Discoidin domain receptor 1-deletion ameliorates fibrosis and promotes adipose tissue beiging, brown fat activity, and increased metabolic rate in a mouse model of cardiometabolic disease.

Abstract

OBJECTIVE:

Discoidin domain receptor 1 (DDR1) is a collagen binding receptor tyrosine kinase implicated in atherosclerosis, fibrosis, and cancer. Our previous research showed that DDR1 could regulate smooth muscle cell trans-differentiation, fibrosis and calcification in the vascular system in cardiometabolic disease. This spectrum of activity led us to question whether DDR1 might also regulate adipose tissue fibrosis and remodeling.

METHODS:

We have used a diet-induced mouse model of cardiometabolic disease to determine whether DDR1 deletion impacts upon adipose tissue remodeling and metabolic dysfunction. Mice were fed a high fat diet (HFD) for 12 weeks, followed by assessment of glucose and insulin tolerance, respiration via indirect calorimetry, and brown fat activity by FDG-PET.

RESULTS:

Feeding HFD induced DDR1 expression in white adipose tissue, which correlated with adipose tissue expansion and fibrosis. Ddr1-/- mice fed an HFD had improved glucose tolerance, reduced body fat, and increased brown fat activity and energy expenditure compared to Ddr1+/+ littermate controls. HFD-fed DDR1-/- mice also had reduced fibrosis, smaller adipocytes with multilocular lipid droplets, and increased UCP-1 expression characteristic of beige fat formation in subcutaneous adipose tissue. In vitro, studying C3H10T1/2 cells stimulated to differentiate, DDR1 inhibition caused a shift from white to beige adipocyte differentiation, whereas DDR1 expression was increased with TGFβ-mediated pro-fibrotic differentiation.

CONCLUSION:

This study is the first to identify a role for DDR1 as a driver of adipose tissue fibrosis and suppressor of beneficial beige fat formation.

• Authors: Marsel Lino, David Ngai, Alison Liu, Amanda Mohabeer, Cameron Harper, Laura-Lee Caruso, Stephanie A Schroer, Fred Fu, Trevor McKee, Adria Giacca, Minna Woo, Michelle P Bendeck
• Journal: Molecular metabolism (Mol Metab) Vol. 39 Pg. 101006 (09 2020) ISSN: 2212-8778 [Electronic] Germany
• PMID: 32360427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Chemical References

• RNA, Messenger
• Ddr1 protein, mouse
• Discoidin Domain Receptor 1

Topics

• Adipose Tissue, Beige (metabolism)
• Adipose Tissue, Brown (metabolism)
• Animals
• Calorimetry
• Diet, High-Fat (adverse effects)
• Discoidin Domain Receptor 1 (genetics, metabolism)
• Disease Models, Animal
• Disease Susceptibility
• Energy Metabolism
• Fibrosis
• Gene Deletion
• Immunohistochemistry
• Metabolic Syndrome (diagnosis, etiology, metabolism)
• Mice
• Mice, Knockout
• Positron-Emission Tomography
• RNA, Messenger (genetics)
• Subcutaneous Fat (metabolism)
• Tomography, X-Ray Computed