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Harvard study finds inflammation-fighting pathway in fat cells
06-12-2008
by Amy Swinderman  |  Email the author
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BOSTON—Scientists from the Harvard School of Public Health (HPSH) recently reported they have identified a new molecular signaling pathway in body fat cells that suppresses harmful inflammation, a discovery that could lead to the development of drugs that would fight inflammation and reduce the risk of insulin resistance, diabetes or other ailments.

In a study published June 3 in the journal Cell Metabolism, researchers said they have shown that fat-storing cells, or adipocytes, contain a protective anti-inflammatory immune mechanism that prevents the cells from overreacting to inflammation-causing stimuli, such as fatty acids in the diet. The signaling pathway serves as a natural counterbalance to a parallel signaling chain that promotes inflammation and can lead to insulin resistance—a prelude to diabetes—and other ailments such as heart disease, said the authors.

The study, led by senior author Chih-Hao Lee, assistant professor of Genetics and Complex Diseases at HSPH, and first author Kihwa Kang, a research fellow in the same department, adds a new element to the growing understanding of how obesity exerts its unhealthful effects through signals generated by adipocytes. Until now, the mechanisms controlling the activation of M2 macrophages, immune cells residing within fat tissues, had been unclear, as was whether adipocytes themselves controlled this process.

The researchers found that what activates the M2 pathway within fat tissues is the fat cells' production of "Th2" pro-inflammatory cytokines. A molecule known as PPAR-d receives the Th2 cytokine signals and turns on a cascade of genes and proteins that results in M2 macrophage activation.

To their surprise, Lee and his coworkers found that the same switching mechanism is present in hepatocytes, or liver cells, and macrophages in the liver, where they control metabolism of fats. Mice lacking PPAR-d developed the condition known as "fatty liver," which also occurs in humans who have metabolic disruption.

By boosting the protective side of the two-pronged mechanism, it may be possible to develop drugs that more strongly suppress inflammation and reduce the risk of these diseases, the scientists said.

"Here we show that adipocytes are a source of Th2 cytokines, including IL-13 and to a lesser extent IL-4, which induce macrophage PPARδ/β (Ppard/b) expression through a STAT6 binding site on its promoter to activate alternative activation. Co-culture studies indicate that Ppard ablation renders macrophages incapable of transition to the M2 phenotype, which in turns causes inflammation and metabolic derangement in adipocytes. Remarkably, a similar regulatory mechanism by hepatocyte-derived Th2 cytokines and macrophage PPARδ is found to control hepatic lipid metabolism. The physiological relevance of this paracrine pathway is demonstrated in myeloid-specific PPARδ−/− mice, which develop insulin resistance and show increased adipocyte lipolysis and severe hepatosteatosis. These findings provide a molecular basis to modulate tissue-resident macrophage activation and insulin sensitivity," the researchers wrote.

The study, Adipocyte-Derived Th2 Cytokines and Myeloid PPARd Regulate Macrophage Polarization and Insulin Sensitivity, was supported by NIH grants, the American Heart Association and the American Diabetes Association.
 

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