Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis
Open accessAbstract
Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases.
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Metrnl was originally identified as a secreted protein induced by exercise and cold exposure in murine models.
“Metrnl was originally identified as a secreted protein induced by exercise and cold exposure in murine models [65].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [65]
Increased METRNL gene expression was described at 1 and 4 h following an acute bout of combined resistance and endurance exercise in healthy young adult males.
“Increased METRNL gene expression at 1 and 4 h following an acute bout of combined resistance and endurance exercise in healthy young adult males was described [98].”
METRNL promotes M2 macrophage polarization.
“It was found to promote M2 Mφ polarization [98]”
METRNL was able to indirectly stimulate M2 macrophage polarization by inducing eosinophils to secrete IL-4 and IL-13.
“In addition, METRNL was able to indirectly stimulate M2 Mφ polarization by inducing eosinophils to secrete IL-4 and IL-13 [98].”
METRNL indirectly promotes WAT browning by favoring M2 polarization of macrophages.
“as exemplified by METRNL, which has been found to indirectly promote WAT browning by favoring M2 polarization of Mφ [98] (4b).”
In mice, elevated expression and secretion of Metrnl has been associated with increased thermogenesis and glucose homeostasis.
“In mice, elevated expression and secretion of Metrnl has been associated with increased thermogenesis and glucose homeostasis (29).”
From Combined Training Enhances Skeletal Muscle Mitochondrial Oxidative Capacity Independent of Age (2015) · cites this paper as [29]
During acute exercise, muscle-secreted exerkines such as fractalkine mobilize immune cells to enhance regeneration in humans, and METRNL increases beige adipose tissue thermogenesis in an animal model.
“During acute exercise, immune cells are mobilized by muscle secretion of exerkines such as fractalkine to enhance regeneration (in humans)133 or meteorin-like (METRNL) to increase beige adipose tissue thermogenesis (animal model)134.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [134]
Metrnl can be produced by exercising muscle and cold exposed adipose tissue.
“The use of unbiased genetic and proteomic approaches also allowed the identification of a novel secreted protein, Meteorin‐like (Metrnl), that can be produced by exercising muscle and cold exposed adipose tissue.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [136]
Metrnl promotes adipose tissue browning by recruiting IL‐4 and IL‐13 producing eosinophils and thus promoting anti‐inflammatory macrophage activation.
“Metrnl promotes adipose tissue browning by recruiting IL‐4 and IL‐13 producing eosinophils and thus promoting anti‐inflammatory macrophage activation 136.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [136]
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References 43 · Cited by 973
- Authors
- Rao, R. R., Long, J. Z., White, J. P., Svensson, K. J., Lou, J., Lokurkar, I., Jedrychowski, M. P., Ruas, J. L., Wrann, C. D., Lo, J. C., Camera, D. M., Lachey, J., Gygi, S., Seehra, J., Hawley, J. A., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- Karolinska Institutet (SE)
- Australian Catholic University (AU)
- Liverpool John Moores University (GB)
- Corresponding author
- Spiegelman, Bruce M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 157
- Issue
- 6
- Pages
- 1279-1291
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4131287
- OpenAlex
- W2086562954
- Cited by
- 973
- References
- 43
- Citations by year
- 2026: 86 · 2025: 78 · 2024: 84 · 2023: 88 · 2022: 77 · 2021: 77 · 2020: 87 · 2019: 75 · 2018: 67 · 2017: 81 · 2016: 76 · 2015: 73 · 2014: 22 · 2013: 1
- FWCI
- 55.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Bank (Australian Catholic University) (submittedVersion)
- Funders
- Novo Nordisk Fonden (NNF12OC1016062)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK061562, K08DK097303, R01DK061562, P30DK043351)
- National Institute of Neurological Disorders and Stroke (R00NS087096, K99NS087096)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- meteorin-like, exercise training, cold exposure, eosinophils, IL-4, alternative macrophage activation, adipose tissue macrophages, energy expenditure, glucose tolerance, energy homeostasis, tissue inflammation, obesity, diabetes mellitus
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Adipose Tissue, Brown, Glucose, Liver, Macrophages, Mice, Transgenic, Nerve Growth Factors, Transcription Factors, Interleukin-4, Muscle, Skeletal, Interleukin-13, Thermogenesis, Mice
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