WO2008120797A1 - Ampk activator - Google Patents

Abstract

Disclosed is a food, a pharmaceutical agent or the like. Specifically disclosed is an AMPK activator comprising lysine as an active ingredient, which relies on a finding that lysine has an AMPK-activating activity. An AMPK can regulate the metabolism of a sugar and a lipid, and therefore has an important role on the energy metabolism in a living body. The AMPK activator can be administered to activate an AMPK, and is therefore expected to have effects including an effect of increasing the oxidation of a fatty acid, an effect of preventing fatty liver, an effect of inhibiting the increase in blood glucose level, an anti-diabetic effect, an anti-hypercholesterolemic effect and an anti-arteriosclerotic effect.

Description

 Specification

 AM PK Activator Technical Field

 The present invention relates to an AMPK (AMP-activate terotinkinase) activator characterized by containing lysine as an active ingredient. Background technology

 AMPK is a factor that regulates energy metabolism and regulates sugar and lipid metabolism.

 When AMP K is activated, ACC (Acetyl Co A carboxylase) is inactivated and the metabolism of acetyl K o A to malonyl Co A is inhibited. When malonyl CoA concentration decreases, the ability to take in long-chain fatty acids into mitochondria is activated, which activates runitin palmitoyltransferase (CPT-1) and increases fatty acid oxidation. Are known. It is also known that activation of AMPK causes a decrease in fatty acid synthesis, inhibition of gluconeogenesis, and a decrease in cholesterol synthesis (Non-patent Documents 1, 2, and 3).

 Thus, AMPK controls sugar and lipid metabolism and plays an important role in the energy metabolism of the body. Therefore, activation of AMPK can be expected to have effects such as increased fatty acid oxidation, suppression of fatty liver, suppression of blood glucose elevation, anti-diabetes, anti-hypercholesterolemia, and suppression of arteriosclerosis. Is desired.

 [Non-Patent Document 1] B. Xue, B. B. Kah n, J. Ph s i o l., Δ 74 73-83, 2006

[Non-Patent Document 2] D. G. Hardie, J. W. Scout, J. Physio 1., 574, 7—15, 2006

[Non-Patent Document 3] BB K ahn, DG Hardie, Cell M etabo 1 i sm, 1, 1 5-26, 2005 Disclosure of the Invention

 [Problems to be solved by the invention]

 Under the background art described above, an object of the present invention is to provide an AMPK activator.

 [Means for solving the problems]

 As a result of intensive studies to achieve the above-mentioned object, the present inventor has found that lysine, which is one of amino acids, has an AMP K activating action, and has completed the present invention. That is, the present invention provides an AMP K activator characterized by containing lysine as an active ingredient. The present invention includes the following.

 (1) An AMP K activator containing lysine as an active ingredient.

 (2) A fatty liver inhibitor containing lysine as an active ingredient.

 (3) An antidiabetic agent containing lysine as an active ingredient.

 (4) A blood sugar elevation inhibitor containing lysine as an active ingredient.

 (5) An antihypercholesterolemic agent containing lysine as an active ingredient.

 (6) An arteriosclerosis inhibitor containing lysine as an active ingredient.

 (7) An AMPK activator characterized by containing lysine in an amount of 40 to 20 Omg in terms of amino acid free body equivalent per 1 kg body weight of the ingestion object as a daily intake.

 (8) A fatty liver inhibitor characterized by containing lysine in an amount of 40 to 20 Omg in terms of amino acid free body equivalent per 1 kg of body weight of the ingestion target as the daily intake Diabetes agent, antihyperglycemic agent, antihypercholesterolemia agent or arteriosclerosis inhibitor. .

 (9) An AMPK activator characterized by containing lysine per unit package in an amount equivalent to an amino acid free form, greater than 1 g and 12 g or less.

(10) More than 1 lg of lysine per unit package in terms of amino acid free form 1 2 g or less, a fatty liver inhibitor, an antidiabetic agent, an antihyperglycemic agent, an antihypercholesterolemia agent or an arteriosclerosis inhibitor.

 (1 1) The AMP K activator according to (1), (7) or (9), which is in the form of food, supplement, pharmaceutical or feed.

 (12) Food, supplement, pharmaceutical or feed form (2) to (6), (8) or (10) The fatty liver inhibitor, antidiabetic agent, antihyperglycemic agent, antihypercholesterol blood according to (10) Or arteriosclerosis inhibitor.

 (13) A method for activating AMPK, comprising administering lysine.

 (14) A method for inhibiting fatty liver, comprising administering lysine.

 (1 5) A method for preventing or treating diabetes, comprising administering lysine.

