Liver-Specific Inhibition of ChREBP Improves Hepatic Steatosis and Insulin Resistance in ob/ob Mice

Jul 29, 2006Diabetes

Blocking a liver protein improves fat buildup and insulin resistance in obese mice

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Abstract

ChREBP gene expression is significantly increased in the liver of ob/ob mice, which may contribute to insulin resistance.

Increased lipogenesis in leptin-deficient mice is associated with elevated ChREBP gene expression and protein levels.
Inhibition of ChREBP expression in the liver of ob/ob mice leads to a marked reduction in hepatic steatosis.
Decreased lipogenic rates following ChREBP inhibition result in lower plasma triglycerides and nonesterified fatty acids.
Improvement in insulin signaling was observed in the liver, skeletal muscles, and white adipose tissue after ChREBP suppression.
Overall glucose tolerance and insulin sensitivity were restored in ob/ob mice after 7 days of treatment targeting ChREBP.

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Obesity is a metabolic disorder often associated with type 2 diabetes, insulin resistance, and hepatic steatosis. Leptin-deficient (ob/ob) mice are a well-characterized mouse model of obesity in which increased hepatic lipogenesis is thought to be responsible for the phenotype of insulin resistance. We have recently demonstrated that carbohydrate responsive element-binding protein (ChREBP) plays a key role in the control of lipogenesis through the transcriptional regulation of lipogenic genes, including acetyl-CoA carboxylase and fatty acid synthase. The present study reveals that ChREBP gene expression and ChREBP nuclear protein content are significantly increased in liver of ob/ob mice. To explore the involvement of ChREBP in the physiopathology of hepatic steatosis and insulin resistance, we have developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) were used to inhibit ChREBP expression in vivo. Liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by specifically decreasing lipogenic rates. Correction of hepatic steatosis also led to decreased levels of plasma triglycerides and nonesterified fatty acids. As a consequence, insulin signaling was improved in liver, skeletal muscles, and white adipose tissue, and overall glucose tolerance and insulin sensitivity were restored in ob/ob mice after a 7-day treatment with the recombinant adenovirus expressing shRNA against ChREBP. Taken together, our results demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development of the hepatic steatosis and of insulin resistance in ob/ob mice.

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Liver-Specific Inhibition of ChREBP Improves Hepatic Steatosis and Insulin Resistance in ob/ob Mice

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