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

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.
AuthorsDaniel F Vatner, Dirk Weismann, Sara A Beddow, Naoki Kumashiro, Derek M Erion, Xiao-Hui Liao, Gary J Grover, Paul Webb, Kevin J Phillips, Roy E Weiss, Jonathan S Bogan, John Baxter, Gerald I Shulman, Varman T Samuel
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 305 Issue 1 Pg. E89-100 (Jul 1 2013) ISSN: 1522-1555 [Electronic] United States
PMID23651850 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • 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
  • Acetates (pharmacology)
  • Anilides (pharmacology)
  • Animals
  • Dietary Fats (pharmacology)
  • Fatty Liver (drug therapy, metabolism, prevention & control)
  • Gene Expression (drug effects)
  • Gluconeogenesis (drug effects, physiology)
  • Glucose Transporter Type 4 (metabolism)
  • Hyperglycemia (chemically induced, metabolism)
  • Hyperinsulinism (chemically induced, metabolism)
  • Insulin Resistance (physiology)
  • Male
  • Muscle, Skeletal (drug effects, metabolism)
  • Non-alcoholic Fatty Liver Disease
  • Phenols (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction (drug effects, physiology)
  • Thyroid Hormone Receptors beta (agonists, metabolism)
  • Triglycerides (metabolism)

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