The role of proteins in fat breakdown
A study conducted by Ruth Birner-Grünberger, biochemist at the Medical University of Graz, and supported by the Austrian Science Fund (FWF), investigated the complex interaction of activation and regulation in fat breakdown.
When we exercise continuously at a low pulse rate, lipolysis (the breakdown of stored fat) starts after about 30 minutes. The same thing happens when we are hungry: the fat cells receive a hormonal signal telling them to make a depot available and break down the stored lipid droplets into fatty acids. A study conducted by Ruth Birner-Grünberger, biochemist at the Medical University of Graz, and supported by the Austrian Science Fund (FWF), investigated the complex interaction of activation and regulation in fat breakdown.
Birner-Grünberger set out to study three things: which proteins are involved in fat burning, where their interaction in fat cells occurs, and how they are mobilized or inhibited. In preliminary studies, she discovered several lipases (proteins that break down fat) and other proteins that regulate the process. Particularly striking for the researchers was the amount of phosphorylation they found. Phosphorylation is a chemical modification that binds phosphates to proteins and thereby serves to activate or inhibit proteins in cells.
The research project was designed to answer the question as to when and where chemical modifications unlock or inhibit the proteins involved in lipolysis. In vitro studies were not sufficient, however, to explain the interaction of the lipolytic proteins. Success was achieved only when the scientists observed animal cells by means of a confocal laser-scan microscope. To get an adequate amount and quality level of protein for the test series, Birner-Grünberger collaborated with Monika Oberer, structural biologist at the University of Graz, and Dawn Brasaemle, cell biologist at Rutgers University.
This led to the discovery of the first steps of spatial and chemical interaction on the fat droplets in tissue cells. In order to activate the first (of three) lipases, one needs a chain of command including the activator CGI58 and the regulator perilipin. When the fat cells are in a basal state, the two proteins are sitting on the lipid droplet bound together. Upon marking with phosphate, the proteins separate and CGl58 travels to another spot on the droplet in order to activate the first lipase (ATGL). As a regulator, perilipin prevents the lipases from being activated when they are not required.
Birner-Grünberger is planning a follow-up project during which she intends to use phosphoproteomics (the global analysis of thousands of protein phosphorylation processes in cells) to understand which energetic processes are regulated simultaneously with lipolysis, such as glycogen degradation, and to observe the temporal sequence.