FGF1 and insulin control lipolysis by convergent pathways

Gencer Sancar; Sihao Liu; Emanuel Gasser; Jacqueline G Alvarez; Christopher Moutos; Kyeongkyu Kim; Tim van Zutphen; Yuhao Wang; Timothy F Huddy; Brittany Ross; Yang Dai; David Zepeda; Brett Collins; Emma Tilley; Matthew J Kolar; Ruth T Yu; Annette R Atkins; Theo H van Dijk; Alan Saghatelian; Johan W Jonker; Michael Downes; Ronald M Evans

doi:10.1016/j.cmet.2021.12.004

FGF1 and insulin control lipolysis by convergent pathways

Gencer Sancar, Sihao Liu, Emanuel Gasser, Jacqueline G Alvarez, Christopher Moutos, Kyeongkyu Kim, Tim van Zutphen, Yuhao Wang, Timothy F Huddy, Brittany Ross, Yang Dai, David Zepeda, Brett Collins, Emma Tilley, Matthew J Kolar, Ruth T Yu, Annette R Atkins, Theo H van Dijk, Alan Saghatelian, Johan W JonkerMichael Downes^*, Ronald M Evans^*

^*Corresponding author voor dit werk

Onderzoeksoutput: Article › Academic › peer review

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Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.

Originele taal-2	English
Pagina's (van-tot)	171-183.E6
Aantal pagina's	20
Tijdschrift	Cell Metabolism
Volume	34
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1016/j.cmet.2021.12.004
Status	Published - 4-jan.-2022

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Sancar, G., Liu, S., Gasser, E., Alvarez, J. G., Moutos, C., Kim, K., van Zutphen, T., Wang, Y., Huddy, T. F., Ross, B., Dai, Y., Zepeda, D., Collins, B., Tilley, E., Kolar, M. J., Yu, R. T., Atkins, A. R., van Dijk, T. H., Saghatelian, A., ... Evans, R. M. (2022). FGF1 and insulin control lipolysis by convergent pathways. Cell Metabolism, 34(1), 171-183.E6. https://doi.org/10.1016/j.cmet.2021.12.004

@article{b5fac37b87e54748a76858576879b579,

title = "FGF1 and insulin control lipolysis by convergent pathways",

abstract = "Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.",

keywords = "CAMP-SPECIFIC PHOSPHODIESTERASE, HORMONE-SENSITIVE LIPASE, DEPENDENT PROTEIN-KINASE, ADIPOSE-TISSUE, PERFUSED LIVERS, PHOSPHORYLATION, GLUCOSE, ACTIVATION, GLUCONEOGENESIS, ADIPOCYTES",

author = "Gencer Sancar and Sihao Liu and Emanuel Gasser and Alvarez, {Jacqueline G} and Christopher Moutos and Kyeongkyu Kim and {van Zutphen}, Tim and Yuhao Wang and Huddy, {Timothy F} and Brittany Ross and Yang Dai and David Zepeda and Brett Collins and Emma Tilley and Kolar, {Matthew J} and Yu, {Ruth T} and Atkins, {Annette R} and {van Dijk}, {Theo H} and Alan Saghatelian and Jonker, {Johan W} and Michael Downes and Evans, {Ronald M}",

year = "2022",

month = jan,

day = "4",

doi = "10.1016/j.cmet.2021.12.004",

language = "English",

volume = "34",

pages = "171--183.E6",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "1",

}

Sancar, G, Liu, S, Gasser, E, Alvarez, JG, Moutos, C, Kim, K, van Zutphen, T, Wang, Y, Huddy, TF, Ross, B, Dai, Y, Zepeda, D, Collins, B, Tilley, E, Kolar, MJ, Yu, RT, Atkins, AR, van Dijk, TH, Saghatelian, A, Jonker, JW, Downes, M & Evans, RM 2022, 'FGF1 and insulin control lipolysis by convergent pathways', Cell Metabolism, vol. 34, nr. 1, blz. 171-183.E6. https://doi.org/10.1016/j.cmet.2021.12.004

TY - JOUR

T1 - FGF1 and insulin control lipolysis by convergent pathways

AU - Sancar, Gencer

AU - Liu, Sihao

AU - Gasser, Emanuel

AU - Alvarez, Jacqueline G

AU - Moutos, Christopher

AU - Kim, Kyeongkyu

AU - van Zutphen, Tim

AU - Wang, Yuhao

AU - Huddy, Timothy F

AU - Ross, Brittany

AU - Dai, Yang

AU - Zepeda, David

AU - Collins, Brett

AU - Tilley, Emma

AU - Kolar, Matthew J

AU - Yu, Ruth T

AU - Atkins, Annette R

AU - van Dijk, Theo H

AU - Saghatelian, Alan

AU - Jonker, Johan W

AU - Downes, Michael

AU - Evans, Ronald M

PY - 2022/1/4

Y1 - 2022/1/4

N2 - Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.

AB - Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.

KW - CAMP-SPECIFIC PHOSPHODIESTERASE

KW - HORMONE-SENSITIVE LIPASE

KW - DEPENDENT PROTEIN-KINASE

KW - ADIPOSE-TISSUE

KW - PERFUSED LIVERS

KW - PHOSPHORYLATION

KW - GLUCOSE

KW - ACTIVATION

KW - GLUCONEOGENESIS

KW - ADIPOCYTES

U2 - 10.1016/j.cmet.2021.12.004

DO - 10.1016/j.cmet.2021.12.004

M3 - Article

C2 - 34986332

SN - 1550-4131

VL - 34

SP - 171-183.E6

JO - Cell Metabolism

JF - Cell Metabolism

IS - 1

ER -

FGF1 and insulin control lipolysis by convergent pathways

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