title: 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.
authors: Diabetes and Metabolic Disease Program, Houston Methodist Research Institute, Houston, Texas, United States of America; Escuela de Biotecnología y Alimentos, Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, NL, Mexico.
authors: Alexandro J
authors: AJ
authors: Martagón
authors: Diabetes and Metabolic Disease Program, Houston Methodist Research Institute, Houston, Texas, United States of America; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, United States of America.
authors: Jean Z
authors: JZ
authors: Lin
authors: Diabetes and Metabolic Disease Program, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors: Stephanie L
authors: SL
authors: Cimini
authors: Diabetes and Metabolic Disease Program, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors: Paul
authors: P
authors: Webb
authors: Diabetes and Metabolic Disease Program, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors: Kevin J
authors: KJ
authors: Phillips
mesh_terms: D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D011988:Receptors, Thyroid Hormone / Q000819:agonists*; D013997:Time Factors
chemical_list: C526273:3-((3,5-dibromo-4-(4-hydroxy-3-(1-methylethyl)phenoxy)phenyl)amino)-3-oxopropanoic acid; D000085:Acetates; D000813:Anilides; D001786:Blood Glucose; C413355:GC 1 compound; D010636:Phenols; D011988:Receptors, Thyroid Hormone; D005952:Glucose-6-Phosphatase