BOSTON—Scientists from the Harvard School of Public Health(HPSH) recently reported they have identified a new molecular signaling pathwayin body fat cells that suppresses harmful inflammation, a discovery that couldlead to the development of drugs that would fight inflammation and reduce therisk of insulin resistance, diabetes or other ailments.
In a study published June 3 in the journal Cell Metabolism, researchers said theyhave shown that fat-storing cells, or adipocytes, contain a protectiveanti-inflammatory immune mechanism that prevents the cells from overreacting toinflammation-causing stimuli, such as fatty acids in the diet. The signalingpathway serves as a natural counterbalance to a parallel signaling chain thatpromotes inflammation and can lead to insulin resistance—a prelude todiabetes—and other ailments such as heart disease, said the authors.
The study, led by senior author Chih-Hao Lee, assistantprofessor of Genetics and Complex Diseases at HSPH, and first author KihwaKang, a research fellow in the same department, adds a new element to thegrowing understanding of how obesity exerts its unhealthful effects throughsignals generated by adipocytes. Until now, the mechanisms controlling theactivation of M2 macrophages, immune cells residing within fat tissues, hadbeen unclear, as was whether adipocytes themselves controlled this process.
The researchers found that what activates the M2 pathwaywithin fat tissues is the fat cells' production of "Th2" pro-inflammatorycytokines. A molecule known as PPAR-d receives the Th2 cytokine signals andturns on a cascade of genes and proteins that results in M2 macrophageactivation.
To their surprise, Lee and his coworkers found that the sameswitching mechanism is present in hepatocytes, or liver cells, and macrophagesin the liver, where they control metabolism of fats. Mice lacking PPAR-ddeveloped the condition known as "fatty liver," which also occurs in humans whohave metabolic disruption.
By boosting the protective side of the two-prongedmechanism, it may be possible to develop drugs that more strongly suppressinflammation 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 activatealternative activation. Co-culture studies indicate that Ppard ablation rendersmacrophages incapable of transition to the M2 phenotype, which in turns causesinflammation and metabolic derangement in adipocytes. Remarkably, a similarregulatory mechanism by hepatocyte-derived Th2 cytokines and macrophage PPARδis found to control hepatic lipid metabolism. The physiological relevance ofthis paracrine pathway is demonstrated in myeloid-specific PPARδ−/− mice, whichdevelop insulin resistance and show increased adipocyte lipolysis and severehepatosteatosis. These findings provide a molecular basis to modulatetissue-resident macrophage activation and insulin sensitivity," the researcherswrote.
The study, Adipocyte-DerivedTh2 Cytokines and Myeloid PPARd Regulate Macrophage Polarization and InsulinSensitivity, was supported by NIH grants, the American Heart Associationand the American Diabetes Association.
