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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 TGF?-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.

SUBMITTER: Lino M

PROVIDER: S-EPMC7242876 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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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.

Lino Marsel M Ngai David D Liu Alison A Mohabeer Amanda A Harper Cameron C Caruso Laura-Lee LL Schroer Stephanie A SA Fu Fred F McKee Trevor T Giacca Adria A Woo Minna M Bendeck Michelle P MP

Molecular metabolism 20200428

<h4>Objective</h4>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.<h4>Methods</h4>We have used a diet-induced mouse model ...[more]

PMID: 32360427

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Project description:BackgroundThe amount of intra-thoracic fat, of which mediastinal adipose tissue comprises the major depot, is related to various cardiometabolic risk factors. Autopsy and imaging studies indicate that the mediastinal depot in adult humans could contain brown adipose tissue (BAT). To gain a better understanding of this intra-thoracic fat depot, we examined possible BAT characteristics of human mediastinal in comparison with subcutaneous adipose tissue.Materials and methodsAdipose tissue biopsies from thoracic subcutaneous and mediastinal depots were obtained during open-heart surgery from 33 subjects (26 male, 63.7±13.8 years, body mass index 29.3±5.1 kg m(-2)). Microarray analysis was performed on 10 patients and genes of interest confirmed by quantitative PCR (qPCR) in samples from another group of 23 patients. Adipocyte size was determined and uncoupling protein 1 (UCP1) protein expression investigated with immunohistochemistry.ResultsThe microarray data showed that a number of BAT-specific genes had significantly higher expression in the mediastinal depot than in the subcutaneous depot. Higher expression of UCP1 (24-fold, P<0.001) and PPARGC1A (1.7-fold, P=0.0047), and lower expression of SHOX2 (0.12-fold, P<0.001) and HOXC8 (0.14-fold, P<0.001) in the mediastinal depot was confirmed by qPCR. Gene set enrichment analysis identified two gene sets related to mitochondria, which were significantly more highly expressed in the mediastinal than in the subcutaneous depot (P<0.01). No significant changes in UCP1 gene expression were observed in the subcutaneous or mediastinal depots following lowering of body temperature during surgery. UCP1 messenger RNA levels in the mediastinal depot were lower than those in murine BAT and white adipose tissue. In some mediastinal adipose tissue biopsies, a small number of multilocular adipocytes that stained positively for UCP1 were observed. Adipocytes were significantly smaller in the mediastinal than the subcutaneous depot (cross-sectional area 2400±810 versus 3260±980 μm(2), P<0.001).ConclusionsHuman mediastinal adipose tissue displays some characteristics of BAT when compared with the subcutaneous depot at microscopic and molecular levels.

Dataset Information

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.

Publications

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.

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