A. Melnyk et al., RAISING AT THERMONEUTRALITY PREVENTS OBESITY AND HYPERPHAGIA IN BAT-ABLATED TRANSGENIC MICE, American journal of physiology. Regulatory, integrative and comparative physiology, 41(4), 1997, pp. 1088-1093
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.