title: Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways.
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.
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Daniel F
authors: DF
authors: Vatner
authors: Dirk
authors: D
authors: Weismann
authors: Sara A
authors: SA
authors: Beddow
authors: Naoki
authors: N
authors: Kumashiro
authors: Derek M
authors: DM
authors: Erion
authors: Xiao-Hui
authors: XH
authors: Liao
authors: Gary J
authors: GJ
authors: Grover
authors: Paul
authors: P
authors: Webb
authors: Kevin J
authors: KJ
authors: Phillips
authors: Roy E
authors: RE
authors: Weiss
authors: Jonathan S
authors: JS
authors: Bogan
authors: John
authors: J
authors: Baxter
authors: Gerald I
authors: GI
authors: Shulman
authors: Varman T
authors: VT
authors: Samuel
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism; D006946:Hyperinsulinism / Q000139:chemically induced / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D037042:Thyroid Hormone Receptors beta / Q000819:agonists* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: C526273:3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid; D000085:Acetates; D000813:Anilides; D004041:Dietary Fats; C413355:GC 1 compound; D051275:Glucose Transporter Type 4; D010636:Phenols; C495694:Slc2a4 protein, rat; D037042:Thyroid Hormone Receptors beta; D014280:Triglycerides
keywords: hepatic steatosis; insulin resistance; thyroid hormone receptor-β agonists
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