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FOR IMMEDIATE RELEASE
APRIL 30, 1997
BAR HARBOR -- Unexpected results from an experiment at The Jackson Laboratory designed to probe the role of a protein implicated in human obesity will help researchers identify the complex thermogenic mechanisms that control regulation of body weight.
The results are reported in the May 1 issue of the British journal Nature by Leslie P. Kozak, Senior Staff Scientist at The Jackson Laboratory, and his colleagues. Title of the report is "Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese."
Co-authors include Elizabeth M. Simpson and Carmen Guerra, both of The Jackson Laboratory; Mary-Ellen Harper, University of Ottawa; and former Jackson Lab researchers Sven Enerback (University of Goteborg, Sweden), Anders Jacobsson (Stockholm University, Sweden), and Hitoshi Yamashita (National Defense Medical College, Japan).
The scientists built on research conducted at the Laboratory by Dr. Kozak into the mitochondrial uncoupling protein (UCP1). The only known function of UCP1 in mice is the production of heat by "nonshivering" thermogenesis in so-called brown fat. Several species of mammals, including humans, have an abundance of brown fat as newborns to protect them from cold before their body mass and metabolic systems are fully developed.
To further investigate the role of UCP1 in energy balance, Dr. Kozak and his colleagues specifically inactivated the UCP1 gene in their transgenic mouse model. A previous experiment in which UCP1 was overexpressed in brown fat had yielded the expected result of reduced obesity. Now, the scientists fully expected to observe in the UCP-deficient mouse an increase in obesity and/or overeating behavior.
Instead, the experiment reported in Nature showed a "striking resistance" to obesity and overeating in the UCP-deficient mice. However, the mice were very sensitive to cold, indicating a defect in thermoregulation.
"What we've identified is an important pathway for the regulation of body temperature, but surprisingly it's not directly associated with mechanisms controlling body weight," said Dr. Kozak. "It suggests that there must be other mechanisms that are able to compensate for UCP1 loss, and underscores the complexity of body weight regulation."
One candidate is UCP2, a recently described homologue of UCP1 that is broadly expressed in different mouse tissues, including brown fat. The discovery of UCP2 has generated enormous interest in the obesity field because it could provide a mechanism for reducing obesity by stimulating thermogenesis in a number of target tissues.
Dr. Kozak and his colleagues have initiated experiments to construct mouse models in which the UCP2 gene is overexpressed in brown fat or inactivated in the absence of UCP1 expression, to determine whether UCP2 is indeed a thermogenic protein. These transgenic mice will enable the team to rigorously determine the role of UCP2 in energy expenditure and obesity.
