June 18, 2003
La Jolla, CA – A cellular receptor that helps tailor responses to stress also keeps the body lean despite high-fat diets, a Salk Institute research team has found. But this leanness only appears under certain conditions, including a high-fat diet.
This receptor is a component of the body’s response to stress. While the findings suggest a possible new avenue for finding treatments for obesity and such associated diseases as heart disease, diabetes and stroke, this role of the receptor has only been studied in experimental rodents. The study appears in the June issue of Endocrinology.
Wylie Vale, professor, and Tracy Bale, a postdoctoral fellow in the of peptide biology laboratories at the Salk Institute and colleagues at the Salk, the Scripps Research Institute and the University of Alabama at Birmingham, found that, despite a high-fat diet, mice that lacked the receptor CRFR2 had more body muscle and less fat, and showed a less harmful response to processing sugar than normal mice.
“The mice bred with missing receptors showed a healthier response to such stresses as high-fat diets or cold environments, but we observed in earlier experiments that they were more anxious than normal,” said Vale. “This study indicates that we may be able to design treatments that prevent or treat obesity, but such treatments will have to determine a way to not upset the optimal sensitivity to stress. Any possible treatment, of course, will come only after years of research in the laboratory before it is ready to test with humans.”
The researchers found that mice on high-fat diets and missing CRFR2 had lower percentages of body fat, higher percentages of muscle mass, and lower levels of potentially harmful triglycerides and cholesterol in their blood when compared to mice that had CRFR2s. This occurred despite the fact that mice with the missing receptor actually ate more than the normal mice and gained about as much weight.
The mutant mice had smaller fat cells than the normal mice, were better able to handle large doses of sugar in the blood and were more sensitive to the sugar-processing actions of insulin.
The researchers also found that other kinds of stress besides a high-fat diet produced the same results in the mutated mice. For example, exposure to an hour of cold (39.2° F) temperatures resulted in lower fat levels and higher fat burning among the mutant mice. Mice on low-fat diets showed no differences in fat burning or body composition between mutant and normal forms.
Throughout the experiments, the leaner, mutant mice were more anxious than the normal mice. The researchers believe this is due to the interactions between the CRFR2 and its sibling receptor, CRFR1. A stress hormone called CRF, short for corticotropin releasing factor, activates CRFR1, while related hormones, called Urocortins, act on CRFR2. CRF, which Vale and his colleagues at the Salk isolated in 1981, is a key regulator of energy balance and of the body’s response to stress (Urocortins were identified later, also at the Salk).
This hormone works through the first CRF receptor, CRFR1, and activates a cascade of endocrine events that begin in the brain’s hypothalamus, travel down through the pituitary gland and end in the adrenal glands above the kidneys. This cascade forms the crux of the body’s hormonal response to stress. CRFR2, the researchers believe, helps “put the brakes” on CRFR1, reducing anxiety while still maintaining the body’s ability to handle such stresses as cold, heat, and high-fat intake.
“The CRFR2-mutant mice were better able to burn and utilize fat stores, indicating that an increased sensitivity to outside stress enhanced their ability to stay lean,” said Bale. “Clearly, this indicates a certain amount of stress is beneficial to healthy fat storage, and may help with designing therapies to combat obesity, heart disease and diabetes.”
About 65 percent of people in the United States are estimated to be overweight, and about 30 percent obese. Obesity has been linked to heart disease, currently the number one killer of Americans, as well as diabetes and stroke.
Vale’s colleagues included Kuo-Fen Lee and Keith Anderson of the Salk Institute, Amanda Roberts of the Scripps Research Institute and Tim Nagy of the University of Alabama, Birmingham.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.