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

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

doi:10.1016/j.molmet.2020.101006

Marsel Lino, David Ngai + Show 10 more

Open Access

https://doi.org/10.1016/j.molmet.2020.101006

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Abstract

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

Highlights

Type 2 diabetes (T2D) and metabolic syndrome (MetS) affect millions of people worldwide and have reached epidemic proportions [1]
There was no significant difference in weight between genotypes from 0 to 6 weeks on high fat diet (HFD); after 6 weeks through to 12 weeks of HFD, Ddr1À/À; LdlrÀ/- (Ddr1À/À) mice weighed significantly less compared to Ddr1þ/þ; LdlrÀ/- (Ddr1þ/þ) mice (Figure 1B), despite no difference in food consumption (Figure 1C)
There was no significant difference in fasting plasma triglycerides and fasting blood glucose between Ddr1þ/þ and Ddr1À/À mice fed an HFD (Supplemental Table S2)

Summary

Introduction

Type 2 diabetes (T2D) and metabolic syndrome (MetS) affect millions of people worldwide and have reached epidemic proportions [1]. The disorders underlying these systemic syndromes include insulin resistance, hypertriglyceridemia, hepatic steatosis and obesity [2]. Excessive adipose tissue expansion can be accompanied by hypoxia, inflammation, and fibrosis, which lead to adipose tissue dysfunction, an early step in the progression towards insulin resistance and T2D [4]. Brown adipose tissue can be found within white adipose tissue and here it is referred to as beige fat.

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