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

Abstract

VT. Thyroid hormone receptor-␤ agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am J Physiol Endocrinol Metab 305: E89-E100, 2013. First published May 7, 2013; doi:10.1152/ajpendo.00573.2012.-Liver-specific thyroid hormone receptor-␤ (TR␤)-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 TR␤ 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 TR␤-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 TR␤ agonists must consider the potential adverse effects on insulin sensitivity. thyroid hormone receptor-␤ agonists; insulin resistance; hepatic steatosis THE BURGEONING EPIDEMICS OF obesity and diabetes necessitate novel therapies. Thyroid hormone agonism remains a tantalizing modality (1, 54). It has the potential to mediate favorable effects on lipid metabolism and energy expenditure, decreasing plasma low-density lipoprotein (LDL) and increasing energy expenditure through futile substrate cycling (34,35,46) and increasing thermogenesis (21). However, generalized thyroid hormone excess has a number of untoward effects, including tachyarrhythmias, pulmonary hypertension, osteoporosis, agitation, and even psychosis.Thyroid hormones act primarily via three nuclear receptors, TR␣ 1 , TR␤ 1 , and TR␤ 2 ; most tissues express both TR␣ and TR␤, although one isoform often predominates (1, 10, 26, 31, 55). For example, TR␣ 1 expression predominates in the cardiac and skeletal muscle, osteoclast, and many regions of the brain. In comparison, TR␤ 1 predominates in liver, and TR␤ 2 plays a critical role in the regulation of the hypothalamic-pituitary-thyroid axis (8,10,19,27). Activating TR␤ in the liver could be therapeutic for metabolic diseases by lowering plasma and intrahepatic lipid content. However, natural thyroid hormones have nearly equivalent affinities for TR␤ and TR␣ [K D (TR␣ 1 )/K D (TR␤ 1 ) ϭ 0.7 (11)]. Thus, any attempts to re...

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