 (16) A method for suppressing an increase in blood glucose, comprising administering lysine.

 (17) A method for preventing or treating hypercholesterolemia, comprising administering lysine.

 (18) A method for suppressing arteriosclerosis, comprising administering lysine.

 (19) Use of lysine for the production of an AMPK activator.

 (20) Use of lysine for the manufacture of a fatty liver inhibitor.

 (2 1) Use of lysine for the manufacture of antidiabetic agents.

 (22) Use of lysine for the production of an antihyperglycemic agent.

 (23) Use of lysine for the production of an antihypercholesterolemic agent.

 (24) Use of lysine for the production of an arteriosclerosis inhibitor. Brief Description of Drawings

 Fig. 1 shows the AMP K activity in the liver in Experimental Example 1.

 Fig. 2 shows AMPK activity in muscle in Experimental Example 1.

 Fig. 3 shows changes in blood glucose levels in Experimental Example 2.

Figure 4 shows the lipid content in the liver in Experimental Example 3. BEST MODE FOR CARRYING OUT THE INVENTION

 The lysine used in the present invention may be in any form. Specifically, it can take a form such as a free form, a peptide form, a salt and a solvate. The peptide state here refers to a peptide in which 2 to 50 amino acids are bound, more preferably 2 to 10 amino acids, and refers to an oligopeptide such as lysyl lysine. The peptide state may consist of lysine alone or may contain other amino acids in addition to lysine. Examples of the salt include an ammonium salt, a salt with an alkali metal such as sodium or potassium, a salt with an alkaline earth metal such as calcium or magnesium, an aluminum salt, or a zinc salt. Salts with organic amines such as triethylamine, ethanolamine, etc., basic salts with inorganic salts such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citrate, benzoic acid, maleic acid, fumaric acid Salts with organic carboxylic acids such as tartaric acid and succinic acid, salts with organic sulfonic acids such as methanesulfonic acid and P_toluenesulfonic acid, and complex salts with L-amino acids such as L-glutamic acid and L-aspartic acid be able to. Examples of solvates include hydrates and alcohol adducts. The lysine is preferably L-form and may be D-L-form. It goes without saying that various forms of lysine can be used in combination of two or more. Of these, the salt form is preferable for human consumption from the viewpoint of experience in use as a food. In particular, L-lysine hydrochloride, L 'monolysine acetate and L-lysine L monoglutamate are preferred. It is particularly preferred to use L-lysine L-aspartate.

In the present invention, it is preferable that lysine is contained in an amount of 40 to 20 O mg per kg body weight of the intake subject as the daily intake weight. More preferred is 100-200 mg. This range was determined as follows. That is, when the present inventors ingested 20% by weight protein diet to mice, the intake of lysine was 0.8 to 4% by weight per meal based on the dry weight of the meal. In addition, the increase in body fat was suppressed safely and maximally, and this action was confirmed to be due to activation of AMPK. This is 4 to 20% by weight based on the protein intake weight. In the case of humans, the amount of protein intake per day is about 1 g per kg of body weight, so when converted to the intake weight of lysine per day, the amount of protein is 40 to 20 O mg per kg of body weight. Become. Regarding the upper limit, although the maximum allowable intake of amino acids is not clearly shown by FDA, etc., taking into account the safety against cucumber, when taking more than 20 O mg per kg of human weight, One amino acid is taken in a large amount, and the upper limit should be 20 O mg even considering that it is not preferable from the viewpoint of amino acid balance. Although there are various forms of lysine, the lysine intake weight referred to in the present invention refers to the weight of lysine in terms of free form.

 The AM PK activator and the like of the present invention can be put into circulation in the form of powder or liquid mixture. In addition, the product classification includes lipid metabolism improvement, fatty liver suppression, blood glucose rise suppression (diabetic patients, those who do not have diabetes, but who are worried about blood glucose levels, especially postprandial blood glucose levels) (somewhat higher people) and healthy For the purpose of improving or preventing blood sugar levels, especially postprandial blood glucose levels), anti-diabetes (for treating diabetes), anti-hypercholesterolemia, arteriosclerosis, etc. Can be distributed as supplements, beverages, seasonings, processed foods, pharmaceuticals, etc.

 In the case of a supplement form, it can be mixed with emulsifiers, pigments, fragrances, etc. to take a dosage form such as a tablet, a capsule or a liquid.

