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Papers In Press, published online ahead of print December 6, 2005
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Medicine, Anatomie & Physiologie, Centre de Recherche Hôpital Laval, Québec, Québec G1V 4G5
Corresponding Author: Katherine.Cianflone{at}crhl.ulaval.ca
Acylation Stimulating Protein (ASP, C3adesArg) stimulates triglyceride synthesis (TGS) and glucose transport in preadipocytes and adipocytes. Recently, we have demonstrated that C5L2, a G protein coupled receptor, is functionally responsible for mediating ASP responses. However, little is known of the intracellular signalling pathway involved. In the present study, ASP signalling is compared to insulin-mediated stimulation of TGS in 3T3-L1 cells. ASP stimulation is not Gas or Gai mediated (neither pertussis toxin nor cholera toxin sensitive), suggesting that Gaq is a likely candidate. Phospholipase C (PLC) is required since Ca2+ chelator BAPTA-AM and PLC inhibitor U73122 decreased ASP stimulation of TGS by 93.1% (p<0.0.001) and 86.1% (p<0.004), respectively. Both wortmannin and LY294002 effectively blocked ASP effect by 69% (p<0.001) and 116.1% (p<0.003), respectively, supporting a role for PI3 kinase (PI3K). ASP treatment led to a rapid but transient 3.5 fold increase in Akt phosphorylation (maximal at 5 minutes, basal by 45 minutes) which was blocked by Akt inhibition, resembling treatment by insulin. Downstream of PI3K, the mTOR pathway is required for insulin but not ASP action. By contrast, both ASP and insulin activate the MAPK/ERK1/2 pathway with rapid (10 minutes) and pronounced (30 fold) increases in ERK1/2 phosphorylation. These effects were partially blocked by PD98059, a MAPK inhibitor (64.7% and 65.9% inhibition, respectively, p<0.001). Using anti-cPLA2-Ser505 (phosphorylation site of MAPK/ERK1/2), time-dependent (maximal at 30 minutes) and transient cPLA2 phosphorylation was demonstrated by Western. Thus ASP signaling involves sequential activation of PI3K and PLC with downstream activation of PKC, Akt, MAPK/ERK1/2 and cPLA2, all of which leads to an effective and prolonged stimulation of TG synthesis.
Accepted on December 5, 2005
Targeting the signaling pathway of acylation stimulating protein
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