Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB

Nat. Med. 11, 183-190, (2005)

Speaker : 莊旭翔                                Time :2005/06/01,15:00-16:00

Commentator : 楊倍昌 老師                      Place : Room 601

Abstract :

  Obesity threatens to become the foremost cause of chronic disease in the world. Obesity can induce multiple metabolic abnormalities that contribute to cardiovascular disease, type 2 diabetes mellitus, and other chronic disorders. Type 2 diabetes mellitus (T2D), characterized mainly by peripheral insulin resistance, increased hepatic glucose production and impaired insulin secretion. However, the cellular and molecular mechanisms that obesity induces formation of type 2 diabetes mellitus are unknown.

In this paper, authors show that NF-kB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). Therefore, they designed a transgenic mice (LIKK) that selectively express constitutively active IKK-b in hepatocytes to mimic the state of  HFD induction. LIKK mice can express proinflammatory cytokines, including TNF-a, IL-6 and IL-1b in liver to a similar extent as induced by HFD in wild-type mice.

Moreover, systemic neutralization of IL-6 or salicylate inhibition of IKK-b can improve insulin resistance . Hepatic expression of the IκBα superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicated that through the production of proinflammatory cytokines, including IL-6 and potentially IL-1β, hepatic inflammation can cause both local hepatic and systemic insulin resistance.

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2. Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293, 1673–1677 (2001).

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