GDF15 links adipose tissue lipolysis with anxiety
Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15-GFRAL signalling might reduce acute anxiety.
Authors
- Daniel M. Marko (ORCID: https://orcid.org/0000-0001-6742-9731)
- Marc G. Jeschke (ORCID: https://orcid.org/0000-0003-0870-1664)
- Eric M. Desjardins (ORCID: https://orcid.org/0000-0003-2687-055X)
- Jonathan D. Schertzer (ORCID: https://orcid.org/0000-0002-1547-5856)
- Denis P. Blondin (ORCID: https://orcid.org/0000-0001-6805-0985)
- Ahmad Mohammad
- Kyle D. Medak (ORCID: https://orcid.org/0000-0001-5176-3524)
- Katherine Mary Morrison (ORCID: https://orcid.org/0000-0002-1737-256X)
- David C. Wright (ORCID: https://orcid.org/0000-0003-3867-8901)
- André C. Carpentier (ORCID: https://orcid.org/0000-0002-3983-8156)
- Shawn M. Beaudette (ORCID: https://orcid.org/0000-0002-8427-3959)
- Léa J. Becker (ORCID: https://orcid.org/0000-0002-5995-6088)
- Evangelia E. Tsakiridis
- Gregory R. Steinberg (ORCID: https://orcid.org/0000-0001-5425-8275)
- Jordan G. McCall (ORCID: https://orcid.org/0000-0001-8295-0664)
- Philip Payne (ORCID: https://orcid.org/0000-0002-9532-2998)
- Junfeng Lu (ORCID: https://orcid.org/0000-0002-2640-8595)
- Carly M. Knuth (ORCID: https://orcid.org/0000-0002-7329-2476)
- Logan K. Townsend (ORCID: https://orcid.org/0000-0002-4311-2702)
- Dongdong Wang (ORCID: https://orcid.org/0000-0002-6195-4428)
- Rebecca E. K. MacPherson (ORCID: https://orcid.org/0000-0002-1577-2658)
- Russta Fayyazi (ORCID: https://orcid.org/0009-0007-7119-5684)
- Celina M Valvano (ORCID: https://orcid.org/0009-0008-5164-4224)
- Zeel Patel
- Ofure Itua
Institutions
- Sunnybrook Health Science Centre (CA)
- University of British Columbia (CA)
- University of Toronto (CA)
- Brock University (CA)
- Washington University in St. Louis (US)
- Hamilton General Hospital (CA)
- McMaster University Medical Centre (CA)
- Centre Hospitalier Universitaire de Sherbrooke (CA)
- Population Health Research Institute (CA)
- BC Children's Hospital (CA)
- Thrombosis and Atherosclerosis Research Institute (CA)
- Hamilton Health Sciences (CA)
- University of Guelph (CA)
- McMaster University (CA)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1038/s42255-025-01264-3
- Citations
- 18
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 28.36