Hematopoietic cell– versus enterocyte-derived dipeptidyl peptidase-4 differentially regulates triglyceride excursion in mice
Elodie M. Varin, Antonio A. Hanson, Jacqueline L. Beaudry, My-Anh Nguyen, Xiemin Cao, Laurie L. Baggio, Erin E. Mulvihill, Daniel J. Drucker
Elodie M. Varin, Antonio A. Hanson, Jacqueline L. Beaudry, My-Anh Nguyen, Xiemin Cao, Laurie L. Baggio, Erin E. Mulvihill, Daniel J. Drucker
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Research Article Endocrinology

Hematopoietic cell– versus enterocyte-derived dipeptidyl peptidase-4 differentially regulates triglyceride excursion in mice

Abstract

Postprandial triglycerides (TGs) are elevated in people with type 2 diabetes (T2D). Glucose-lowering agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, also reduce postprandial TG excursion. Although the glucose-lowering mechanisms of DPP-4 have been extensively studied, how the reduction of DPP-4 activity improves lipid tolerance remains unclear. Here, we demonstrate that gut-selective and systemic inhibition of DPP-4 activity reduces postprandial TG excursion in young mice. Genetic inactivation of Dpp4 simultaneously within endothelial cells and hematopoietic cells using Tie2-Cre reduced intestinal lipoprotein secretion under regular chow diet conditions. Bone marrow transplantation revealed a key role for hematopoietic cells in modulation of lipid responses arising from genetic reduction of DPP-4 activity. Unexpectedly, deletion of Dpp4 in enterocytes increased TG excursion in high-fat diet–fed (HFD-fed) mice. Moreover, chemical reduction of DPP-4 activity and increased levels of GLP-1 were uncoupled from TG excursion in older or HFD-fed mice, yet lipid tolerance remained improved in older Dpp4–/– and Dpp4EC–/– mice. Taken together, this study defines roles for specific DPP-4 compartments, age, and diet as modifiers of DPP-4 activity linked to control of gut lipid metabolism.

Authors

Elodie M. Varin, Antonio A. Hanson, Jacqueline L. Beaudry, My-Anh Nguyen, Xiemin Cao, Laurie L. Baggio, Erin E. Mulvihill, Daniel J. Drucker

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Figure 9

Lipid-lowering effects of sitagliptin are attenuated in older mice.

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Lipid-lowering effects of sitagliptin are attenuated in older mice. (A) ...
(A) Plasma TG and AUC over 180 minutes in 25- to 30-week-old mice fed a regular chow (RC) diet during a lipid tolerance test (LTT) in response to water or a systemic dose of sitagliptin (10 mg/kg) (n = 16/group). (B–E) Plasma DPP-4 activity before (time –30 minutes) and 90 minutes after oral gavage of water or sitagliptin as indicated (B, n = 9–14/group), plasma TG and AUC over 3 hours (C, n = 9–14/group), and apoB48 and apoB100 protein levels measured by Western blot (WB) (D and E, n = 3–5/group) after oral gavage of water or sitagliptin, followed by i.v. injection of 0.5 g/kg tyloxapol and oral gavage of 200 μl olive oil, as described in Figure 1A. Data are presented as mean ± SEM. Each n represents a biological replicate from 2 independent cohorts of sex- and age-matched animals. ***P < 0.001, ****P < 0.0001, using Student’s t test for the indicated groups.