Daniele Piomelli, professor of psychiatry and pharmacology, and colleagues found that the fatty acid, called OEA (oleylethanolamide), activates its cell receptor molecules to regulate hunger and metabolism. The team also discovered that by increasing OEA levels while maintaining normal levels of these cell receptors, they could reduce appetite and weight in rodents, as well as lower their blood cholesterol and triglyceride levels.
The study appears in the Sept. 4 issue of Nature. "In earlier studies, we found that OEA can be an important regulator of eating behavior, but we didn't know how it worked," Piomelli said. "We were excited to find that OEA activates cell receptors that have already been the focus of successful drug development. This gives us hope for a new class of anti-obesity drugs based on natural chemicals."
To test the role of OEA and its receptors, Jin Fu, Silvana Gaetani, Fariba Oveisi and Jesse Lo Verme on the Piomelli team fed a high-fat diet to two groups of mice - one a group of regular mice, the other a mutant group with its OEA cell receptors genetically removed. After the mice became obese, they were treated with OEA for four weeks. Normal mice ate less and lost weight, while OEA had no effect on the group that lacked the cell receptors, suggesting that OEA only can reverse weight gain when active cell receptors are in place.
They also found that in normal mice, OEA lowered blood cholesterol and triglyceride levels by reducing levels of hunger-inducing nitric-oxide molecules. These reductions were not seen in the mutant mice group.
"This shows the receptors are not only necessary for the hunger-curbing and weight-reducing actions of OEA, but may contribute to the overall stability and maintenance of our feeding system," Piomelli said.
Piomelli believes OEA is attractive for drug development because it is a fatty acid naturally produced in the body and could be safer than current drugs when used as a long-term therapy for obesity.
"There are many drugs being tested for obesity in current clinical trials, but most don't succeed because they are not well tolerated by patients," Piomelli said. "As an endogenous compound, OEA has the potential for being much less toxic than other man-made compounds."
Nearly 30 percent of Americans are obese, according to the Centers for Disease Control, which has declared obesity an epidemic disease. The occurrence of obesity has risen by almost 60 percent since 1991. Obesity greatly increases the risk of premature death and diseases such as diabetes, heart disease, stroke and some cancers.
Piomelli's other colleagues in the study include Fernando Rodríguez de Fonseca and Antonia Serrano of the Fundacion Hospital Carlos Haya in Malaga, Spain; Barbara Di Giacomo and Giorgio Tarzia of the University of Urbino in Italy; and Anja Rosengarth and Hartmut Luecke of UCI.
The study was funded by the National Institute of Drug Abuse. UCI has filed several patents covering various aspects of this technology.
About OEA and its cell receptors
OEA belongs to a group of chemicals called fatty acid ethanolamides, fats that are produced in response to metabolic stimuli and nervous system activity. OEA is related to a neurotransmitter known as anandamide, which is similar to marijuana's active ingredient and controls a number of nervous system functions. When food is ingested, OEA is manufactured in the small intestine, where it finds nerve endings that carry its hunger-curbing message to the brain. The Piomelli team found that OEA compounds bind with a member of the peroxisome proliferatory-activated receptor (PPAR) family. OEA specifically activates the PPAR-alpha receptor, which sets off the body's metabolism of fats.
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