RAISING AT THERMONEUTRALITY PREVENTS OBESITY AND HYPERPHAGIA IN BAT-ABLATED TRANSGENIC MICE

Transgenic mice with ablation of brown adipocytes induced by brown adi pocyte-specific expression of diphtheria toxin A chain (DTA) driven by the uncoupling protein (UCP) promoter (UCP-DTA mice) become obese and hyperphagic (Lowell, B. B., V. S. Susulic, A. Hamann, J. A. Lawitts, J. Himms-Hagen, B. B. Boyer, L. P. Kozak, and J. S. Flier. Nature 366: 740-742, 1993). A deficit in energy expenditure for brown adipose tis sue (BAT) thermogenesis in these mice is presumed to contribute to the development of obesity. The objective of the present study was to obv iate any deficit in BAT thermogenesis by raising transgenic and contro l mice at thermoneutrality (35 degrees C), where both would have equal ly inactive BAT, to see whether this would prevent the obesity and the hyperphagia. Transgenic and control mice were raised from weaning (3 wk of age) to 8 wk of age at either 24 or 35 degrees C. Raising at 35 degrees C completely prevented development of obesity of UCP-DTA mice, as indicated by their normal carcass fat, normal weights of four majo r white adipose tissue depots, and normal size of white adipocytes. As seen before, transgenic mice raised at 24 degrees C had excess weight gain by 6 wk of age and by 8 wk had doubled carcass fat, an obesity c haracterized by increased white adipocyte size with no increase in num ber of adipocytes. The treatment also prevented hyperphagia of UCP-DTA mice, consistent with the hypothesized role of BAT thermogenesis in c ontrol of thermoregulatory feeding (Himms-Hagen, J. Proc. Sec. Exp. Bi ol. Med. 208: 159-169, 1995). UCP-DTA mice thus differ from geneticall y obese mice (oblob, db/db) for which raising at thermoneutrality is k nown not to prevent either the obesity or the hyperphagia. Both the ob esity and the hyperphagia of UCP-DTA mice appear to be due to their de ficit in BAT thermogenesis.