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

Daniel 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

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E89-E100
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume305
Issue number1
DOIs
StatePublished - Jul 1 2013

Keywords

  • Hepatic steatosis
  • Insulin resistance
  • Thyroid hormone receptor-β agonists

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Vatner, D. F., Weismann, D., Beddow, S. A., Kumashiro, N., Erion, D. M., Liao, X. H., Grover, G. J., Webb, P., Phillips, K. J., Weiss, R. E., Bogan, J. S., Baxter, J., Shulman, G. I., & Samuel, V. T. (2013). Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. American Journal of Physiology - Endocrinology and Metabolism, 305(1), E89-E100. https://doi.org/10.1152/ajpendo.00573.2012