Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B.
The lipid-lowering effect of niacin has been attributed to the inhibition of cAMP production in adipocytes, thereby inhibiting intracellular lipolysis and release of nonesterified fatty acids (NEFA) to the circulation. However, long-term niacin treatment leads to a normalization of plasma NEFA levels and induces insulin resistance, for which the underlying mechanisms are poorly understood. The current study addressed the effects of long-term niacin treatment on insulin-mediated inhibition of adipocyte lipolysis and focused on the regulation of cAMP levels. APOE*3-Leiden.CETP transgenic mice treated with niacin for 15 wk were subjected to an insulin tolerance test and showed whole body insulin resistance. Similarly, adipocytes isolated from niacin-treated mice were insulin resistant and, interestingly, exhibited an increased response to cAMP stimulation by 8Br-cAMP, β1- and β2-adrenergic stimulation. Gene expression analysis of the insulin and β-adrenergic pathways in adipose tissue indicated that all genes were downregulated, including the gene encoding the cAMP-degrading enzyme phosphodiesterase 3B (PDE3B). In line with this, we showed that insulin induced a lower PDE3B response in adipocytes isolated from niacin-treated mice. Inhibiting PDE3B with cilostazol increased lipolytic responsiveness to cAMP stimulation in adipocytes. These data show that long-term niacin treatment leads to a downregulation of PDE3B in adipocytes, which could explain part of the observed insulin resistance and the increased responsiveness to cAMP stimulation.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;
Mattijs M
MM
Heemskerk
Sjoerd A A
SA
van den Berg
Amanda C M
AC
Pronk
Jan-Bert
JB
van Klinken
Mariëtte R
MR
Boon
Louis M
LM
Havekes
Patrick C N
PC
Rensen
Ko Willems
KW
van Dijk
Vanessa
V
van Harmelen
D000222:Adaptation, Physiological / Q000187:drug effects; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009525:Niacin / Q000494:pharmacology*; D011941:Receptors, Adrenergic / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D018663:Adrenergic Agents; D000960:Hypolipidemic Agents; D011941:Receptors, Adrenergic; D009525:Niacin; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3
adenosine 3′,5′-cyclic monophosphate; adipose tissue; lipolysis; phosphodiesterases