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I need help answering the questions 1-6 at the end of this case study . Case 23 The Role of Uncoupling Proteins in Obesity Focus concept The

I need help answering the questions 1-6 at the end of this case study.


Case 23

The Role of Uncoupling Proteins in Obesity


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 UCP1 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 UCP1 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 UCP1 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 UCP1 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 UCP1 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.

1


Questions

1. Why is it that heat is produced when the UCP1 protein uncouples oxidative phosphorylation from electron transport?


2. The compound 2,4-dinitrophenol (DNP) also causes uncoupling of oxidative phosphorylation and electron transport. DNP is lipid soluble and literally dissolves in the inner mitochondrial membrane. Its structure is shown in Figure 23.1. It has an acidic phenolic hydrogen which is lost in the somewhat higher pH environment of the mitochondrial matrix. The resonance stabilized anion that results is more lipid soluble than a fully charged ion would be and also has the ability to cross the inner mitochondrial membrane.

a. Describe the mechanism of the uncoupling.

b. DNP has been used in the past as a weight-loss aid, but it proved to be toxic and even caused a

few deaths before it was taken off the market. Why might someone with a limited knowledge of biochemistry think that DNP would be an effective diet aid? Why did the compound eventually cause death in some of the people who took it?

Cytosol (low pH)

OH

H+

Matrix (high pH)

O- O O

NO2 NO2- NO2

    NO2

      H+

 NO2

NO2

NO2 NO2-

Figure 23.1: The lipid compound 2,4-dinitrophenol is also a weak acid.


3. In their study, the investigators injected a β-3 adrenergic agonist which stimulated UCP1 in adipose tissue. When they injected the agonist into normal mice, they noted that oxygen consumption increased over two-fold. But when the agonist was injected into knockout mice, oxygen consumption increased only slightly. Explain these results.


4. The investigators who produced the UCP1 knockout mice noted that the knockouts were normal in every way except that there was increased lipid deposition in their adipose tissue. Explain why.


5. The investigators carried out an experiment in which normal mice and UCP1 knockout mice were placed in a cold (5°C) room for 24 hours. The normal mice were able to maintain their body temperature at 37°C even after 24 hours in the cold. But when the knockout mice were placed in a cold room, their body temperature decreased 10°C or more. Explain.


6. Investigators wanted to know whether UCP1 synthesis could be induced by overeating, and if so, if it could be involved in burning excess fat such that an organism's adipose tissue content remained 2 relatively constant. Along these lines, it was assumed that UCP1 knockout mice, unable to synthesize UCP1, would become obese if fed a high fat diet. Interestingly, knockout mice did not become obese even when fed a high fat diet. Instead, overfeeding caused the synthesis of a second protein to be induced. Separate experiments indicated that this second protein was also able to uncouple oxidative phosphorylation, and this protein was given the name UCP2. How would the induction of UCP2 help animals maintain a constant amount of adipose tissue?

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