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

Lim,Junxian, Iyer, Abishek, Suen, Jacky Y., Seow, Vernon, Reid, Robert C., 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: 822-831. doi:10.1096/fj.12-220582


Author Lim,Junxian
Iyer, Abishek
Suen, Jacky Y.
Seow, Vernon
Reid, Robert C.
Brown, Lindsay
Fairlie, David P.
Title C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling
Journal name The FASEB Journal   Check publisher's open access policy
ISSN 1530-6860
0892-6638
Publication date 2013-02-01
Year available 2012
Sub-type Article (original research)
DOI 10.1096/fj.12-220582
Open Access Status Not Open Access
Volume 27
Issue 2
Start page 822
End page 831
Total pages 10
Place of publication Bethesda, MD, United States
Publisher Federation of American Societies for Experimental Biology
Language eng
Formatted abstract
Mammalian survival depends on metabolizing nutrients, storing energy, and combating infection. Complement activation in blood triggers energydepleting 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 receptorselective 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 PGE2 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.
Keyword Adipose inflammation
Complement
GPCR
Metabolism
Immunity
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Tue, 03 May 2016, 19:11:39 EST by Mr James Lim on behalf of Institute for Molecular Bioscience