A Stress Signaling Pathway in Adipose Tissue Regulates Hepatic Insulin Resistance

Guadalupe Sabio et al Science 322(5907):1539-43 2008

Speaker: Tsung-Ying Hsieh(謝宗穎)                           Time: 13:00~14:00, April. 22, 2009

Commentator: Dr. Yau-Sheng Tsai (蔡曜聲老師)     Place: Room 601

Abstract:

        Type II diabetes, often called non-insulin dependent diabetes (NIDDM), is defined as reduced insulin sensitivity (insulin resistance) and defect in insulin secretion. And it had been related to obesity which is the major cause of insulin resistance and metabolic syndrome. The mechanism how obesity triggers insulin resistance is still unclear. Recent studies showed that infiltration by macrophage in adipose tissue lead to fat inflammation and finally became insulin resistance. Because the proinflammatory cytokine such as IL-6, TNF-a produced by macrophage will interfere with insulin signaling at adipose, liver and muscle. At 2002, it showed that protein kinase c-Jun NH2-terminal 1 (JNK1) is a crucial mediator of obesity and insulin resistance. When feeding mice a high-fat diet induced obesity and insulin resistance, it can activate JNK1 in various organ including the adipose, liver and muscle. But whether a specific organ is responsible for JNK1-mediated insulin resistance is still unknown. In this paper, the authors generated JNK1 knock mouse at specific tissue including myeloid cell, hematopoietic cell and adipocyte. Feeding these mice with high-fat diet, authors found mice with JNK1 deficiency in adipocyte improve insulin sensitivity but others were not. Next, author perform hyperinsulinemic-euglycemic clamp to assess organ-specific glucose metabolism and found JNK1 deficiency in adipocyte improved high-fat diet–induced insulin resistance in the liver. Confirming insulin sensitivity again with testing insulinstimulated Ser/Thr phosphorylation and activation of AKT, the results is consistent with clamp. Further, JNK1-dependent secretion of the inflammatory cytokine interleukin-6 by adipose tissue caused increased expression of liver SOCS3, a protein that induces hepatic insulin resistance. To test the effect of IL-6, authors inject IL-6 back into knockout mice and found IL-6 can restore high-fed diet induced resistance in knockout mice.

The author suggested a new pathway that inflammatory response within adipocytes via JNK1 activation and IL-6 secretion, play a key role in regulating insulin sensitivity in the liver.

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