Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways

Am J Physiol Endocrinol Metab. 2013 Jul 1;305(1):E89-100. doi: 10.1152/ajpendo.00573.2012. Epub 2013 May 7.

Abstract

Liver-specific thyroid hormone receptor-β (TRβ)-specific agonists are potent lipid-lowering drugs that also hold promise for treating nonalcoholic fatty liver disease and hepatic insulin resistance. We investigated the effect of two TRβ agonists (GC-1 and KB-2115) in high-fat-fed male Sprague-Dawley rats treated for 10 days. GC-1 treatment reduced hepatic triglyceride content by 75%, but the rats developed fasting hyperglycemia and hyperinsulinemia, attributable to increased endogenous glucose production (EGP) and diminished hepatic insulin sensitivity. GC-1 also increased white adipose tissue lipolysis; the resulting increase in glycerol flux may have contributed to the increase in EGP. KB-2115, a more TRβ- and liver-specific thyromimetic, also prevented hepatic steatosis but did not induce fasting hyperglycemia, increase basal EGP rate, or diminish hepatic insulin sensitivity. Surprisingly, insulin-stimulated peripheral glucose disposal was diminished because of a decrease in insulin-stimulated skeletal muscle glucose uptake. Skeletal muscle insulin signaling was unaffected. Instead, KB-2115 treatment was associated with a decrease in GLUT4 protein content. Thus, although both GC-1 and KB-2115 potently treat hepatic steatosis in fat-fed rats, they each worsen insulin action via specific and discrete mechanisms. The development of future TRβ agonists must consider the potential adverse effects on insulin sensitivity.

Keywords: hepatic steatosis; insulin resistance; thyroid hormone receptor-β agonists.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetates / pharmacology*
  • Anilides / pharmacology*
  • Animals
  • Dietary Fats / pharmacology
  • Fatty Liver / drug therapy
  • Fatty Liver / metabolism*
  • Fatty Liver / prevention & control*
  • Gene Expression / drug effects
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / physiology
  • Glucose Transporter Type 4 / metabolism
  • Hyperglycemia / chemically induced
  • Hyperglycemia / metabolism
  • Hyperinsulinism / chemically induced
  • Hyperinsulinism / metabolism
  • Insulin Resistance / physiology*
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Non-alcoholic Fatty Liver Disease
  • Phenols / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Thyroid Hormone Receptors beta / agonists*
  • Thyroid Hormone Receptors beta / metabolism
  • Triglycerides / metabolism

Substances

  • 3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid
  • Acetates
  • Anilides
  • Dietary Fats
  • GC 1 compound
  • Glucose Transporter Type 4
  • Phenols
  • Slc2a4 protein, rat
  • Thyroid Hormone Receptors beta
  • Triglycerides