Case 23 The Role of Uncoupling Proteins in Obesit Focus concept The properties o

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Case 23 The Role of Uncoupling Proteins in Obesit Focus concept The properties of adipose tissue factors that uncouple oxidative phosphorylation are discussed and possible links between uncoupling proteins and obesity are examined Prerequisites Electron transport and oxidative phosphorylation. Mechanisms of uncoupling agents, such as 2.4-dinitrophenol. Fatty acid oxidation. Background Hibernating animals and human infants contain brown fat deposits, so-called because of the presence of large numbers of mitochondria, the site of electron transport and oxidative phosphorylation. In brown fat, given the appropriate stimulus, oxidative phosphorylation and electron transport can be uncoupled, causing energy to be dissipated as heat. The protein responsible for the uncoupling is a brown fat inner mitochondrial membrane protein previously named UCP (for uncoupling protein), but now referred to as UCP1, since a second uncoupling protein has since been discovered. Previous experiments have shown that UCPI protects against cold and is involved in regulation of energy expenditure. The ability of UCP1 to stimulate the consumption of calories solely for the production of heat led some investigators to postulate that UCP1 was involved in regulating body weight. Scientists have always wondered why some people seem to be able to ingest a large number of calories without gaining weight, whereas others eat moderately but are obese. If the UCPI of brown fat were involved, scientists postulated that obese people would be efficient "burners", whereas humans of moderate weight might burn calories inefficiently, releasing a greater proportion of energy as heat. But the role of UCPI in humans has always been debated since infants contain a large amount of brown fat but mature adults do not. In order to examine the biochemical role of UCPI more fully, the investigators in this case worked with mice referred to as knockouts. Knockout mice have been genetically engineered such that the gene coding for a particular protein is missing. By examining the characteristics of knockout mice, the biochemical and physiological roles of a particular protein can be ascertained. The investigators produced UCP1-knockout mice that are missing the gene for the UCPl protein. They carried out experiments using these mice that are described below, studies that led to the discovery of a second uncoupling protein referred to as UCP2. The UCP2 protein may play a more significant role in obesity, since UCP2 is found in abundant amounts in white fat.

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Answer 5: Since the protein UCP1 is necessarily required to burn the body fat/adipose tissue, knockout mice will not be able to survive a drop in ambient temperature. On the other hand, the normal mice will be easily able to metabolize the stored body fat to maintain body temperuate by generating heat. This is why the core body temperature of normal mice was normal and knockout mice was much lower than normal when placed in a cold environment.

Answer 6: According to the information, the knockout mice developed expression of another type of uncoupling protein called UCP2. The expression of this protein helped the mice to maintain a core body weight even when the primary maintenance protein UCP1 was not present. .This suggests that unlike UCP1 (ubiquitously expressed protein), UCP2 is stress/stimulus induced in nature and thus exposure of these knockout mice to extreme stress/stimulus promoted expression of this protein. Consequently, this protein maintained the homeostasis as much as possible.

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