In the case of food forms such as beverages, seasonings, and processed foods, they can be prepared by conventional methods using appropriate additives. Such additives include fruit juices that adjust and improve the taste, excipients such as dexamerine, flavoring agents such as vanillin, pigments such as safflower pigment, cyclic oligosaccharides, sugars (fructose, glucose, liquid sugar, sucrose ), Acidulants, fragrances, powdered green tea powder, fats and oils, emulsifiers that improve texture, collagen, whole milk powder, thickening polysaccharides and agar (in the case of jelly drinks). In addition, carbohydrates, lipids, proteins, amino acids, vitamins, especially vitamin B2, vitamin C, eggshell calcium, calcium pantothenate, other minerals, especially calcium, royal jelly, propolis, honey, dietary fiber, agaricus, Chitin, chitosan, capsaicin, polyphenol, carotenoid, fatty acid, mucopolysaccharide, coenzyme, antioxidant Can be blended.

 In the case of pharmaceuticals, pharmaceutically acceptable carriers or diluents, for example, cellulose derivatives such as carboxymethyl cellulose and ethyl cellulose, starches such as potato starch and corn starch, lactose and sugars such as sucrose, peanut oil and corn oil · Blended with vegetable oils such as sesame oil, polyethylene glycol, alginic acid, gelatin, talc, etc., tablets · powders · pills, granules · capsules · oral preparations such as syrup, subcutaneous injections · intravenous injections · Intramuscular injections, epidural injections, injections such as subarachnoid injections, nasal preparations, transdermal preparations, external preparations such as ointments, rectal suppositories, suppositories such as vaginal suppositories, It can be made into dosage forms such as drops. The pharmaceutical agent of the present invention can be administered orally or parenterally, for example, enterally or intravenously.

 The subject who ingests or feeds the AM PK activator of the present invention is a human or an animal, and the animal is a pet such as a dog, a cat, a rabbit, a ferret, a hamster, a bird, or a zoo animal, or (racing) Animals such as horses, cattle, sheep, pigs, birds, and other livestock (industrial animals) with no special restrictions. Therefore, the product of the present invention may be a feed. For example, according to a method well known in the art, the AM PK activator of the present invention can be used as a solid or liquid additive for feed.

 As a specific ingestion method, there is a method of taking 40 to 20 O mg of lysine per kilogram of body weight of chick per day as a supplement. There is no limitation on the timing and frequency of ingestion.

It is preferable to take it with or before meals. For example, when a person weighing 60 kg takes, the daily intake range for lysine is 2.4 g to 12 g.

In the case of supplements and pharmaceuticals, the AM of the present invention in a packaged form containing lysine per unit package in an amino acid free form conversion amount of more than 1 g to 12 g or less, preferably more than 1 g to 4 g or less. Take PK activator, etc. and take 1 to 3 bags per day. For food, for example, frozen food, more than lg per serving, less than 12 g, preferably more than 2.4 g and less than 4 g Even if you eat 1 to 3 times a day good. What is necessary is just to use the same amount in combination with a supplement etc.

. Example

 Examples The present invention will be illustrated more specifically with reference to the following examples, but the present invention is not limited to these examples.

<Experimental example 1>

C 57 BLZ6 J male male, 9 weeks old, 16 mice were used. After fasting for 16 hours, after dark period, 1) 25% high fat diet (HF), or 2) 3% L-lysine hydrochloride added 25% high fat diet (HF 3K) was fed for 4 hours (8 Animals / group). Table 1 shows the feed composition used in Experimental Example 1 below. Four hours later, the mice were decapitated and the liver and muscles were collected. The liver and muscle were homogenized, and the resulting supernatant protein solution was subjected to SDS-PAGE, and then phosho-AMPK (p AMPK) or AMP K was detected by Western blotting. The detected band intensity was quantified, and the activation of cocoon was evaluated using the phosphorylation of cocoon as an index. In other words, the ρΑΜΡΚ band intensity / ΑΜΡΚ band intensity of the HF group was taken as 1, and the relative value of the HF 3Κ group was evaluated. Fig. 1 shows the ρρ / ΑΜΡΚ ratio in the liver, and Fig. 2 shows the pAM Ρ Κ / ΑΜ Ρ ratio in the muscle. In all cases, an increase in AMPK activity was observed in the HF 3 K group as compared with the HF group, particularly in the liver, indicating that the lysine included in the present invention activates AMPK.

table 1]

 Table 1 Composition of experimental food

 Diet composition (%)

