Brown-fat tissue, whose color is due to the presence of abundant mitochondria, is specialized for the generation of heat. In contrast, white-fat tissue is specialized for the storage of fat and contains relatively few mitochondria.
The inner membranes of brown-fat mitochondria contain thermogenin, a protein that functions as a natural uncoupler of oxidative phosphorylation and generation of a proton motive force. Thermogenin, or UCP1, is one of several un coupling proteins (UCPs) found in most eukaryotes (but not in fermentative yeasts). Thermogenin dissipates the proton motive force by rendering the inner mitochondrial mem brane permeable to protons. As a consequence, the energy released by NADH oxidation in the electron-transport chain and used to create a proton gradient is not then used to syn thesize ATP via ATP synthase. Instead, when protons move back into the matrix down their concentration gradient via thermogenin, the energy is released as heat. Thermogenin is a proton transporter, not a proton channel, and shuttles protons across the membrane at a rate that is 1-million- fold slower than that of typical ion channels. Thermogenin is similar in sequence to the mitochondrial ATP/ADP transporter, as are many other mitochondrial transporter proteins that compose the ATP/ADP transporter family. Certain small-molecule poisons also function as un couplers by rendering the inner mitochondrial membrane permeable to protons. One example is the lipid-soluble chemical 2,4-dinitrophenol (DNP), which can reversibly bind to and release protons and shuttle them across the inner membrane from the intermembrane space into the matrix.
Environmental conditions regulate the amount of thermogenin in brown-fat mitochondria. For instance, when rats adapt to cold temperatures, the ability of their tissues to generate heat is increased by the induction of thermogenin syn thesis. In cold-adapted animals, thermogenin may constitute up to 15 percent of the total protein in the inner membranes of brown-fat mitochondria.
For many years, it was known that small animals and human infants expressed significant amounts of brown fat, but there was scant evidence for it playing a significant role in adult humans. In the newborn human, thermogenesis by brown-fat mitochondria is vital to survival, as it is in hibernating mammals. In fur seals and other animals naturally acclimated to the cold, muscle-cell mitochondria contain thermogenin; as a result, much of the proton-motive force is used for generating heat, thereby maintaining body temperature. Recently investigators have used sophisticated functional imaging methods (such as positron-emission tomography) to definitively establish the presence of brown fat in adult humans in the neck, clavicle, and other sites, the levels of which are significantly increased upon exposure to cold. Furthermore, detailed analyses of the biochemical properties and developmental origins of thermogenic fat cells have uncovered the existence of at least two subtypes of such cells: classic brown-fat cells that develop from precursor cells also used to generate skeletal muscle cells, and beige-fat cells whose detailed properties (gene expression pattern, responses to hormonal signals) differ from those of brown-fat cells. Further characterization of beige-fat cells and their influence on normal metabolism and disease may lead to new approaches to treat or prevent some metabolic disorders.
