FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

Farnaz Shamsi; Ruidan Xue; Tian Lian Huang; Morten Lundh; Yang Liu; Luiz O. Leiria; Matthew D. Lynes; Elena Kempf; Chih Hao Wang; Satoru Sugimoto; Pasquale Nigro; Kathrin Landgraf; Tim Schulz; Yiming Li; Brice Emanuelli; Srinivas Kothakota; Lewis T. Williams; Niels Jessen; Steen Bønløkke Pedersen; Yvonne Böttcher; Matthias Blüher; Antje Körner; Laurie J. Goodyear; Moosa Mohammadi; C. Ronald Kahn; Yu Hua Tseng

doi:10.1038/s41467-020-15055-9

FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

Farnaz Shamsi, Ruidan Xue, Tian Lian Huang, Morten Lundh, Yang Liu, Luiz O. Leiria, Matthew D. Lynes, Elena Kempf, Chih Hao Wang, Satoru Sugimoto, Pasquale Nigro, Kathrin Landgraf, Tim Schulz, Yiming Li, Brice Emanuelli, Srinivas Kothakota, Lewis T. Williams, Niels Jessen, Steen Bønløkke Pedersen, Yvonne BöttcherMatthias Blüher, Antje Körner, Laurie J. Goodyear, Moosa Mohammadi, C. Ronald Kahn, Yu Hua Tseng

Molecular Pathobiology

Research output: Contribution to journal › Article › peer-review

Abstract

Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.

Original language	English (US)
Article number	1421
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15055-9
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Shamsi, F., Xue, R., Huang, T. L., Lundh, M., Liu, Y., Leiria, L. O., Lynes, M. D., Kempf, E., Wang, C. H., Sugimoto, S., Nigro, P., Landgraf, K., Schulz, T., Li, Y., Emanuelli, B., Kothakota, S., Williams, L. T., Jessen, N., Pedersen, S. B., ... Tseng, Y. H. (2020). FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis. Nature communications, 11(1), Article 1421. https://doi.org/10.1038/s41467-020-15055-9

Shamsi, F, Xue, R, Huang, TL, Lundh, M, Liu, Y, Leiria, LO, Lynes, MD, Kempf, E, Wang, CH, Sugimoto, S, Nigro, P, Landgraf, K, Schulz, T, Li, Y, Emanuelli, B, Kothakota, S, Williams, LT, Jessen, N, Pedersen, SB, Böttcher, Y, Blüher, M, Körner, A, Goodyear, LJ, Mohammadi, M, Kahn, CR & Tseng, YH 2020, 'FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis', Nature communications, vol. 11, no. 1, 1421. https://doi.org/10.1038/s41467-020-15055-9

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title = "FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis",

abstract = "Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.",

author = "Farnaz Shamsi and Ruidan Xue and Huang, {Tian Lian} and Morten Lundh and Yang Liu and Leiria, {Luiz O.} and Lynes, {Matthew D.} and Elena Kempf and Wang, {Chih Hao} and Satoru Sugimoto and Pasquale Nigro and Kathrin Landgraf and Tim Schulz and Yiming Li and Brice Emanuelli and Srinivas Kothakota and Williams, {Lewis T.} and Niels Jessen and Pedersen, {Steen B{\o}nl{\o}kke} and Yvonne B{\"o}ttcher and Matthias Bl{\"u}her and Antje K{\"o}rner and Goodyear, {Laurie J.} and Moosa Mohammadi and Kahn, {C. Ronald} and Tseng, {Yu Hua}",

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doi = "10.1038/s41467-020-15055-9",

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T1 - FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

AU - Shamsi, Farnaz

AU - Xue, Ruidan

AU - Huang, Tian Lian

AU - Lundh, Morten

AU - Liu, Yang

AU - Leiria, Luiz O.

AU - Lynes, Matthew D.

AU - Kempf, Elena

AU - Wang, Chih Hao

AU - Sugimoto, Satoru

AU - Nigro, Pasquale

AU - Landgraf, Kathrin

AU - Schulz, Tim

AU - Li, Yiming

AU - Emanuelli, Brice

AU - Kothakota, Srinivas

AU - Williams, Lewis T.

AU - Jessen, Niels

AU - Pedersen, Steen Bønløkke

AU - Böttcher, Yvonne

AU - Blüher, Matthias

AU - Körner, Antje

AU - Goodyear, Laurie J.

AU - Mohammadi, Moosa

AU - Kahn, C. Ronald

AU - Tseng, Yu Hua

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.

AB - Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.

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FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis

Abstract

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