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Cell Metab. 2019 Feb 5;29(2):320-334.e5. doi: 10.1016/j.cmet.2018.10.001. Epub 2018 Nov 1.

Circulating Levels of Soluble Dipeptidyl Peptidase-4 Are Dissociated from Inflammation and Induced by Enzymatic DPP4 Inhibition.

Author information

1
Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada.
2
INSERM U1065, Mediterranean Center of Molecular Medicine, University Côte d'Azur, Faculty of Medicine, 06204 Nice, France.
3
Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, LTRI, 600 University Avenue TCP5-1004, Toronto, ON M5G 1X5, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 2J7, Canada. Electronic address: drucker@lunenfeld.ca.

Abstract

Dipeptidyl peptidase-4 (DPP-4) controls glucose homeostasis through enzymatic termination of incretin action. We report that plasma DPP-4 activity correlates with body weight and fat mass, but not glucose control, in mice. Genetic disruption of adipocyte Dpp4 expression reduced plasma DPP-4 activity in older mice but did not perturb incretin levels or glucose homeostasis. Knockdown of hepatocyte Dpp4 completely abrogated the obesity-associated increase in plasma DPP-4 activity, reduced liver cytokine expression, and partially attenuated inflammation in adipose tissue without changes in incretin levels or glucose homeostasis. In contrast, circulating levels of soluble DPP4 (sDPP4) were dissociated from inflammation in mice with endothelial-selective or global genetic inactivation of Dpp4. Remarkably, inhibition of DPP-4 enzymatic activity upregulated circulating levels of sDPP4 originating from endothelial or hematopoietic cells without inducing systemic or localized inflammation. Collectively, these findings reveal unexpected complexity in regulation of soluble versus enzymatic DPP-4 and control of inflammation and glucose homeostasis.

KEYWORDS:

adipocyte; diabetes; glucose; hepatocyte; incretin; inflammation; insulin resistance; obesity; soluble dipeptidylpeptidase 4

PMID:
30393019
DOI:
10.1016/j.cmet.2018.10.001

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