Nicotinic acid timed to ing reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

  1. Nicholas D. Oakes
  1. Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health,* Swedish University of Agricultural Sciences, Uppsala, Sweden
  2. AstraZeneca R&D, CVMD iMed, Gothenburg, Sweden
  1. 1To whom correspondence should be addressed. e-mail: tobias.kroon{at}astrazeneca.com

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 ing-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 ing 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 ing 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 ing periods, profoundly improves the metabolic phenotype of this animal model.

Footnotes

  • Abbreviations:
    ACC1
    acetyl-CoA carboxylase 1
    AUC
    area under the curve
    CD36
    cluster of differentiation 36/fatty acid translocase
    ChREBP
    carbohydrate-responsive element-binding protein
    CV
    coefficient of variation
    DNL
    de novo lipogenesis
    Elovl6
    fatty acid elongase 6
    FABP4
    fatty acid binding protein-4
    FFA
    free fatty acid
    GPR
    G protein-coupled receptor
    lbm
    lean body mass
    NiAc
    nicotinic acid
    OGTT
    oral glucose tolerance test
    RPLP0
    ribosomal protein large P0
    SCD1
    stearoyl-CoA desaturase-1
    SREBP-1c
    sterol regulatory element binding protein-1c

  • N.D.O. and A.O. are full time employees, T.B. is a Graduate Program student employee, and J.G. and T.K. are former employees at AstraZeneca R&D, Gothenburg, Sweden.

  • Received April 12, 2016.
  • Revision received October 17, 2016.
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This Article

  1. The Journal of Lipid Research, 58, 31-41.
  1. All Versions of this Article:
    1. jlr.M068395v1
    2. 58/1/31 most recent

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