Berberine attenuates cAMP-induced lipolysis via reducing the inhibition of phosphodiesterase in 3T3-L1 adipocytes.
Berberine, a hypoglycemic agent, has been shown to decrease plasma free fatty acids (FFAs) level in insulin-resistant rats. In the present study, we explored the mechanism responsible for the antilipolytic effect of berberine in 3T3-L1 adipocytes. It was shown that berberine attenuated lipolysis induced by catecholamines, cAMP-raising agents, and a hydrolyzable cAMP analog, but not by tumor necrosis factor α and a nonhydrolyzable cAMP analog. Unlike insulin, the inhibitory effect of berberine on lipolysis in response to isoproterenol was not abrogated by wortmannin, an inhibitor of phosphatidylinositol 3-kinase, but additive to that of PD98059, an extracellular signal-regulated kinase kinase inhibitor. Prior exposure of adipocytes to berberine decreased the intracellular cAMP production induced by isoproterenol, forskolin, and 3-isobutyl-1-methylxanthine (IBMX), along with hormone-sensitive lipase (HSL) Ser-563 and Ser-660 dephosphorylation, but had no effect on perilipin phosphorylation. Berberine stimulated HSL Ser-565 as well as adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. However, compound C, an AMPK inhibitor, did not reverse the regulatory effect of berberine on HSL Ser-563, Ser-660, and Ser-565 phosphorylation, nor the antilipolytic effect of berberine. Knockdown of AMPK using RNA interference also failed to restore berberine-suppressed lipolysis. cAMP-raising agents increased AMPK activity, which was not additive to that of berberine. Stimulation of adipocytes with berberine increased phosphodiesterase (PDE) 3B and PDE4 activity measured by hydrolysis of (3)[H]cAMP. These results suggest that berberine exerts an antilipolytic effect mainly by reducing the inhibition of PDE, leading to a decrease in cAMP and HSL phosphorylation independent of AMPK pathway.
Shanghai Institute of Endocrine and metabolic Disease, Department of Endocrine and Metabolic Disease, Shanghai Clinical Center for Endocrine and Metabolic disease, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Libin
L
Zhou
Xiao
X
Wang
Ying
Y
Yang
Ling
L
Wu
Fengying
F
Li
Rong
R
Zhang
Guoyue
G
Yuan
Ning
N
Wang
Mingdao
M
Chen
Guang
G
Ning
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D002352:Carrier Proteins; D002395:Catecholamines / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000070778:Perilipin-1; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D002787:Sterol Esterase / Q000378:metabolism
D002352:Carrier Proteins; D002395:Catecholamines; D007004:Hypoglycemic Agents; D000070778:Perilipin-1; D010726:Phosphodiesterase Inhibitors; D010750:Phosphoproteins; D001599:Berberine; D005576:Colforsin; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases; D002787:Sterol Esterase; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D015056:1-Methyl-3-isobutylxanthine