HK1119403B - Visceral fat accumulation inhibitor - Google Patents
Visceral fat accumulation inhibitor Download PDFInfo
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- HK1119403B HK1119403B HK08111297.9A HK08111297A HK1119403B HK 1119403 B HK1119403 B HK 1119403B HK 08111297 A HK08111297 A HK 08111297A HK 1119403 B HK1119403 B HK 1119403B
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Description
Technical Field
The present invention relates to a visceral fat accumulation inhibitor comprising a compound having a 4-methyl-7-cholestanol skeleton as an active ingredient, and to a food or beverage comprising the same. In particular, the present invention relates to a visceral fat accumulation inhibitor capable of reducing the amount of fat accumulated in the abdominal cavity and preventing or improving visceral fat type obesity, which is considered to be a main factor of metabolic syndrome, and to a physiologically functional food or beverage, such as a specific health food, containing the visceral fat accumulation inhibitor.
Background
In recent years, the rapid increase in obesity involved in westernization of lifestyle has become a serious problem. Obesity refers to a state in which excessive energy is accumulated due to excessive calorie intake and reduction in calorie consumption caused by insufficient exercise or the like, and refers to a "state in which excessive body fat tissue (body fat) is accumulated". Obesity is indicated as the basis for the onset of so-called lifestyle-related diseases such as diabetes, hypertension, and hyperlipidemia.
Obesity shows a state of excessive body fat accumulation and a phenomenon of weight gain. It is reported that when the body weight is rapidly reduced to improve obesity, the number of muscles that play a role in energy consumption is also reduced together with fat, and some symptoms such as blood pressure disorders and hip joint injury may occur in the case of elderly (non-patent document 1). In addition, in the case of fat mass reduction without reducing body weight, it is reported that exercise therapy is expected to exert an effect of improving muscle tissues (non-patent document 2). As described above, a method of improving obesity by inhibiting accumulation of body fat, not by reducing body weight, has been noticed in recent years.
Adipose tissue is classified into subcutaneous fat accumulated inside the skin and visceral fat accumulated around the visceral organs in the abdominal cavity, which are collectively called "body fat". Obesity is known to be divided into two types: subcutaneous adiposity related to subcutaneous fat accumulation and visceral adiposity related to visceral fat accumulation. Visceral fat accumulation has a great influence, in particular, on the incidence of complications in obesity (e.g. metabolic abnormalities and cardiovascular diseases) and the severity thereof.
Conventionally, it is known that a morbidity of one person suffering from a combination of various lifestyle-related diseases (i.e., "multiple risk factor syndrome") significantly increases the risk of the onset of arteriosclerotic diseases, and some concepts such as syndrome X and metabolic syndrome have been proposed as risk factors for arteriosclerotic diseases. In order to evaluate the risk of multiple risk factors and prevent the onset of arteriosclerotic diseases in those syndromes, the definition of metabolic syndrome and its diagnostic criteria unified internationally is made (non-patent document 3). In the diagnostic criteria for metabolic syndrome proposed in japan at 4 months of 2005, the standard corresponding to 100cm was adopted2Or a larger visceral fat area, as a basic item instead of the Body Mass Index (BMI) or body fat rate, which is generally used to indicate the degree of obesity. Therefore, it has been recognized that visceral fat accumulation is largely associated with metabolic syndrome.
Exercise, diet and behavior therapy are recommended as measures for reducing body fat. However, in those cases where the therapy is difficult to perform or persists, a drug therapy or surgery may be performed. Currently, mazindol, which is an appetite suppressant, is used as an obesity therapeutic drug and is mainly intended for highly obese persons with a BMI of 35 or more. However, fenamidone not only causes side effects (e.g. headache and dry mouth), but also has a number of problems: mazindol is contraindicated when there is severe dysfunction in the kidney, liver or pancreas; and cannot be administered for a long time due to its dependence and the like.
It is known that phytosterols such as β -sitosterol, campesterol, stigmasterol have an effect of lowering blood cholesterol by inhibiting the absorption of cholesterol, and a lipid metabolism-promoting agent comprising diglycerides and phytosterols as active ingredients is disclosed (patent document 1). Further, an antiobesity agent and a lipid metabolism promoter containing a cholestenone compound as an active ingredient, which is synthesized by using phytosterol such as β -sitosterol and campesterol or 4-cholesten-3-one as a raw material, are disclosed (patent documents 2 to 5).
