Protective mechanism fails when obesity sets in

Scientists have discovered a previously unknown molecular signaling pathway in body-fat cells that normally acts to suppress harmful inflammation. Cellular stress caused by obesity, however, can override this protective function and convert the pathway into a trigger of chronic inflammation that raises the risk of insulin resistance, diabetes, and other metabolic disorders.

Reporting in the journal Cell Metabolism, researchers from the Harvard School of Public Health (HSPH) said they have shown for the first time 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.

This 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. Chih-Hao Lee, assistant professor of genetics and complex diseases at HSPH, was the senior author. Kihwa Kang, research fellow in the HSPH Department of Genetics and Complex Diseases, was first author.

The dueling pathways maintain a healthy balance — but only up to a point. “Overt obesity eventually overwhelms the protective effect of this pathway and flips it into the pro-inflammatory pathway,” said Lee.

The scientists also identified the molecular switch that determines which pathway is activated under different conditions. It may be possible, they suggest, to develop drugs that would boost the protective side of the two-pronged mechanism to more strongly suppress inflammation and reduce the risk of insulin resistance, diabetes, or other ailments.

In identifying the compensatory pathway and molecular switch, the scientists have added a new element to the growing understanding of how obesity exerts its unhealthful effects through signals generated by adipocytes.