Brown adipose tissue uncoupling proteins

Because the rate of the ETC increases, with no ATP synthesis, energy is released as heat. Important uncouplers include 2,4-dinitrophenol (2,4-DNP) and aspirin (and other salicylates). Brown adipose tissue contains a natural uncoupling protein (UCP, formerly called thernio-genin), which allows energy loss as heat to maintain a basal temperature around the kidneys, neck, breastplate, and scapulae in newborns. 

In order to provide heat when it is required to maintain or increase body temperature, a mechanism must exist for the regulation of the activity of this uncoupling protein. The mechanism has been established by following the principles described in Chapter 3. The properties of the uncoupling protein are studied using mitochondria isolated from brown adipose tissue in vitro (as described in Appendix 9.9). 

The properties are as follows, (i) The activity of the protein (i.e. the inward transport of protons) is inhibited by ATP. (ii) The activity of the protein is increased by the presence of long-chain fatty acids, since they relieve the ATP inhibition, (iii) When mitochondria, isolated from brown adipose tissue, are incubated in the presence of fatty acids, there is a sharp increase in the rates of electron transfer, substrate utilisation and oxygen consumption, whereas the rate of ATP generation remains low. These studies indicate that the rate of proton transport, by the uncoupling protein, depends on the balance between the concentrations of ATP and fatty acids, (iv) In adipocytes isolated from brown adipose tissue, the rate of oxygen consumption (i.e. electron transfer) is increased in the presence of catecholamines. 

Figure 9.29 Control of heat production in brown adipose tissue. Catecholamines increase cyclic AMP concentrab on which stimulates triacylglycerol lipase which increases the long-chain fatty acid level, which increases the fluxes through P-oxidation and the Krebs cycle, and the activity of the uncoupling protein. Uncoupling decreases the ATP concentration which further increases the activity of the uncoupling.

Klingenberg, M. Huang, S.-G. (1999) Structure and function of the uncoupling protein from brown adipose tissue. Biochim. Biophys. Acta 1415, 271-296. 

Freake, H.C. (1998) Uncoupling proteins beyond brown adipose tissue. Nutr. Rev. 56, 185-189. 

It has been suggested that brown adipose tissue may also function to convert excess dietary fat into heat and thereby to resist obesity.k m Mice lacking the gene for the mitochondrial uncoupling protein are cold-sensitive but not obese. However, other proteins, homologous to UCP1, have been discovered. They may partially compensate for the loss.m,h... 

With our present understanding, the thermogenic qualities of brown adipose tissue mitochondria are a consequence of the existence in the mitochondrial inner membrane of a polypeptide, thermogenin, uniquely [13-15] found in brown adipose tissue. (For technical and historical reasons, thermogenin is also known under several other names, such as the GDP-binding protein, the 32000 protein, the purine-nucleotide-binding protein (NbP), the uncoupling protein (UCP), the proton conductance pathway, etc.)... 

Tray hum, P. (1996). Uncoupling protein in brown adipose tissue. tfiocheTn. Stx. Tfaim. 24, 402-106. 

In the neonate, neural NE promotes nonshivering thermogenesis, i.e., heat production via stimulation of lipolysis and fatty acid oxidation in brown adipose tissue ( 63) with the support of thyroid hormone. Brown adipose tissue contains a high density of mitochondria with an uncoupling protein that allows the cells to oxidize fatty acids and generate heat as a major product NE released at nerve endings stimulates cAMP-mediated lipolysis in these cells and promotes thermogenesis by this y83-mechanism (Chapter 14). 

The entire process of heat generation from brown fat, called nonshivering thermogenesis, is regulated by norepinephrine. (In shivering thermogenesis, heat is produced by nonvoluntary muscle contraction.) Norepinephrine, a neurotransmitter released from specialized neurons that terminate in brown adipose tissue, initiates a cascade mechanism that ultimately hydrolyzes fat molecules. The fatty acid products of fat hydrolysis activate the uncoupler protein. Fatty acid oxidation continues until the norepinephrine signal is terminated or the cell s fat reserves are depleted. 

NPY injection into the PVN of the hypothalamus causes a decrease in brown adipose tissue (BAT) thermogenesis as indicated by the measurement of BAT mitochondrial GDP binding and uncoupling protein mRNA (Billington et al., 1991, 1994). This occurs even when NPY-treated animals are pair-fed, which involves allowing... 

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