Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B

Heemskerk, Mattijs M.; Berg, Sjoerd A.A. van den; Pronk, Amanda; Klinken, Jan-Bert van; Boon, Mariëtte R.; Havekes, Louis M.; Rensen, Patrick C.N.; Dijk, Ko Willems van; Harmelen, Vanessa van

doi:10.1152/ajpendo.00641.2013

Cited by 27 publications

(38 citation statements)

References 27 publications

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Section: Gwat Gene Expression Analysissupporting

confidence: 84%

“…As previously published ( 16 ), niacin treatment did not lead to differences in body weight nor gWAT weight in these mice. However, plasma lipids (i.e., total cholesterol, TGs, and phospholipids) were all decreased ( 16 ). Gene expression analysis generated 24 differentially expressed genes due to niacin treatment after multiple test correction (adjusted P < 0.05, see Table 1 ).…”

Section: Gwat Gene Expression Analysissupporting

confidence: 84%

“…Intriguingly, these acute effects decrease upon prolonged niacin treatment. Adipocyte lipolysis normalizes ( 15,16 ) and fl ushing diminishes ( 17 ).…”

Section: Quantitative Pcrmentioning

confidence: 99%

“…The difference between these time points was equal to 24 h food intake of the mice. The mice in this study are the same as in our previously published study ( 16 ). All experiments were performed after a 15 week dietary intervention period.…”

Section: Mouse Experimentsmentioning

confidence: 99%

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Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile

Heemskerk

Dharuri

Berg

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words drug therapy/hypolipidemic drugs • adipocytes • fatty acid/biosynthesis • omega-3 fatty acids • cytochrome P450 • polyunsaturated fatty acid Niacin (vitamin B3) treatment reduces CVD and atherosclerosis development ( 1 ). These benefi cial effects are mediated, in part, by lowering circulating levels of LDLcholesterol, VLDL-TG, and lipoprotein(a) ( 2 ), as well as by increasing HDL-cholesterol ( 3 ). In addition, prolonged niacin treatment also decreases plasma, adipose tissue, and vascular infl ammation ( 4, 5 ), which might contribute to reducing CVD. The induction of these benefi cial effects after prolonged niacin treatment is in striking contrast to the unwanted acute niacin effects.Acutely, niacin binds to the inhibitory hydroxycarboxylic acid receptor 2 (HCA 2 ) (previously known as GPR109A). In adipocytes, this leads to an inhibition of adipocyte lipolysis followed by an acute reduction of plasma nonesterifi ed fatty acid (NEFA) levels. Lowering NEFA levels causes metabolic stress ( 6, 7 ), which increases stress hormone levels ( 8-12 ) after niacin treatment. In the skin Langerhans cells and keratinocytes, acute niacin binding to the

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Section: Gwat Gene Expression Analysissupporting

confidence: 84%

Section: Gwat Gene Expression Analysissupporting

confidence: 84%

“…Intriguingly, these acute effects decrease upon prolonged niacin treatment. Adipocyte lipolysis normalizes ( 15,16 ) and fl ushing diminishes ( 17 ).…”

Section: Quantitative Pcrmentioning

confidence: 99%

Section: Mouse Experimentsmentioning

confidence: 99%

See 2 more Smart Citations

Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile

Heemskerk

Dharuri

Berg

et al. 2014

Journal of Lipid Research

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“…has also been reported to occur in mice ( 41 ). In the lean (Sprague Dawley) rats used in the current study, we observed no signifi cant change in PDE-3B mRNA after 5 days of continuous NiAc infusion.…”

Section: Discussionsupporting

confidence: 60%

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Kroon

Kjellstedt

Thalén

et al. 2015

Journal of Lipid Research

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explored and provide evidence supporting this concept. This includes inactivation of hormone sensitive lipase (HSL) ( 5, 6 ) and A 1 -adenosine receptor agonists ( 7 ). In addition, several other G protein-coupled receptors (GPRs) are involved in controlling adipocyte FFA release, including GPR43, GPR81, and GPR109A ( 8-10 ).The GPR109A agonist nicotinic acid (NiAc) has been used clinically ever since its antidyslipidemic effects (HDL elevation and reductions of total cholesterol, LDL-cholesterol, and TG) were discovered more than 50 years ago ( 11-15 ). Although NiAc potently lowers FFA acutely, large-scale clinical studies, with repeated oral NiAc administration, often report increased levels of fasting glycemia ( 16-19 ). NiAc has not been optimized to achieve durable and therapeutically meaningful FFA lowering. By this, we specifi cally mean reducing around-the-clock FFA area under the curve (AUC). In theory, this might be achieved by sustained NiAc exposure; however, the FFA-lowering effect seen initially appears to be lost over time despite maintained NiAc exposure (tolerance development) ( 20 ). Time-dependent loss of both FFA lowering and glucose control improvement also occur in patients with type 2 diabetes, treated with the NiAc analog acipimox ( 21,22 ). To avoid tolerance development, drug holidays are needed. However, at the end of each NiAc exposure period, there is the risk of FFA rebound (here referring to the situation where FFA overshoots pretreatment levels in connection with NiAc decline) due to the short NiAc plasma half-life ( 23 ). FFA rebound is associated with impaired glucose control ( 24, 25 ). The question of whether there might be an optimal balance between periods of continuous exposure (which would minimize rebound) and drug holidays (which would minimize tolerance) in order to achieve maximal FFA lowering has not been addressed. Lipid overload in nonadipose tissues has been linked to the pathogenesis of insulin resistance and atherogenesis ( 1-4 ). A potential means for reversing peripheral lipid overload is to restrict the release of FFAs from adipose tissues. A number of independent mechanisms have been N.D. Oakes, P. Thalén, and A. Kjellstedt Abbreviations: ATGL, adipocyte triglyceride lipase; AUC, area under the curve; ER, extended release; GIR, glucose infusion rate; GPR, G protein-coupled receptor; HOMA-IR, homeostasis model assessment for insulin resistance; HSL, hormone sensitive lipase; NiAc, nicotinic acid; PDE-3B, phosphodiesterase-3B .

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Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments

Andersson

Kroon

Almquist

et al. 2017

J Pharmacokinet Pharmacodyn

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Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc–FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague–Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 , respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be 2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures.

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Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B

Cited by 27 publications

References 27 publications

Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile

Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments

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