Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism

Lim, Junxian and Iyer, Abishek and Liu, Ligong and Suen, Jacky Y. and Lohman, Rink-Jan and Seow, Vernon and Yau, Mei-Kwan and Brown, Lindsay and Fairlie, David P. (2013) Diet-induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. The FASEB Journal, 27 (12). pp. 4757-4767. ISSN 0892-6638

Abstract

Excessive uptake of fatty acids and glucose by adipose tissue triggers adipocyte dysfunction and infiltration of immune cells. Altered metabolic homeostasis in adipose tissue promotes insulin resistance, type 2 diabetes, hypertension, and cardiovascular disease. Inflammatory and metabolic processes are mediated by certain proteolytic enzymes that share a common cellular target, protease-activated receptor 2 (PAR2). This study showed that human and rat obesity correlated in vivo with increased expression of PAR2 in adipose tissue, primarily in stromal vascular cells (SVCs) including macrophages. PAR2 was expressed more than other PARs on human macrophages and was increased by dietary fatty acids (palmitic, stearic, and myristic). A novel PAR2 antagonist, GB88 (5-isoxazoyl- Cha-Ile-spiroindene-1,4-piperidine), given orally at 10 mg/kg/d (wk 8-16) reduced body weight by 10% in obese rats fed a high-carbohydrate high-fat (HCHF) diet for 16 wk, and strongly attenuated adiposity, adipose tissue inflammation, infiltrated macrophages and mast cells, insulin resistance, and cardiac fibrosis and remodeling; while reversing liver and pancreatic dysfunction and normalizing secretion of PAR2-directed glucose-stimulated insulin secretion in MIN6 cells. In summary, PAR2 is a new biomarker for obesity, and its expression is stimulated by dietary fatty acids; PAR2 is a substantial contributor to inflammatory and metabolic dysfunction; and a PAR2 antagonist inhibits diet-induced obesity and inflammatory, metabolic, and cardiovascular dysfunction.


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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: Published version restricted in accordance with the copyright policy of the publisher.
Faculty / Department / School: Historic - Faculty of Health, Engineering and Sciences - School of Health, Nursing and Midwifery
Date Deposited: 07 Feb 2014 06:57
Last Modified: 06 Jan 2016 02:16
Uncontrolled Keywords: aAdipocyte; biomarker; inhibitor; macrophage; protease-activated receptor
Fields of Research : 11 Medical and Health Sciences > 1101 Medical Biochemistry and Metabolomics > 110107 Metabolic Medicine
11 Medical and Health Sciences > 1111 Nutrition and Dietetics > 111103 Nutritional Physiology
11 Medical and Health Sciences > 1115 Pharmacology and Pharmaceutical Sciences > 111501 Basic Pharmacology
Socio-Economic Objective: E Expanding Knowledge > 97 Expanding Knowledge > 970111 Expanding Knowledge in the Medical and Health Sciences
Identification Number or DOI: 10.1096/fj.13-232702
URI: http://eprints.usq.edu.au/id/eprint/24562

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