Letter | Published:

Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance

Nature volume 555, pages 673677 (29 March 2018) | Download Citation

Abstract

Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT)1. In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs)2,3. In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance4,5, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity6,7,8. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.

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Acknowledgements

We thank F. S. Katz for assistance with FPLC; R. Kaufman for adeno-ATF4; C. Adams and S. Bullard for Atf4fl/fl mice; and A. Ferrante, S. Ramakrishnan, J. Weitz and T. McGraw for discussions. E.C. was supported by NIH grant 5P30CA013696-42. I.T. was funded by grants from the NIH (HL087123 and HL075662) and by a grant from the Merck Investigator Studies Program. L.O. was funded by the NIH grant DK106045 and a grant from the Columbia University Diabetes Research Center (P30 DK063608). Y.S., S.M.N. and M.P.C. were funded by NIH grant DK103047. M.B. was funded by the Deutsche Forschungsgemeinschaft grant SFB1052.

Author information

Affiliations

  1. Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA

    • Devram S. Ghorpade
    • , Lale Ozcan
    • , Ze Zheng
    •  & Ira Tabas
  2. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    • Sarah M. Nicoloro
    • , Yuefei Shen
    •  & Michael P. Czech
  3. Proteomics Shared Resource in the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA

    • Emily Chen
  4. Herbert Irving Comprehensive Cancer Center Proteomics Shared Resource, Columbia University Medical Center, New York, New York 10032, USA

    • Emily Chen
  5. Department of Medicine, University of Leipzig, Leipzig 04103, Germany

    • Matthias Blüher
  6. Department of Pathology & Cell Biology and Department of Physiology, Columbia University Medical Center, New York, New York 10032, USA

    • Ira Tabas

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Contributions

D.S.G., L.O. and I.T. designed the study, analysed data and wrote the manuscript. D.S.G., L.O. and Z.Z. conducted the experiments. S.M.N., Y.S. and M.P.C. made the glucan-encapsulated siRNA particles (GERPs) and helped design these experiments and analyse the data. E.C. conducted the LC–MS/MS studies and assisted with data analysis. M.B. helped with interpretation of data.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lale Ozcan or Ira Tabas.

Reviewer Information Nature thanks P. Scherer and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Data

    This file contains Supplementary Figures 1-16: Uncropped versions of blots. Uncropped blots are shown for the indicated cropped blots in the main and Extended Data figures.

  3. 3.

    Supplementary Tables

    This file contains Supplementary Table 1: Gene primers used for RT-qPCR. Primer sets are shown for the R-qPCR assays used in the study. Supplementary Table 2: LC-MS/MS spectral analyses. Supplementary Table 2a shows the normalized LC-MS/MS spectral counts of selected FPLC fractions of plasma from DIO mice (see Extended Data Figure 2f). The first set of data show proteins with higher normalized spectral counts in FPLC fraction 44 (F44; active in inducing Mcp1 in macrophages) than in fractions F42 and F46, which were inactive in this assay. The second set of data show normalized spectral counts of other proteins identified fractions 42, 44, and/or 46. Supplementary Table 2b shows normalized LC-MS/MS spectral counts in selected FPLC fractions of plasma from DIO mice that was immunodepleted of DPP4 (see Extended Data Figure 7c). The first set of data show proteins with higher normalized spectral counts in FPLC fraction 44 (F44; active in inducing Mcp1 in macrophages) than in fractions F42 and F46, which were inactive in this assay. The second set of data show normalized spectral counts of other proteins identified fractions 42, 44, and/or 46.

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DOI

https://doi.org/10.1038/nature26138

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