title: Thyroid hormone receptor-α gene knockout mice are protected from diet-induced hepatic insulin resistance.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the United States and is strongly associated with hepatic insulin resistance. We examined whether the thyroid hormone receptor-α (Thra) would be a potential therapeutic target to prevent diet-induced NAFLD and insulin resistance. For that purpose, we assessed insulin action in high-fat diet-fed Thra gene knockout (Thra-0/0) and wild-type mice using hyperinsulinemic-euglycemic clamps combined with (3)H/(14)C-labeled glucose to assess basal and insulin-stimulated rates of glucose and fat metabolism. Body composition was assessed by (1)H magnetic resonance spectroscopy and energy expenditure by indirect calorimetry. Relative rates of hepatic glucose and fat oxidation were assessed in vivo using a novel proton-observed carbon-edited nuclear magnetic resonance technique. Thra-0/0 were lighter, leaner, and manifested greater whole-body insulin sensitivity than wild-type mice during the clamp, which could be attributed to increased insulin sensitivity both in liver and peripheral tissues. Increased hepatic insulin sensitivity could be attributed to decreased hepatic diacylglycerol content, resulting in decreased activation of protein kinase Cε and increased insulin signaling. In conclusion, loss of Thra protects mice from high-fat diet-induced hepatic steatosis and hepatic and peripheral insulin resistance. Therefore, thyroid receptor-α inhibition represents a novel pharmacologic target for the treatment of NAFLD, obesity, and type 2 diabetes.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
authors.forename: François R
authors.initials: FR
authors.lastname: Jornayvaz
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Tiago C
authors.initials: TC
authors.lastname: Alves
authors.forename: Fitsum
authors.initials: F
authors.lastname: Guebre-Egziabher
authors.forename: Blas A
authors.initials: BA
authors.lastname: Guigni
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: J Enrique
authors.initials: JE
authors.lastname: Silva
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D004032:Diet / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics; D015398:Signal Transduction; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D007328:Insulin; D037021:Thyroid Hormone Receptors alpha