circuits in energy and glucose homeostases. Nature. 2018;556:505–9. Article  CAS  Google Scholar  * Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, et al. Rapid rewiring

of arcuate nucleus feeding circuits by leptin. Science. 2004;304:110–5. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS This project was supported in part by grants from

the National Health and Medical Research Council (NHMRC) of Australia, Diabetes Australia and the St Vincent’s Clinic Foundation. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * St Vincent’s

Centre for Applied Medical Research, St Vincent’s Hospital and University of New South Wales, Sydney, NSW, 2010, Australia Vicky Wang-Wei Tsai, Hong Ping Zhang, Rakesh Manandhar, Ka Ki

Michelle Lee-Ng, Yasmin Husaini, David A. Brown & Samuel N. Breit * St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia Vicky

Wang-Wei Tsai, Peter Schofield, Daniel Christ, Yasmin Husaini & Samuel N. Breit * Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia Peter Schofield & Daniel Christ *

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia Hélène Lebhar & Christopher Peter Marquis * Institute of Clinical

Pathology and Medical Research, New South Wales Health Pathology, Westmead, NSW, Australia David A. Brown * Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, 2145,

Australia David A. Brown Authors * Vicky Wang-Wei Tsai View author publications You can also search for this author inPubMed Google Scholar * Hong Ping Zhang View author publications You can

also search for this author inPubMed Google Scholar * Rakesh Manandhar View author publications You can also search for this author inPubMed Google Scholar * Peter Schofield View author

publications You can also search for this author inPubMed Google Scholar * Daniel Christ View author publications You can also search for this author inPubMed Google Scholar * Ka Ki Michelle

Lee-Ng View author publications You can also search for this author inPubMed Google Scholar * Hélène Lebhar View author publications You can also search for this author inPubMed Google

Scholar * Christopher Peter Marquis View author publications You can also search for this author inPubMed Google Scholar * Yasmin Husaini View author publications You can also search for

this author inPubMed Google Scholar * David A. Brown View author publications You can also search for this author inPubMed Google Scholar * Samuel N. Breit View author publications You can

also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Samuel N. Breit. ETHICS DECLARATIONS CONFLICT OF INTEREST DAB and SNB are inventors on patents

owned by St Vincent’s Hospital that pertain to the clinical use of GDF15. The other authors declare that they have no conflict of interest. ADDITIONAL INFORMATION PUBLISHER’S NOTE: Springer

Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTAL MATERIAL SUPPLEMENTAL FIGURE 1

SUPPLEMENTAL FIGURE 2 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Tsai, V.WW., Zhang, H.P., Manandhar, R. _et al._ GDF15 mediates adiposity

resistance through actions on GFRAL neurons in the hindbrain AP/NTS. _Int J Obes_ 43, 2370–2380 (2019). https://doi.org/10.1038/s41366-019-0365-5 Download citation * Received: 29 August 2018

* Revised: 01 February 2019 * Accepted: 17 February 2019 * Published: 31 May 2019 * Issue Date: December 2019 * DOI: https://doi.org/10.1038/s41366-019-0365-5 SHARE THIS ARTICLE Anyone you

share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the

Springer Nature SharedIt content-sharing initiative