@article{64ef312975af41839cd8c8f4cc3ac22a,
title = "Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure",
abstract = "Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting upregulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.",
keywords = "CCR4-NOT deadenylase complex, FGF21, GDF15, energy expenditure, food intake, hepatokine, inter-organ communication, mRNA degradation, metabolic syndrome",
author = "Sakie Katsumura and Nadeem Siddiqui and Goldsmith, {Michael Rock} and Cheah, {Jaime H.} and Teppei Fujikawa and Genki Minegishi and Atsushi Yamagata and Yukako Yabuki and Kaoru Kobayashi and Mikako Shirouzu and Takeshi Inagaki and Huang, {Tim H.M.} and Nicolas Musi and Ivan Topisirovic and Ola Larsson and Masahiro Morita",
note = "Funding Information: We thank T. Yamamoto for Cnot6l −/− mice, M. Kato-Murayama for the protein preparation, D.E. Moller for LY2405319, the Animal Facility and the Histology Facility at the University of Texas Health Science Center at San Antonio (UTHSCSA) for mouse experiments and histological analyses, and the Genome Sequencing Facility and the Bioanalytics and Single-Cell Core Facility at UTHSCSA for RNA-seq and technical assistance. This work was supported by the University of Texas Rising Stars Award , Cancer Prevention and Research Institute of Texas (CPRIT) Award ( RP220267 ), Helen F. Kerr Foundation Grant, Shelby Tengg Foundation Grant, Cancer Center Support Grant ( P30 CA054174 ), Grant-in-Aid for Scientific Research ( 18K07237 and 21K07102 ), and JST FOREST Program ( JPMJFR216D ). S.K. was supported by AHA Postdoctoral Fellowship, JSPS Overseas Research Fellowship, and Uehara Memorial Foundation Postdoctoral Fellowship. T.H.-M.H. was supported by NIH grants U54 CA217297 and P30 CA054174 and CPRIT grant RP150600 . I.T. is a Senior Scholar of the Fonds de la recherche du Qu{\'e}bec—Sant{\'e} (FRQS) and was supported by a grant from the Canadian Institutes of Health Research (CIHR PJT-175050 ). O.L. is a Wallenberg Academy Fellow and was supported by grants from the Swedish Research Council ( 2020-01665 ) and the Swedish Cancer Society ( 19 0314 Pj ). N.M. was supported by the San Antonio Claude D. Pepper Older Americans Independence Center ( P30 AG044271 ), the San Antonio Nathan Shock Center of Excellence on the Biology of Aging ( P30 AG021890 ), grants from the NIH ( R01-DK80157 and R01-DK089229 ), and the American Diabetes Association . Funding Information: We thank T. Yamamoto for Cnot6l−/− mice, M. Kato-Murayama for the protein preparation, D.E. Moller for LY2405319, the Animal Facility and the Histology Facility at the University of Texas Health Science Center at San Antonio (UTHSCSA) for mouse experiments and histological analyses, and the Genome Sequencing Facility and the Bioanalytics and Single-Cell Core Facility at UTHSCSA for RNA-seq and technical assistance. This work was supported by the University of Texas Rising Stars Award, Cancer Prevention and Research Institute of Texas (CPRIT) Award (RP220267), Helen F. Kerr Foundation Grant, Shelby Tengg Foundation Grant, Cancer Center Support Grant (P30 CA054174), Grant-in-Aid for Scientific Research (18K07237 and 21K07102), and JST FOREST Program (JPMJFR216D). S.K. was supported by AHA Postdoctoral Fellowship, JSPS Overseas Research Fellowship, and Uehara Memorial Foundation Postdoctoral Fellowship. T.H.-M.H. was supported by NIH grants U54 CA217297 and P30 CA054174 and CPRIT grant RP150600. I.T. is a Senior Scholar of the Fonds de la recherche du Qu{\'e}bec—Sant{\'e} (FRQS) and was supported by a grant from the Canadian Institutes of Health Research (CIHR PJT-175050). O.L. is a Wallenberg Academy Fellow and was supported by grants from the Swedish Research Council (2020-01665) and the Swedish Cancer Society (19 0314 Pj). N.M. was supported by the San Antonio Claude D. Pepper Older Americans Independence Center (P30 AG044271), the San Antonio Nathan Shock Center of Excellence on the Biology of Aging (P30 AG021890), grants from the NIH (R01-DK80157 and R01-DK089229), and the American Diabetes Association. S.K. and M.M. conceived the project and designed research. S.K. performed all the experiments together with contributions from other authors. N.S. and M.R.G. performed in silico screening and modeling. N.S. and J.H.C. performed FRET-based HTS. Y.Y. performed SPR measurement. A.Y. Y.Y. and M.S. analyzed SPR data. T.F. performed IF experiments. G.M. and K.K. measured the concentrations of iD1 in mouse tissues and serum. S.K. and O.L. analyzed data, and T.I. T.H.-M.H. and N.M. contributed analytic tools and data analyses. S.K. I.T. O.L. and M.M. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = apr,
day = "5",
doi = "10.1016/j.cmet.2022.03.005",
language = "English (US)",
volume = "34",
pages = "564--580.e8",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",
}