PHYSIOLOGY OF TRANSGENIC MICE WITH BROWN FAT ABLATION - OBESITY IS DUE TO LOWERED BODY-TEMPERATURE

We investigated the physiological basis for development of obesity in uncoupling protein-diphtheria toxin A chain (UCP-DTA) transgenic mice. In these mice the promoter of the brown adipose tissue (BAT)-specific UCP was used to drive expression of DTA, resulting in decreased BAT f unction and development of obesity and insulin resistance (Lowell, B. B., S. V. Susulic, A. Hamann, J. A. Lawitts, J. Himms-Hagen, B. B. Foy er, L. Kozak, and J. S. Flier. Nature 366: 740-742, 1994). In adult UC P-DTA mice, we measured food intake and food assimilation, locomotor a ctivity, metabolic rate, and body temperature in comparison to control animals. No differences could be observed in food intake or assimilat ion and locomotor activity. Weight-specific metabolic rates at tempera tures between 20 and 37 degrees C, however were consistently lower in transgenic mice. Continuous telemetric recording of core body temperat ure showed that transgenic mice displayed a downshift in body temperat ure levels of similar to 0.9 degrees C. In summary, we provide evidenc e that attenuated body temperature levels alone can be responsible for development of obesity and that BAT thermogenesis is a major determin ant of body temperature levels in rodents.