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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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.
Extended data figures
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.
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.