JNK in the trunk without extra sugar in the tank
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November 19, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [1]
San Diego, CA
The importance of inflammation in insulin resistance is gaining more support. New research has examined the importance of hematopoietic cell expression of an enzyme called JNK1 (c-Jun NH2-terminal kinase 1) for the development of the obesity-induced insulin resistance. Investigators have demonstrated that a mouse without hematopoietic expression of JNK1 become obese when fed a high fat diet, however this mouse has much less inflammation and does not develop insulin resistance. This research supports a role for inflammatory cells in the pathogenesis of type II diabetes.
Previous studies have shown that JNK1 knockout mice were resistant to obesity and the development of insulin resistance. Because this protein is widely expressed, the purpose of the current study was to determine which cell types mediate the obesity-resistance and which cell types mediate the resistance to diet-induced insulin resistance.
To answer this question, the researchers generated bone marrow chimaeras. Mice were given a lethal dose of radiation, which damages hematopoietic (bone marrow-derived) cell lineages. They were then rescued with bone marrow cells from wild-type (WT) or JNK1 knockout (JNK1-KO) animals. The bone marrow cells engraft in the lethally irradiated mice, creating a chimaeric mouse: most cells in the body have the recipient genotype, while the hematopoietic-derived cells have the donor genotype.
Mice that lack JNK1 in non-hematopoietic cells were resistant to diet induced obesity. They had increased food intake per body mass but also had an increased metabolic rate. The hyperinsulinemic response to glucose load was blunted in these animals, and these mice had a higher glucose requirement during insulin infusion. Together, these studies demonstrate increased insulin sensitivity when JNK1 was deficient in non-hematopoietic cells.
In contrast, WT mice rescued with JNK1-KO hematopoietic cells became obese on a high fat diet and had no change in their energy expenditure compared to WT mice. However, these mice did demonstrate better glucose control following glucose loading and increased insulin sensitivity. The improved insulin sensitivity was associated with less expression of inflammatory cytokines and fewer “crown-like structure”, macrophages in adipose tissue surrounding dead adipocytes. The authors provide biochemical evidence that free fatty acid activation of macrophages results in JNK activation and expression of inflammatory cytokines. Together, this data suggests that inflammatory cell JNK activation is important for diet-induced insulin resistance but not diet-induced obesity.
This research adds support to the hypothesis that low-grade chronic inflammation contributes to insulin resistance that accompanies obesity. Genetic separation of obesity and insulin resistance has been reported in other mouse models as well. The authors note that hematopoietic-derived cells are much more accessible than liver of pancreatic cells for the delivery of targeted therapeutics. Further research defining a role for molecules such as JNK could lead to new medical therapies for type II diabetes.
1. Giovanni Solinas, Cristian Vilcu, Jaap G. Neels, Gautam K. Bandyopadhyay, Jun-Li Luo, Willscott Naugler, Sergei Grivennikov, Anthony Wynshaw-Boris, Miriam Scadeng, Jerrold M. Olefsky, and Michael Karin. JNK1 in Hematopoietically Derived Cells Contributes to Diet-Induced Inflammation and Insulin Resistance without Affecting Obesity. Cell Metabolism published online.
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