The Amelioration of Hepatic Steatosis by Thyroid Hormone Receptor Agonists Is Insufficient to Restore Insulin Sensitivity in Ob/Ob Mice

Abstract

Thyroid hormone receptor (TR) agonists have been proposed as therapeutic agents to treat non-alcoholic fatty liver disease (NAFLD) and insulin resistance. We investigated the ability of the TR agonists GC-1 and KB2115 to reduce hepatic steatosis in ob/ob mice. Both compounds markedly reduced hepatic triglyceride levels and ameliorated hepatic steatosis. However, the amelioration of fatty liver was not sufficient to improve insulin sensitivity in these mice and reductions in hepatic triglycerides did not correlate with improvements in insulin sensitivity or glycemic control. Instead, the effects of TR activation on glycemia varied widely and were found to depend upon the time of treatment as well as the compound and dosage used. Lower doses of GC-1 were found to further impair glycemic control, while a higher dose of the same compound resulted in substantially improved glucose tolerance and insulin sensitivity, despite all doses being equally effective at reducing hepatic triglyceride levels. Improvements in glycemic control and insulin sensitivity were observed only in treatments that also increased body temperature, suggesting that the induction of thermogenesis may play a role in mediating these beneficial effects. These data illustrate that the relationship between TR activation and insulin sensitivity is complex and suggests that although TR agonists may have value in treating NAFLD, their effect on insulin sensitivity must also be considered.

Pharmacological Activation of Thyroid Hormone Receptors Elicits a Functional Conversion of White to Brown Fat

“…In scWAT, KB2115 induced thermogenic genes (Figure S4D) at a level far lower than that demonstrated by GC-1. Further, in a related study we found that KB2115 does not elicit any of the anti-diabetic actions observed with GC-1 treatment (Martagón et al 2015). Thus, the potential to induce browning and concomitant thermogenesis, at least at the magnitude observed with GC-1, is not a common feature of all TR agonists.…”

Regulation of hepatic glucose metabolism in health and disease

“…Thyroid hormone receptor-β agonists have been tested preclinically for their ability achieve this and, although they can reverse NAFLD, none has been shown to improve the suppression of HGP by insulin (in part due to increased adipose lipolysis) 182,183 . In addition, a T 3 –glucagon conjugate improved glycaemia and NAFLD, without causing the rapid development of cardiac hypertrophy and osteopenia observed with T 3 alone 184 ; additional studies to evaluate the safety and effects of this conjugate on HGP (which was not evaluated in this study 184 ) will help to assess the promise of this class of compounds.…”

Endocrine-disrupting chemicals and fatty liver disease

“…Due to this action, FXR agonists such as obeticholic acid and INT-767 are currently being tested in human NAFLD and NASH clinical trials 2 . Thyroid hormone T 3 , as well as synthetic TR agonists, reduce hepatic steatosis in male Fischer 344 rats fed a diet deficient in choline and methionine 68 and in diabetic mice (for example, ob/ob ) 69 , suggestive of their potential clinical usefulness. Activation of a NR that can trigger increased steatosis does not always result in increased inflammation.…”