All in the enzymes
For Dr. David Brindley, obesity is in the enzymes. The University of Alberta biochemistry professor is known for his work in understanding the regulation of an enzyme called phosphatidate phosphatase (PAP). At the outset of his career in the 1970s, Dr. Brindley was convinced that PAP was one of the most important enzymes that regulate triglycerides (the form in which most fat exists in food as well as in the body). Excessive storage of triglycerides in fat tissue is responsible for obesity. Dr. Brindley's research has focused on factors that influence triglyceride biosynthesis, transport, storage, and oxidation.
He worked in this area for more than 20 years but abandoned the research after it proved impossible to determine the structure of PAP. The situation changed dramatically in 2006 when a yeast enzyme was identified with a similar structure. This development rekindled Dr. Brindley's interest in PAP enzymes. Soon after, he was able to show that three particular enzymes in mammals, called lipins, are indeed PAP enzymes.
Lipins are of great interest because they are necessary for synthesizing and storing fats, mainly triglycerides, as well as for stimulating the production of enzymes involved in fat oxidation (burning fats as fuel in cells). One of Dr. Brindley's collaborators, Dr. Karen Reue at UCLA, found that increased lipin expression in muscles leads to obesity and insulin resistance. (Insulin resistance is a condition where the body produces insulin but does not respond to it properly, which leads to diabetes.) On the other hand, if lipin expression increases in fat tissue, animals get fat but do not become insulin resistant and diabetic. Conversely, animals that do not express one of the lipins, lipin-1, are unable to make any fat tissue at all. Other work demonstrates that variations in lipin-1 expression and differences in the structure of lipin-1 in humans are associated with changes in insulin sensitivity, metabolic rate, and blood pressure. "There are so many connections between diabetes, obesity, and lipin-1, it is obviously a very key enzyme," says Dr. Brindley.
"As a result of the renewed interest in lipins, we now have an entirely different view of triglyceride synthesis and fat oxidation. The old view was that these processes were antagonistic—either fats were stored, or they were oxidized. Now we see that the storage and oxidation of triglycerides is coordinated, and lipins help to promote both pathways. That makes the lipins a potential target for drugs. I emphasize 'potential' because there are three lipins, and we don't fully know what their individual functions are, how each is regulated, or what the consequences of regulation are. Once we understand that, we might be able to figure out why some people are predisposed to obesity and how to overcome it."