@article{cdd8f5b54499474087f9eb1d94869117,
title = "FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes",
abstract = "The contribution of adipose-derived FGF21 to energy homeostasis is unclear. Here we show that browning of inguinal white adipose tissue (iWAT) by β-adrenergic agonists requires autocrine FGF21 signaling. Adipose-specific deletion of the FGF21 co-receptor β-Klotho renders mice unresponsive to β-adrenergic stimulation. In contrast, mice with liver-specific ablation of FGF21, which eliminates circulating FGF21, remain sensitive to β-adrenergic browning of iWAT. Concordantly, transgenic overexpression of FGF21 in adipocytes promotes browning in a β-Klotho-dependent manner without increasing circulating FGF21. Mechanistically, we show that β-adrenergic stimulation of thermogenic gene expression requires FGF21 in adipocytes to promote phosphorylation of phospholipase C-γ and mobilization of intracellular calcium. Moreover, we find that the β-adrenergic-dependent increase in circulating FGF21 occurs through an indirect mechanism in which fatty acids released by adipocyte lipolysis subsequently activate hepatic PPARα to increase FGF21 expression. These studies identify FGF21 as a cell-autonomous autocrine regulator of adipose tissue function.",
keywords = "Beiging, Browning, FGF21, adipose, adrenergic, autocrine, beige, thermogenic",
author = "Mohammad Abu-Odeh and Yuan Zhang and Reilly, {Shannon M.} and Nima Ebadat and Omer Keinan and Valentine, {Joseph M.} and Maziar Hafezi-Bakhtiari and Hadeel Ashayer and Lana Mamoun and Xin Zhou and Jin Zhang and Yu, {Ruth T.} and Yang Dai and Christopher Liddle and Michael Downes and Evans, {Ronald M.} and Kliewer, {Steven A.} and Mangelsdorf, {David J.} and Saltiel, {Alan R.}",
note = "Funding Information: We thank members of Saltiel laboratory at UCSD for helpful discussions, comments, and suggestions. We especially thank Julia H. DeLuca, Benyamin Dadpey, and Tammy-Nhu Nguyen for technical efforts during revision. We thank the UCSD histology core for tissue sectioning and staining. This work was supported by the American Diabetes Association (1-19-PDF-177 to M.A.-O. and 1-19-JDF-012 to S.M.R.), the National Institutes of Health (1K01DK105075, R03DK118195, and R01DK126944 to S.M.R.; F32DK124947 to J.M.V.; R01DK073368 to J.Z.; DK057978 and DK120480 to R.M.E.; R01DK067158, P01AG051459, and R01AA028473 to S.A.K. and D.J.M.; R01DK117551, R01DK125820, R01DK124496, and R01DK076906 to A.R.S.; and P30 DK063491 to R.M.E. and A.R.S.), the Robert A. Welch Foundation (I-1558 to S.A.K. and I-1275 to D.J.M.), and the Howard Hughes Medical Institute (to D.J.M.). Additional support was provided by the Salk Cancer Center (CA014195). Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under award P42ES010337. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conceptualization, M.A.-O. Y.Z. S.M.R. D.J.M. and A.R.S.; formal analysis, M.A.-O. Y.Z. S.M.R. N.E. O.K. J.M.V. M.H.-B. H.A. X.Z. J.Z. R.T.Y. M.D. and C.L.; investigation, M.A.-O. Y.Z. S.M.R. N.E. O.K. J.M.V. M.H.-B. H.A. L.M. X.Z. J.Z. R.T.Y. M.D. Y.D. and C.L.; methodology, M.A.-O. Y.Z. S.M.R. O.K. J.M.V. X.Z. J.Z. R.T.Y. M.D. Y.D. C.L. S.A.K. and D.J.M.; resources, S.A.K. and D.J.M.; supervision, R.M.E. D.J.M. and A.R.S.; visualization, M.A.-O. Y.Z. and S.M.R.; writing – original draft, M.A.-O. and A.R.S.; writing – review & editing, M.A.-O. Y.Z. S.M.R. D.J.M. and A.R.S. A.R.S. is a founder of Elgia Therapeutics. The other authors declare no competing interests. Funding Information: We thank members of Saltiel laboratory at UCSD for helpful discussions, comments, and suggestions. We especially thank Julia H. DeLuca, Benyamin Dadpey, and Tammy-Nhu Nguyen for technical efforts during revision. We thank the UCSD histology core for tissue sectioning and staining. This work was supported by the American Diabetes Association ( 1-19-PDF-177 to M.A.-O. and 1-19-JDF-012 to S.M.R.), the National Institutes of Health ( 1K01DK105075 , R03DK118195 , and R01DK126944 to S.M.R.; F32DK124947 to J.M.V.; R01DK073368 to J.Z.; DK057978 and DK120480 to R.M.E.; R01DK067158 , P01AG051459 , and R01AA028473 to S.A.K. and D.J.M.; R01DK117551 , R01DK125820 , R01DK124496 , and R01DK076906 to A.R.S.; and P30 DK063491 to R.M.E. and A.R.S.), the Robert A. Welch Foundation ( I-1558 to S.A.K. and I-1275 to D.J.M.), and the Howard Hughes Medical Institute (to D.J.M.). Additional support was provided by the Salk Cancer Center ( CA014195 ). Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under award P42ES010337 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = jun,
day = "29",
doi = "10.1016/j.celrep.2021.109331",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}