Uncoupling protein 4 (UCP-4)

Details Uncoupling protein 4 (UCP-4) Uncoupling protein 4 (UCP-4)

2001-06-27

2003-08-05

Eyler, Yvonne (Department: 1646)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

C530S350000, C530S333000

Reexamination Certificate

active

06602694

ABSTRACT:

FIELD OF THE INVENTION
A novel uncoupling protein, which we have designated UCP-4, that is expressed in various tissues, including brain, heart, pancreas, and muscle tissue, and nucleic acid molecules which encode said novel protein, are described. Methods of screening for compounds that regulate the expression and the activity of UCP-4 are described, as well as methods of treating diseases or conditions in which the regulation of thermogenesis, or respiratory ATP synthesis, is desired. Such conditions include obesity, diabetes, malignant hyperthermia, and fever. The construction of cell lines that express UCP-4 is also described.
BACKGROUND
Uncoupling protein (UCP-1; thermogenin) is a transmembrane proton-translocating protein present in the mitochondria of brown adipose tissue, a specialized tissue which functions in heat generation and energy balance (Nicolls, D. G., and Locke, R. M.,
Physiol. Rev
. 64:2-40, (1984); Rothwell,. N. J. and Stock, M. J.
Nature
, 281:31-35 (1979)). Mitochondrial oxidation of substrates is accompanied by proton transport out of the mitochondrial matrix, creating a transmembrane proton gradient. Re-entry of protons into the matrix via ATP synthase is coupled to ATP synthesis. However, UCP-1 functions as a transmembrane proton transporter, permitting re-entry of protons into the mitochondrial matrix unaccompanied by ATP synthesis. Environmental exposure to cold evokes neural and hormonal stimulation of brown adipose tissue, which increases UCP-mediated proton transport, brown fat metabolic activity, and heat production.
Recent studies with transgenic models indicate that brown fat and UCP-1 have an important role in energy expenditure in rodents. Transgenic mice in which brown adipocyte tissue was ablated by a toxin coupled to the UCP-promoter developed obesity and diabetes (Lowell, B. B., et al.,
Nature
, 366:740 (1993)). Obesity in these transgenic animals developed in the absence of hyperphagia, suggesting that the uncoupled mitochondrial respiration of brown fat is an important component of energy expenditure. In a separate transgenic mouse model, ectopic expression of UCP-1 in white adipose tissue of genetically-obese mice led to a significant reduction in body weight and fat stores (Kopecky J., et al.,
J. Clin. Invest
. 96:2914-23, (1995)). These studies indicate that activity of UCP-1 is accompanied by energy expenditure and weight loss in rodents.
Two other UCP proteins have recently been cloned. The first uncoupling protein-like protein (UCPL) or UCP-2, is expressed in multiple tissues, and is enriched in tissues of the lymphoid lineage (Fleury, C., et al.
Nature Genetics
, 15:269-272, (1997)). The second, UCP-3, is predominantly localized to skeletal muscle (U.S. Ser. No. 60,043,407, filed Apr. 4, 1997, U.S. Ser. No. 60/046,154, filed May 8, 1997, and PCT/US98/005892 filed Mar. 25, 1998, all of which are hereby incorporated by reference herein; Boss, O., et al., (
FEBS Lett
. 408:3942, 1997). UCP-3 has been found to be regulated by cold and thyroid hormone (Larkin, S., et al.,
Biochem. Biophys. Res. Comm
. 240:222-227, (1997)).
Thermogenic protein activity, such as that found with UCP-1, may be useful in reducing, or preventing the development of excess adipose tissue, such as that found in obesity. Obesity is becoming increasingly prevalent in developed societies. For example, approximately 30% of adults in the U.S. were estimated to be 20 percent above desirable body weight—an accepted measure of obesity sufficient to impact a health risk. (
Harrison's Principles of Internal Medicine
12
th Edition
, McGraw Hill, Inc. (1991) p. 411). The pathogenesis of obesity is believed to be multifactorial, but the basic problem is that in obese subjects food intake and energy expenditure do not come into balance until there is excess adipose tissue. Attempts to reduce food intake, or to decrease hypernutrition, are usually fruitless in the medium term because the weight loss induced by dieting results in both increased appetite and decreased energy expenditure. (Leibel et al.,
New England Journal of Medicine
322:621-28, (1995)). The intensity of physical exercise required to expend enough energy to materially lose adipose mass is too great for many obese people to undertake on a sufficiently frequent basis. Thus, obesity is currently a poorly treatable, chronic, essentially intractable metabolic disorder. In addition obesity carries a serious risk of co-morbities including, Type 2 diabetes, increased cardiac risk, hypertension, atherosclerosis, degenerative arthritis, and increased incidence of complications of surgery involving general anesthesia. An increased level in thermogenesis in obese individuals, or individuals with a predisposition toward obesity should help to reduce the level of adipose tissue, and therefore avoid the complications associated with obesity.
Too high of a level of thermogenesis may also be detrimental for certain individuals, thus a method of decreasing the level of thermogenesis in such individuals is desirable. It would be desirable, for example, to treat or prevent conditions such as malignant hyperthermia, which occurs in approximately 1 in 50,000 anesthetic procedures, and can have about a 70% mortality rate. Studies in pigs, which are susceptible to malignant hyperthermia, have suggested that it may be caused by inappropriate activation of a sarcoplasmic reticulum Ca+ release channel (the ryanodine receptor) which then acts in a positive feedback manner to further release intracellular calcium and, thus affecting myotonic contraction and thermal overload (Mickelson, J. R., and Louis, C. F.,
Physiol. Rev
. 76:537-92 (1996)). However, defects in the ryanodine receptor are found in only approximately 50% of patients with malignant hyperthermia (MacLennan, D. H.,
Curr. Opin. Neurol
. 8:397-401 (1995)). There is discord between actual incidence and predicted genetic susceptibility based upon detection of mutant ryanodine receptors in some, but not all humans with malignant hyperthermia (MacLennan, D. H.,
Curr. Opin. Neurol
., 8:397-401 (1995)). Four chromosomal loci linked to malignant hyperthermia have been identified in familiar studies, but for only one has the genetic defect been localized to mutations of a particular gene, the ryanodine calcium channel gene on chromosome 19 (Id.; Steinfath, M., et al.,
Anasthesiol. Intensivmed Notfallmed Schmerzther
31:334-43 (1996)). It would therefore be useful to identify the protein involved in human malignant hyperthermia, and to design methods of regulating its expression to prevent or treat malignant hyperthermia.
Another condition where thermogenesis is increased is in fever, an increase in body temperature in response to infection or inflammation. Fever is observed not only in mammals and birds (warm-blooded animals; homeotherms), but also in some poikiothermic (cold-blooded) animals such as lizards, which increase their temperature behaviorally, by seeking warmer surroundings. Inoculated poikilothermic animals that are denied access to a warmer environment have a higher mortality, supporting a general advantage of being able to increase body temperature during infection. The mechanism underlying this advantage has been elusive, but may involve changes in properties of iron-binding proteins, resulting in a drop of free iron in body fluids, to which bacteria are particularly susceptible.
However, there are clinical settings in which fever is dangerous or unpleasant. These include epileptic patients where fever may precipitate convulsions; elderly patients with cardiac or cerebrovascular disease; children, who are at risk for febrile convulsions (which may then predispose to later epilepsy); patients with hyponutrition and chronic fever, where the increased metabolic demand of maintaining a higher body temperature compromises body energy stores; patients with fluid balance disturbances where the sweating associated with rapid up and down resetting of body temperature can exacerbate salt loss and electrolyte disturbance.
As opposed to the unregulated he

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