ArticleExperimental & molecular medicine2025
GDF15 regulates development and growth of sympathetic neurons to enhance energy expenditure and thermogenesis.
Article in Experimental & molecular medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Therapeutic Gfral silencing via antisense oligonucleotides ameliorates cancer-associated cachexia and extends survival in tumor-bearing mice.Cell reports. Medicine · 2026Article
- GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Immunomodulatory functions of growth differentiation factor 15 in skin aging and inflammatory dermatoses.Frontiers in immunology · 2026Review
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Authors and funding
11 authors.
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Abstract
Growth differentiation factor 15 (GDF15) induces weight loss and increases sympathetic activity through its receptor GFRAL. Given that RET, a GFRAL coreceptor, influences neuronal growth, we studied whether GDF15 can induce the development or growth of sympathetic neurons, in addition to its effect on sympathetic activity. Here we we used GDF15-transgenic and Gdf15-knockout mice to explore the role of GDF15 in the development and activity of sympathetic neurons. GDF15-transgenic mice exhibited increased surface area and volume of sympathetic neurite in adipose tissues. Furthermore, these mice showed heightened energy expenditure, thermogenesis, cold tolerance and an elevated sympathetic response to hypoglycemia. GFRAL was expressed in sympathetic ganglion cells, which was enhanced by GDF15. RET and its downstream signaling molecules such as AKT, ERK and CREB were activated in the sympathetic ganglia by transgenic expression of GDF15 in vivo or treatment with GDF15 in vitro, an leading to increased expression of genes related to thermogenesis, neurite growth or extension and catecholamine synthesis. An ex vivo treatment of sympathetic ganglia with GDF15 also promoted neurite growth and extension. By contrast, Gdf15-knockout mice showed opposite phenotypes, underscoring the physiological role of GDF15 in the development and activity of the sympathetic nervous system. These findings indicate that GDF15 regulates not only the sympathetic activity but also the development or growth of sympathetic neurons through GFRAL expressed in sympathetic ganglion cells, which could contribute to energy expenditure and weight loss. The modulation of GDF15 could be a therapeutic option against diseases or conditions associated with dysregulated sympathetic activity.
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