As typical plants belonging to the genus Aloe of the family liliaceae, Aloe vera (aloebadenosis Miller) and Aloe arborescens (Aloe arborescen Miller var. natalensis berger) are known, and various effects of these plants have been reported. Specifically, it is disclosed that aloe extract has an effect of preventing or improving obesity (patent document 6). In addition, an additive having a weight-reducing effect containing 0.25% aloe vera powder (patent document 7) and an essential oil composition for controlling body weight containing aloe vera (patent document 8) are disclosed, respectively. Further, it has been reported that the administration of whole leaves of Aloe arborescens to rats significantly reduces the body weight of the rats depending on the concentration of Aloe arborescens (non-patent document 4 or 5).
[ patent document 1] Japanese patent application laid-open No. 2005-15425
[ patent document 2] Japanese patent application laid-open No. H07-165587
[ patent document 3] Japanese patent application laid-open No. 11-193296
[ patent document 4] Japanese patent application laid-open No. 2001-240544
[ patent document 5] Japanese patent application laid-open No. 5-170651
[ patent document 6] Japanese patent laid-open No. 2000-319190
[ patent document 7] New Zealand patent No. 330439
[ patent document 8] U.S. Pat. No. 6280751
[ non-patent document 1] Journal of Applied Physiology, volume 95, page 1728-1736, 2003
[ non-patent document 2] Journal of Applied Physiology, volume 99, page 1220-1225, 2005
[ non-patent document 3] Adiposcience, Vol.2, pp.11-15, 2005
[ non-patent document 4] Medical and Biology, 125(5), pp 189 and 194
[ non-patent document 5] Bulletin of the Fujita Medical Society, 22(2), pp.153-
Disclosure of Invention
Patent document 1 does not describe the effect of phytosterol taken alone, and does not describe or suggest the effect of phytosterol on visceral fat at all.
Further, it is disclosed that the 3-ketosteroid compound disclosed in patent document 2, the cholestenone compound disclosed in patent document 3 and the 24-alkyl-cholesten-3-one compound (for example, 24-methylcholest-5-en-3-one) disclosed in patent document 4 have an effect of reducing body weight, body fat mass and blood fat mass. However, the effect of inhibiting visceral fat accumulation without affecting oral dose and weight loss is not described or suggested.
The 4-cholesten-3-one disclosed in patent document 5 is significantly different from the active ingredient of the present invention. Specifically, the 4-cholesten-3-one described in patent document 5 has the effects of: while the compound reduces excess intraperitoneal fat when normal rats are caloric, it also unnecessarily reduces the fat content in the normal range. Therefore, the effect of 4-cholesten-3-one is significantly different from that of the present invention, that is, the present invention is effective only to suppress fat components accumulated in the vicinity of internal organs in the case of an obese state or in the case of excessive calorie intake in an amount more than necessary.
In addition, it is disclosed that the drug for preventing and improving obesity of patent document 6 inhibits the development of obesity accompanied by weight gain, and thus effectively maintains standard body weight without excessive dietary restriction. However, an effect on body fat is not described, and an effect of inhibiting accumulation of visceral fat to reduce the amount of visceral fat without reducing body weight is not described.
In addition, the active ingredient described in patent document 6 is an aloe extract. However, no components related to the inhibition of the development of obesity accompanied by weight gain have been specifically pointed out at all. Therefore, it is difficult to predict the presence of an effect of inhibiting visceral fat accumulation that merely reduces visceral fat without reducing body weight, i.e., an effect that cannot be expected from the description of patent document 6.
Therefore, in order to selectively reduce visceral fat that is strongly associated with the onset of metabolic syndrome or to prevent or suppress accumulation thereof, there is a need for further development of a functional material that can be safely taken with as little pain as possible every day and that can effectively reduce visceral fat.
In view of the foregoing, the present inventors have intensively studied visceral fat accumulation inhibitors that can prevent or ameliorate visceral fat type obesity that is considered to be a main cause of metabolic syndrome. As a result, the present inventors have found a compound having a 4-methyl-7-cholestanol (lophenol) skeleton having an effect of effectively reducing fat accumulated in the abdominal cavity. In addition, the compound was found to have the effect of maintaining a standard body weight without reducing body weight, and thus can be used to inhibit the development of obesity without requiring excessive dietary restrictions.
