Abstract
Transgenic mice with ablation of brown adipocytes induced by brown adipocyte-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 tissue (BAT) thermogenesis in these mice is presumed to contribute to the development of obesity. The objective of the present study was to obviate any deficit in BAT thermogenesis by raising transgenic and control mice at thermoneutrality (35 degrees C), where both would have equally 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 major 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 characterized by increased white adipocyte size with no increase in number of adipocytes. The treatment also prevented hyperphagia of UCP-DTA mice, consistent with the hypothesized role of BAT thermogenesis in control of thermoregulatory feeding (Himms-Hagen, J. Proc. Soc. Exp. Biol. Med. 208: 159-169, 1995). UCP-DTA mice thus differ from genetically obese mice (ob/ob, db/db) for which raising at thermoneutrality is known not to prevent either the obesity or the hyperphagia. Both the obesity and the hyperphagia of UCP-DTA mice appear to be due to their deficit in BAT thermogenesis.
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