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.