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Multi-tissue transcriptomic atlas reveals systemic effects of FGF19 on metabolism and immunity
Yang Xiao1, Liwen Kuang1, Juan He1
1Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China; Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China; Key Laboratory of Chongqing Education Commission of China for Cancer Immunometabolism Translational Research, Chongqing, China.
Abstract:
Fibroblast growth factor 19 (FGF19) signaling is a promising therapeutic target for metabolic diseases and cancers, and several agents targeting the FGF19 signaling are currently undergoing clinical trials. However, as an endocrine FGF, FGF19's organism-wide functions remain vague, which hinders the advancing of FGF19 signaling-based therapies. To systematically explore its systemic effects, we performed a multi-tissue transcriptomic profiling in an FGF19 knock-in mouse model. Sustained FGF19 exposure induced extensive, tissue‑specific transcriptional reprogramming. For instance, lipid metabolic pathways were broadly altered not only in canonical metabolic organs, but also in immune‑related tissues including the spleen and thymus. Furthermore, integrated analysis and functional validation demonstrated that FGF19 promoted monocyte/macrophage (Mo/MΦ) migration in an FGFR4‑involved manner, associated with an M2-like polarization state. Moreover, we developed a macrophage‑targeted sustained‑release FGF19 delivery system, which significantly accelerated wound healing and enhanced M2 macrophage infiltration in a murine full‑thickness skin injury model. Overall, our study establishes a multi‑tissue transcriptional atlas of FGF19 action, reveals broad metabolic and immune regulatory responses to sustained human FGF19 exposure in mice, and provides a targeted therapeutic strategy for modulating macrophage.
Insights
Fibroblast growth factor 19 (FGF19) broadly reprograms tissues, impacting lipid metabolism and immune cells like macrophages. A novel FGF19 delivery system enhances wound healing by promoting M2 macrophage infiltration.
Area of Science:
- Endocrinology
- Immunology
- Systems Biology
Background:
- Fibroblast growth factor 19 (FGF19) signaling is a key therapeutic target for metabolic diseases and cancers.
- The systemic functions of endocrine FGF19 remain largely uncharacterized, limiting the development of FGF19-based therapies.
Purpose of the Study:
- To systematically investigate the organism-wide effects of sustained FGF19 exposure.
- To elucidate the role of FGF19 in metabolic and immune regulation.
- To develop and validate a targeted FGF19 delivery system for therapeutic applications.
Main Methods:
- Multi-tissue transcriptomic profiling in a FGF19 knock-in mouse model.
- Integrated bioinformatic analysis and functional validation of FGF19 effects.
- Development and testing of a macrophage-targeted, sustained-release FGF19 delivery system in a murine wound healing model.
Main Results:
- Sustained FGF19 exposure induced significant, tissue-specific transcriptional changes, including alterations in lipid metabolic pathways in both metabolic and immune tissues.
- FGF19 was found to promote monocyte/macrophage (Mo/MΦ) migration via FGFR4, driving an M2-like polarization state.
- The macrophage-targeted FGF19 delivery system accelerated wound healing and increased M2 macrophage infiltration in vivo.
Conclusions:
- This study provides a comprehensive multi-tissue transcriptional atlas of FGF19 action.
- Sustained FGF19 exposure elicits broad metabolic and immune regulatory responses in mice.
- Targeted modulation of macrophages using sustained-release FGF19 represents a promising therapeutic strategy.
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