Knockout Mice Document the Function of Brown Fat

Molecular genetic tools have been used to produce laboratory mice that cannot synthesize the type of mitochondrial protein, uncoupling protein 1 (UCP1), that mediates nonshivering thermogenesis (NST). The gene coding for UCP1 is inactivated in these mice. As explained in Box Extension 11.1, research using these knockout mice has provided strong support for two critical concepts: (1) brown fat is the sole tissue in which NST occurs, and (2) UCP1 is the only molecular form of UCP that mediates NST.

Adult mice knocked out for UCP1 can be acclimated to live at 4°C, a temperature that is chilly for the mice and at which—to maintain high body temperatures—they raise their metabolic rates to be four times higher than their basal metabolic rates. Available evidence indicates, however, that in these mice, shivering is the sole mechanism by which heat production is elevated. This discovery—that the knockout mice depend entirely on shivering—greatly bolsters the view that, at least in laboratory mice, brown fat is the only tissue that carries out NST. UCP1 essentially occurs only in brown fat. Brown fat NST is thus specifically eliminated by knocking out UCP1. If there were other tissues that carried out NST besides brown fat, they would presumably be able to produce heat by NST even without UCP1. The fact that the knockout mice show no NST indicates, therefore, that such alternative sites of NST do not occur: Brown fat is the exclusive site of NST.

Besides UCP1, two other molecular forms—intraspecific homologs—of uncoupling protein are known, UCP2 and UCP3. These other forms occur in the mitochondria of a wide variety of tissues, including the skeletal muscles, lungs, spleen, and brain. The question arises of whether UCP2 and UCP3 can uncouple oxidative phosphorylation—and thereby mediate NST—in the same way as UCP1 does. The knockout mice we have been discussing provide a direct answer to this question because they lack only UCP1; they are not knocked out for UCP2 or UCP3. The fact that the knockout mice thermoregulate in cool environments entirely by use of shivering and do not exhibit NST provides evidence that UCP2 and UCP3 do not mediate NST. This conclusion is bolstered by studies of other mice in which UCP2 or UCP3 is knocked out. NST is not impaired in such mice, indicating again that UCP2 and UCP3 are not involved in NST.