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.

Highlights

  • Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease of the developed world, affecting approximately one third of the U.S population [1]

  • GC-1 or KB2115 revealed that both compounds elicited a near complete elimination of lipid filled vacuoles that were characteristic of the livers from untreated control mice (Fig 1A)

  • This study demonstrates clearly that the amelioration of hepatic steatosis by Thyroid hormone receptor (TR) agonists is not sufficient to improve insulin sensitivity, at least in ob/ob mice

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Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease of the developed world, affecting approximately one third of the U.S population [1]. While numerous factors, such as defects in mitochondrial β- oxidation, oxidative stress, or ER stress [4] have been implicated in various stages of NAFLD progression, initiation of the disease is caused by a chronic imbalance between triglyceride acquisition, via dietary intake and de novo synthesis, and triglyceride utilization This imbalance leads to abnormal accumulation of lipid in the liver [3], resulting in hepatic steatosis or fatty liver. We recently reported that TR agonists reduce serum lipids in a mouse model of severe hyperlipidemia [11] During these studies we observed that TR agonist treatment markedly improved hepatic steatosis in these mice; an observation in accordance with other reports indicating that TR agonists can ameliorate fatty liver and NASH in various rodent models of these disorders [12,13]. TR agonists dissociate insulin sensitivity from fatty liver, illustrating that the relationship between TR activation and glycemia is complex and suggesting that the effect of TR agonists on insulin sensitivity must be taken into account when considering the use of these compounds for the treatment of NAFLD

Results
Discussion
Materials and Methods
19. JAX NOTES

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