 HF HF3K Casein 20.00 20.00

 Resistin 0.30 0.30

 Lysine hydrochloride 0.00 3.00

 β-corn starch 31.75 28.75

 α-Corn Starch 13.20 13.20

 Balm oil 4.00 4.00

 Soybean oil 21.00 21.00

 Cellulose 5.00 5.00

 Mineral mixing (A1N-93G) 3.50 3.50

 Vitamin mixture (ΑΙΝ-93) 1.00 1.00

 Choline bitartrate 0.25 0.25

 t-Ptylhydroquinone 0.0014 0.0014

 Total 100.00 100.00

<Experimental example 2>

 Wistar strain male male 9 weeks old was used. Two experimental groups were established: 1) 25% high-fat diet group (HF), 2) 3% L-lysine hydrochloride added 25% high-fat diet group (HF 3 K). ). 1 After 6 hours of fasting, 5 g of each test meal was ingested for 1 hour, blood was collected over time (0, 1, 2, 3, 4 hours), and blood glucose concentration was measured. Figure 3 shows changes in blood glucose levels. Compared to the HF group, the HF 3 K group showed a downward trend and showed a significantly lower value 3 hours after meals. From these results, it was shown that lysine contained in the present invention improved glucose metabolism and suppressed postprandial blood glucose levels.

Example 3>

 C 5 7 BLZ6 J male male, 9 weeks old, 20 mice were used. The experimental group consists of 1) 25% high-fat diet group (HF) and 2) 3% L-lysine hydrochloride added 25% high-fat diet group (HF 3 K) (10 groups). The test meal was provided for 4 weeks. Necropsy was performed on the 4th week of intake of the test food, and the lipid content in the liver was measured.

Fig. 4 shows the lipid content in the liver. Shows a significant decrease in the HF 3 K group compared to the HF group It was. From this result, it was shown that lysine included in the present invention has a fatty liver inhibitory action. Industrial applicability

 According to the present invention, AMP K can be activated. In other words, AMP K is activated to increase fatty acid oxidation, decrease fatty acid synthesis, suppress gluconeogenesis, decrease cholesterol synthesis, etc., thereby improving lipid metabolism, suppressing fatty liver, suppressing blood sugar increase, anti-diabetic, anti-hypercholesterolemia, It is extremely useful in industry because it can produce effects such as suppression of arteriosclerosis.

 This application is based on Japanese Patent Application No. 2007-093527 filed in Japan (filing date: March 30, 2007), the contents of which are incorporated in full herein.

Claims

The scope of the claims  1. An AMP K activator containing lysine as an active ingredient.  2. A fatty liver inhibitor containing lysine as an active ingredient.  3. An antidiabetic agent containing lysine as an active ingredient. 4. A blood sugar elevation inhibitor containing lysine as an active ingredient.  5. An antihypercholesterolemic agent containing lysine as an active ingredient.  6. An arteriosclerosis inhibitor containing lysine as an active ingredient.  7. An AMPK activator characterized by containing lysine in an amount of 40 to 20 Omg in terms of amino acid free form per 1 kg body weight of the ingestion object as a daily intake.  8. Fat liver inhibitor, anti-diabetes, characterized by containing lysine in an amount equivalent to 40-20 Omg in terms of amino acid free body equivalent per 1 kg of body weight of ingested object per day Agent, antihyperglycemic agent, or arteriosclerosis inhibitor. 9. An AMP K activator characterized in that it contains lysine per unit package in an amount equivalent to the amount of amino acids isolated from 1 g to 12 g.  1 0. Fatty liver inhibitor, anti-diabetic agent, anti-hyperglycemic agent, anti-hypercholesterolemia, characterized by containing lysine per unit package in terms of amino acid free form, more than lg and less than 12 g Agent or arteriosclerosis inhibitor.  1 1. The AMP K activator according to claim 1, 7 or 9, which is in the form of food, supplement, medicine or feed.  1 2. Fatty liver inhibitor, antidiabetic agent, antihyperglycemic agent, antihypercholesterolemia agent or antihypercholesterolemic agent according to claims 2 to 6, 8, or 10 in the form of food, supplement, pharmaceutical or feed Arteriosclerosis inhibitor.  13. A method for activating AMPK, comprising administering lysine.  14. A method for inhibiting fatty liver, comprising administering lysine. 1 5. A method for preventing or treating diabetes, comprising administering lysine. 16. A method for suppressing an increase in blood glucose, comprising administering lysine.  17. A method for preventing or treating hypercholesterolemia, comprising administering lysine. 18. A method for inhibiting arteriosclerosis comprising administering lysine. 1 9 .. Use of lysine for the production of AMPK activator. 20. Use of lysine for the manufacture of fatty liver inhibitors. 2 1. Use of lysine for the manufacture of antidiabetic agents. 22. Use of lysine for the production of an antihyperglycemic agent. 23. Use of lysine for the manufacture of antihypercholesterolemic agents. 24. Use of lysine for the manufacture of arteriosclerosis inhibitors.