A New Target for Outsmarting Obesity

01/03/2019

Understanding how fat cells use energy is an area of great interest to obesity and metabolism researchers. Adipocyte (fat cell) metabolism is a complex process that involves many different proteins with various physiological functions. One such regulatory function being studied is called protein phosphorylation.

Phosphorylation involves a chemical change to a protein; specifically, the addition of a phosphate group to an amino acid. It is an essential biological event that influences how proteins function in the body. Phosphorylation is an extremely common, but complex, phenomenon. Understanding the mechanisms behind it helps us to understand how proteins behave and sometimes contribute to disease, including obesity.

Enzymes called kinases control phosphorylation and facilitate the transfer of phosphates to target proteins. Despite the abundance of kinases, relatively little is known about how they select and bind to these proteins. The process is particularly puzzling to researchers when phosphorylation happens multiple times and at different sites within the same target protein.

A research team led by Paul Fox, PhD, has helped to elucidate how multisite phosphorylation alters fat cell metabolism via a kinase called S6K1. They published new findings in Molecular Cell showing that the presence of insulin around adipocytes changes S6K1’s phosphorylation patterns. These chemical changes cause S6K1 to gain affinity for certain proteins. The new target proteins are phosphorylated, altering a complex, multi-step cascade of metabolic events inside the fat cell that influences the synthesis of new fat molecules.

More data is needed to verify the physiological effects of these changes, but this study suggests that manipulating the process could have benefits in reducing insulin-stimulated fat cell metabolism. “Our data suggest that the S6K1 pathway is a novel, attractive target for therapeutic development,” Dr. Fox said. “Our next steps are to clarify the finer mechanistic points of the pathway to narrow the focus of future anti-obesity drug discovery.” Importantly, the Fox laboratory has shown the same kinases are involved in the aging process, and new drugs could both prevent obesity and increase healthspan.

Dr. Fox is a Staff member of the Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, and holds the Robert Canova Endowed Chair in Inflammation Research.

Abul Arif, PhD, who recently moved from the Fox laboratory to the Emory School of Medicine, was first author of the study. The research was funded by Dr. Fox’s NIH grants P01 HL029582, P01 HL076491 and R01GM086430, and by a Scientist Development Grant from the American Heart Association, National Affiliate to Dr. Arif.