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 1

Sitagliptin improves lipid tolerance and TG production in young RC-fed mice.

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Sitagliptin improves lipid tolerance and TG production in young RC-fed m...
(A) Experimental model used for data shown in B–F. 8- to 12-week-old regular chow–fed (RC-fed) WT mice were fasted for 5–6 hours and then given oral administration of water or gut-selective (14 μg/mouse) or systemic (10 mg/kg) doses of sitagliptin at time –30 minutes. Mice were then gavaged with 200 μl olive oil only (for lipid tolerance [LTT] in B and C) or given an i.v. injection of 0.5 g/kg tyloxapol just before olive oil (for TG and ApoB production in D–F). (B and C) Plasma DPP-4 activity just before (time –30 minutes), and at 30 (time 0), 60, 120, and 180 minutes after oral gavage or water of sitagliptin, as indicated (B, n = 6–8/group). (C) Plasma TG and AUC over 3 hours (left and middle) and plasma active GLP-1 levels 30 minutes before and 10 minutes after oral gavage of olive oil (right, n = 23–29/group) during a LTT. (D–F) Plasma TG and AUC over 180 minutes (D), and apoB48 and apoB100 protein levels measured by Western blot (WB) (E and F, n = 6–8/group) after oral gavage of water or sitagliptin, followed by i.v. injection of tyloxapol and oral gavage of olive oil, as described in A. Data are presented as mean ± SEM. Each n represents a biological replicate from 4 independent cohorts (C) and 1 group (B and D–F) of sex- and age-matched animals. (B–D) *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, using 1-way ANOVA with Tukey’s correction for multiple comparisons for indicated groups. (E) *P < 0.05 vs. water, #P < 0.05 and ##P < 0.01 vs. gut-selective dose of sitagliptin using 1-way ANOVA with Tukey’s correction for multiple comparisons for indicated groups.