Long-term Niacin Treatment Induces Insulin Resistance and Adrenergic Responsiveness in Adipocytes by Adaptive Downregulation of Phosphodiesterase 3B

Overview

Journal Am J Physiol Endocrinol Metab

Publisher American Physiological Society

Specialties Endocrinology
Physiology

Date 2014 Jan 30

PMID 24473440

Citations 16

Authors

Mattijs M Heemskerk

Sjoerd A A van den Berg

Amanda C M Pronk

Jan-Bert van Klinken

Mariette R Boon

Louis M Havekes

Patrick C N Rensen

Ko Willems van Dijk

Vanessa van Harmelen

Affiliations

Soon will be listed here.

Abstract

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.

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