C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling

Lim, Junxian and Iyer, Abishek and Suen, Jacky Y. and Seow, Vernon and Reid, Robert C. and Brown, Lindsay and Fairlie, David P. (2013) C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling. The FASEB Journal, 27 (2). pp. 822-831. ISSN 0892-6638

Abstract

Mammalian survival depends on metabolizing nutrients, storing energy, and combating infection. Complement activation in blood triggers energy-depleting immune responses to fight infections. Here we identify surprising energy-conserving roles for complement proteins C5a and C3a and their receptors, C5aR and C3aR, roles that are contraindicated in complement biology. Rats fed a high-carbohydrate high-fat diet developed obesity, visceral adiposity, adipose inflammation, glucose/insulin intolerance, and cardiovascular dysfunction that correlated with increased plasma C3a, adipose C5aR, and C3aR. These in vivo changes were dramatically attenuated by receptor-selective antagonists of either C5aR (5 mg/kg/d p.o.) or C3aR (30 mg/kg/d p.o.), which both reduced proinflammatory adipokines and altered expression of inflammatory genes in adipose tissue. In vitro C5a and C3a (100 nM) exhibited novel insulin-like effects on 3T3-L1 adipocytes, promoting energy conservation by increasing glucose and fatty acid uptake while inhibiting cAMP signaling and lipolysis, and induced PGE(2) release from macrophages, effects all blocked by each respective antagonist (10 μM). These studies reveal important new links between complement signaling and metabolism, highlight new complement functions on adipocytes and in adipose tissue, demonstrate how aberrant immune responses may exacerbate obesity and metabolic dysfunction, and show that targeting C3aR or C5aR with antagonists is a new strategy for treating metabolic dysfunction.


Statistics for USQ ePrint 23280
Statistics for this ePrint Item
Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: © FASEB. Permanent restricted access to published version due to publisher copyright policy.
Faculty / Department / School: Historic - Faculty of Sciences - Department of Biological and Physical Sciences
Date Deposited: 29 Jul 2013 04:55
Last Modified: 11 Jul 2014 03:28
Uncontrolled Keywords: adipose inflammation; complement; GPCR; immunity; metabolism
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 > 970106 Expanding Knowledge in the Biological Sciences
E Expanding Knowledge > 97 Expanding Knowledge > 970111 Expanding Knowledge in the Medical and Health Sciences
Identification Number or DOI: 10.1096/fj.12-220582
URI: http://eprints.usq.edu.au/id/eprint/23280

Actions (login required)

View Item Archive Repository Staff Only