Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue.

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  • Author(s): Oh YT;Oh YT; Oh KS; Choi YM; Jokiaho A; Donovan C; Choi S; Kang I; Youn JH
  • Source:
    American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2011 Jun; Vol. 300 (6), pp. E1012-21. Date of Electronic Publication: 2011 Mar 08.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901226 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1555 (Electronic) Linking ISSN: 01931849 NLM ISO Abbreviation: Am J Physiol Endocrinol Metab Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, MD. : American Physiological Society
    • Subject Terms:
      Adipose Tissue/*drug effects ; Adipose Tissue/*metabolism ; Fatty Acids, Nonesterified/*blood ; Hypolipidemic Agents/*pharmacology ; Insulin Resistance/*physiology ; Lipid Metabolism/*drug effects ; Lipid Metabolism/*genetics ; Lipolysis/*drug effects ; Niacin/*pharmacology; Animals ; Blotting, Western ; Catecholamines/blood ; Corticosterone/blood ; Gene Expression/drug effects ; Glucose/metabolism ; Glucose Clamp Technique ; Glycerol/metabolism ; Hypolipidemic Agents/administration & dosage ; Infusions, Intravenous ; Lipase/metabolism ; Lipolysis/genetics ; Male ; Microarray Analysis ; Niacin/administration & dosage ; Phosphorylation ; RNA/biosynthesis ; RNA/genetics ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction
    • Abstract:
      Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipid-lowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (>60%, P < 0.01), and this effect was maintained for ≥5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P < 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment.
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    • Grant Information:
      R21 DK080233 United States DK NIDDK NIH HHS; DK-080233 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (Catecholamines)
      0 (Fatty Acids, Nonesterified)
      0 (Hypolipidemic Agents)
      2679MF687A (Niacin)
      63231-63-0 (RNA)
      EC 3.1.1.3 (Lipase)
      IY9XDZ35W2 (Glucose)
      PDC6A3C0OX (Glycerol)
      W980KJ009P (Corticosterone)
    • Publication Date:
      Date Created: 20110310 Date Completed: 20110729 Latest Revision: 20211020
    • Publication Date:
      20221213
    • Accession Number:
      PMC3118587
    • Accession Number:
      10.1152/ajpendo.00650.2010
    • Accession Number:
      21386057