Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2002-12-16
2003-08-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S400000, C424S078010
Reexamination Certificate
active
06605297
ABSTRACT:
TECHNICAL FIELD
The present invention is novel substances with the function of specifically accelerating uncoupled respiration and proton leak of the inner membrane of mitochondria which are induced by uncoupling proteins (UCP) (hereafter referred to as proton leak), in the functions of mitochondoria (hereafter referred to as MC), which is infracellular organelles performing the energy metabolism (respiration) using as the substrate fatty acids and pyruvic acid. In further detail, the present invention relates to the novel substances comprising a coupling isomerized highly unsaturated fatty acid and/or its derivative with the function of specifically promoting proton leak of the MC of mammals, including humans, etc., anti-obese (inhibiting the accumulation of visceral fat (particularly mesenteric fat) (hereafter referred to as visceral fat)) and visceral (particularly mesenteric (hereafter referred to as visceral) fat-reducing agents comprising the above-mentioned substance as the active ingredient, food products having anti-obese (inhibiting the accumulation of visceral fat) and visceral fat-reducing activities comprising the above-mentioned substance as the active ingredient, and feed having anti-obese (inhibiting accumulation of visceral fat) and visceral fat-reducing activities comprising the above-mentioned substance as the active ingredient.
BACKGROUND ART
The energy metabolism-regulating system in vivo consists of the food ingestion-regulating system and energy consumption-regulating system. The purpose of the present invention is to realize inhibition of accumulation of visceral fat and reduction thereof, which is considered as a multiple risk factor for lifestyle disease, in relation to joint-control of the energy-regulating system.
The energy consumption-regulating system is classified into energy consumption used for basal metabolism in order to sustain life and other energy consumption. The main energy consumption under the latter category is nonshivering thermogenesis (hereafter nST) and its functional significance is maintenance of body temperature, during exposure to cold, when waking from hibernation, etc., and to prevent obesity and impaired glycolipid metabolism due to consumption of energy from overeating, etc. Uncoupled respiration by mitochondria (MC) and proton leak of the inner membrane of MC, that is, the participation of the electron transport system of the respiration chain of the cells and ATP synthesis, are important to the mode by which nST is induced. The details are given below: ATP is essential for maintaining cell function, and in the cells, fatty acids and the pyruvic acid produced by the glycolysis system of cytoplasm are transported to MC and are oxidized to produce acetyl CoA. This acetyl CoA is oxidized by the citric acid circuit, with carbon dioxide and NADH being produced during this oxidation process and high-energy electrons further being produced from the NADH. The high-energy electrons bond with molecular oxygen in the respiration chain (electron transport system) of the inner membrane of MC to release energy. This energy pumps protons from the matrix through the inner MC to the intermembrane space.
As a result, an electrochemical gradient of protons is formed on both sides of the inner membrane. Then, when the protons of the intermembrane space return to the matrix in accordance with this gradient, ATP synthetase bound to the membrane is actuated to produce ATP from ADP+Pi.
The speed of the electron transport system of the respiration chain is regulated in order to maintain a constant ratio of ATP and ADP in vivo in accordance with the status thereof. If there is an increase in ATP consumption, the speed of electron transport will also become faster and as a result, it will be necessary to feed substrate. When strenuously moving, fatty acids and sugar are oxidized at a speed that is 5-times to 10-times that when resting.
The fat-soluble weak acid 2,4-dinitrophenol (2,4-DNP) acts as a proton ionophore to form a path through which protons other than ATP synthetase will flow through the inner membrane of the MC. Thus, the electrochemical gradient of the protons that was produced by the respiration chain of the inner membrane is consumed and ATP is not synthesized. That is, 2,4-DNP uncouples ATP synthesis with the electron transport system of the respiration chain and therefore acts as an uncoupling agent. Since ATP is not synthesized, electron transport of the respiration chain proceeds at the maximum speed at which feeding of substrate is allowed (Hosoda et al., Mebio, 14 (11), 30-31 (1997)).
A specific protein, uncoupling protein 1 (UCP-1), which uncouples ATP synthesis with the respiration chain electron transport system within the MC of brown adipocytes (BA), is a protein with a molecular weight of 32 kD consisting of approximately 300 amino acids that is present in brown adipose tissue (BAT). UCP-1 consists of 3 repeating domains consisting of approximately 100 amino acids and has 2 membrane-perforation sites in each domain, for a total of 6 sites.
These membrane perforation sites form a channel. UCP-1 is the carrier that transports protons and has the ability to be freely permeated by protons via this proton channel to release heat in accordance with the electrochemical gradient. This becomes nST. There is a reduction in ATP synthesis with uncoupling, and respiration inside the MC is activated in order to keep the ATP and ADP ratio constant and as a result, large amounts of fats and sugar are oxidized to generate heat.
Regulation of the functions of UCP-1 is performed from both aspects of the amount expressed and activity thereof. That is, the noradrenaline secreted from the sympathetic nerve terminals activates adenylic acid cyclase via the &bgr;-adrenaline receptors (&bgr;-AR) on the cell membrane to elevate intracellular cAMP concentrations.
The cAMP breaks down neutral fats via activation of protein kinase A (PKA) and activation of hormone-sensitive lipase (HSL) to produce free fatty acids (FFA). These FFA bind with UCP-1 to open the protein channels that were closed and act as a heat-production substrate. On the other hand, the amount of UCP-1 expressed is regulated mainly on the endonuclear gene transcription level, and UCP-1 gene expression is increased by elevation of cAMP concentrations (Saito et al., Saishin Igaku, 52, 1095-1096 (1997)).
UCP-1 is physiologically significant in that it is important in body temperature maintaining, during exposure to cold, etc., and research using transgenic mice has also made it clear that it participates in the prevention of obesity. That UCP-1 participates in the development, progression and persistence of obesity is indicated by the fact that there is a reduction in UCP-1 expression with various obesity models. Furthermore, it is confirmed that obesity develops without overeating in BAT-reduced transgenic mice (Lowell, B. B et al., Nature, 366, 740-742 (1993)). On the other hand, a reduction in body fat when large amounts of UCP-1 are expressed has beep ascertained in mice forced to express UCP-1 by insertion of the promoter of adipocyte-specific gene aP2 (Kopecky J. et al., J Clin Invest, 96, 2914-2923 (1995)).
Nevertheless, there is the idea that BAT is present in adult humans in only very small amounts and BAT-specific UCP-1 hardly has physiological significance.
On the other hand, there is also the opinion that the idea that the physiological significance of this BAT applies not only to laboratory animals, but also adult humans is supported from the following several points (Teruo Kawada, private message).
(1) As a result if it becoming possible to determine the amount of UCP, it is known that BAT is present perinephric and intra-abdominal in all those assayed, from neonates (1 day) to elderly (86 years), even in humans.
(2) Although more is found in children up to 15 years of age, approximately 50 g are present in adults, and the reduction in this activity may induce a body weight increase of 25 kg in 1 years.
(3) As with adult humans, BAT is converted to white cells in adu
Koga Kenji
Mizuno Masayuki
Nadachi Yoshitaka
Evans Charesse
Janiftec, Inc.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Page Thurman K.
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