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.

Keywords

• Obesity
• Diabetes
• Discoidin domain receptor 1
• Collagen
• brown fat
• Fibrosis