Abstract

Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)—even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines—including excess follistatin (Fst)—that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.

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Change history

  • 15 August 2018

    In the version originally published, many graphs contained units that were formatted inconsistently. The units have been reformatted for consistency throughout the figures. Some units in the Supplementary Information were also updated to correct inconsistent formatting. Additionally, a line erroneously appeared under “GFP” in Fig. 2i, and the “RYGB” labels in Fig. 2h,i were not horizontally aligned. The line has been removed and the labels properly aligned. This article now appears correctly.

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Acknowledgements

We thank S. Biddinger’s lab for providing the cDNA from the LIRKO liver. We thank E. Rosen’s lab for providing the 3T3-L1 cells. We thank U. Ozcan’s lab for providing the pAAV2.TBG.PI vector. We thank R. DePinho’s lab for providing the floxed FoxO1 mice. This work was supported by NIH grants DK098655 and project 2 GM021700 (M.F.W.); DK108642 (N.S.); and DK091592, DK107682 and AA024550 (X.C.D.).

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Affiliations

  1. Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    • Rongya Tao
    • , Caixia Wang
    • , Oliver Stöhr
    • , Wei Qiu
    • , Yue Hu
    • , Ji Miao
    • , Sining Leng
    • , Margaret Stefater
    • , Nicholas Stylopoulos
    • , Lin Lin
    • , Kyle D. Copps
    •  & Morris F. White
  2. Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    • X. Charlie Dong

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Contributions

M.F.W. and R.T. designed the research direction. R.T. performed the majority of the experiments with specialized assistance from C.W., K.D.C., O.S., W.Q., Y.H., J.M., S.L., X.C.D., L.L., M.S. and N.S. All data were analyzed by R.T. and M.F.W. The manuscript was written by R.T. and M.F.W. with assistance from K.D.C.

Competing interests

M.F.W. is a scientific consultant for Housey Pharmaceutical Research Laboratories.

Corresponding author

Correspondence to Morris F. White.

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https://doi.org/10.1038/s41591-018-0048-0

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