Abstract
Nicotinic acid (NiAc) is a potent inhibitor of lipolysis, acutely reducing plasma free fatty acid (FFA) concentrations. However, a major FFA rebound is seen during rapid NiAc washout, and sustained exposure is associated with tolerance development, with FFAs returning to pretreatment levels. Our aim was to find a rational NiAc dosing regimen that preserves FFA lowering, sufficient to reverse nonadipose tissue lipid accumulation and improve metabolic control, in obese Zucker rats. We compared feeding-period versus fasting-period NiAc dosing for 5 days: 12 h subcutaneous infusion (programmable, implantable mini-pumps) terminated by gradual withdrawal. It was found that NiAc timed to feeding decreased triglycerides in liver (-47%; P < 0.01) and heart (-38%; P < 0.05) and reduced plasma fructosamine versus vehicle. During oral glucose tolerance test, plasma FFA levels were reduced with amelioration of hyperglycemia and hypertriglyceridemia. Furthermore, timing NiAc to feeding resulted in a general downregulation of de novo lipogenesis (DNL) genes in liver. By contrast, NiAc timed to fasting did not reduce tissue lipids, ameliorate glucose intolerance or dyslipidemia, or alter hepatic DNL genes. In conclusion, NiAc dosing regimen has a major impact on metabolic control in obese Zucker rats. Specifically, a well-defined NiAc exposure, timed to feeding periods, profoundly improves the metabolic phenotype of this animal model.
Highlights
Nicotinic acid (NiAc) is a potent inhibitor of lipolysis, acutely reducing plasma free fatty acid (FFA) concentrations
After preprogrammed initiation of the step-down protocol at 13:00, plasma NiAc concentrations declined gradually in the NiAc-Stp-Dwn groups, taking 3.8 h to reach acute in vivo IC50 for FFA lowering ( 0.07 μM) versus 1.2 h for abrupt termination in the NiAc-Off groups
The current results demonstrate that timing and shape of the intermittent NiAc exposure profile have a major impact on metabolic control
Summary
Nicotinic acid (NiAc) is a potent inhibitor of lipolysis, acutely reducing plasma free fatty acid (FFA) concentrations. During rapid NiAc washout a major FFA rebound is seen, overshooting pretreatment levels [10]; this phenomenon is observed with oral dosing in humans [8, 11]. This may be one reason for the apparent worsening of glycemic control with NiAc [12,13,14,15,16,17,18]. We tried to reduce tolerance by interspacing abruptly terminated NiAc exposures with drug holidays This approach was partially successful, retaining acute NiAc-induced FFA lowering and insulin sensitivity but without delivering significant peripheral tissue lipid unloading [10]. Our initial study was performed without timing NiAc exposure to the feeding/fasting periods
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