Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation-stimulating protein and insulin.
The effects of acylation-stimulating protein (ASP) and insulin on free fatty acid (FFA) release from isolated human fat cells and the signal transduction pathways to induce these effects were studied. ASP and insulin inhibited basal and norepinephrine-induced FFA release by stimulating fractional FFA re-esterification (both to the same extent) and by inhibiting FFA produced during lipolysis (ASP to a lesser extent than insulin). Protein kinase C inhibition influenced none of the effects of ASP or insulin. Phosphatidylinositol 3-kinase inhibition counteracted the effects of insulin but not of ASP. Phosphodiesterase 3 (PDE3) activity was stimulated by ASP and insulin, whereas PDE4 activity was slightly increased by ASP only. Selective PDE3 inhibition reversed the effects of both ASP and insulin on fractional FFA re-esterification and lipolysis. Selective PDE4 inhibition slightly counteracted the ASP but not the effect of insulin on fractional FFA re-esterification and did not prevent the action of ASP or insulin on lipolysis. Thus, ASP and insulin play a major role in regulating FFA release from fat cells as follows: insulin by stimulating fractional FFA re-esterification and inhibiting lipolysis and ASP mainly by stimulating fractional FFA re-esterification. For both ASP and insulin these effects on FFA release are mediated by PDE3, and for ASP PDE4 might also be involved. The signaling pathway preceding PDE is not known for ASP but involves phosphatidylinositol 3-kinase for insulin.
Van Harmelen
V
V
Department of Medicine and Research Center, Huddinge University Hospital, Karolinska Institute, S-141 86 Huddinge, Sweden.
Reynisdottir
S
S
Cianflone
K
K
Degerman
E
E
Hoffstedt
J
J
Nilsell
K
K
Sniderman
A
A
Arner
P
P
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000215:Acylation; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D001055:Apolipoproteins B / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D015926:Complement C3a / Q000031:analogs & derivatives*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D008066:Lipolysis; D009281:Naphthalenes / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D000077191:Wortmannin
D000730:Androstadienes; D001055:Apolipoproteins B; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D009281:Naphthalenes; D000081082:Phosphoinositide-3 Kinase Inhibitors; C061465:calphostin complex; C044541:complement C3a, des-Arg-(77)-; D015926:Complement C3a; D011493:Protein Kinase C; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000077191:Wortmannin