An object of the present invention is to provide a visceral fat accumulation inhibitor comprising a compound having a 4-methyl-7-cholestanol skeleton as an active ingredient. In addition, another object of the present invention is to provide a physiologically functional food or beverage, such as a specific health food, comprising the visceral fat accumulation inhibitor.
A first aspect of the invention of the present application to solve the aforementioned problems is a visceral fat accumulation inhibitor comprising a compound represented by the following general formula (1) as an active ingredient.
(in the formula, R1 represents a straight-chain or branched alkyl group having 5 to 16 carbon atoms, an alkenyl group having 1 or 2 double bonds, or a substituted alkyl or alkenyl group having a hydroxyl group and/or a carbonyl group, R2 and R3 each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a substituted alkyl group, and R4 forms C ═ O with a carbon atom constituting a ring, or represents-OH or-OCOCH3。)
In addition, the following 1) to 4) are preferred embodiments.
1) In the aforementioned compound, one of R2 and R3 is a hydrogen atom, the other is a methyl group, and R4 is a hydroxyl group.
2) In the aforementioned 1), R1 is represented by any one of the following formulae:
-CH2-CH2-CH(-CH2-CH3)-CH(CH3)2
-CH2-CH2-CH＝C(CH3)2
-CH2-CH＝C(CH3)-CH(CH3)2
-CH2-CH2-C(＝CH-CH3)-CH(CH3)2
-CH2-CH2-CH(Ra)＝C(CH3)Rb
(wherein Ra and Rb are-H, -OH or-CH3Any one of them)
-CH2-CH2-CH(Rc)-CH(CH3)Rd
(wherein Rc and Rd are-H, -OH or-CH3Any of the above).
3) The compound described in 2) is selected from 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstiglin-7-en-3-ol.
4) The content of the compound described in 1) to 3) is at least 0.001 mass%.
A second aspect of the invention of the present application to solve the aforementioned problems is a visceral fat accumulation inhibitor comprising an organic solvent extract or a hot water extract of a liliaceae plant or a fraction thereof containing a compound represented by the following general formula (1), and wherein the aforementioned organic solvent extract or hot water extract of a liliaceae plant or a fraction thereof contains, as an active ingredient, a composition containing at least 0.001% by dry mass of the compound represented by the following general formula (1).
(in the formula, R1 represents a straight-chain or branched alkyl group having 5 to 16 carbon atoms, an alkenyl group having 1 or 2 double bonds, or a substituted alkyl or alkenyl group having a hydroxyl group and/or a carbonyl group, R2 and R3 each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a substituted alkyl group, and R4 forms C ═ O with a carbon atom constituting a ring, or represents-OH or-OCOCH3。)
Further, the following 5) to 7) are preferred embodiments.
5) In the aforementioned compound, one of R2 and R3 is a hydrogen atom, the other is a methyl group, and R4 is a hydroxyl group.
6) In the aforementioned 5), R1 is represented by any one of the following formulae:
-CH2-CH2-CH(-CH2-CH3)-CH(CH3)2
-CH2-CH2-CH＝C(CH3)2
-CH2-CH＝C(CH3)-CH(CH3)2
-CH2-CH2-C(＝CH-CH3)-CH(CH3)2
-CH2-CH2-CH(Ra)＝C(CH3)Rb
(wherein Ra and Rb are-H, -OH or-CH3Any one of them)
-CH2-CH2-CH(Rc)-CH(CH3)Rd
(wherein Rc and Rd are-H, -OH or-CH3Any of the above).
7) The compound described in 6) is selected from 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstiglin-7-en-3-ol.
A third aspect of the invention of the present application to solve the aforementioned problems is a food or beverage containing the visceral fat accumulation inhibitor of the first or second aspect.
Further, the following 8) is a preferred embodiment.
8) The food or drink contains 0.0001% by mass or more of the compound represented by the aforementioned general formula (1).
The fourth invention of the present application for solving the aforementioned problems is the use of the compound represented by the aforementioned general formula (1), or an organic solvent extract or hot water extract of a Liliaceae plant containing at least 0.001 dry mass% of the compound, or a fraction thereof for the preparation of a visceral fat accumulation inhibitor.
A fifth invention of the present application to solve the aforementioned problems is a method for inhibiting visceral fat accumulation, comprising: a compound represented by the general formula (1) or an organic solvent extract or a hot water extract of a plant belonging to the family Liliaceae containing at least 0.001 dry mass% of the compound, or a fraction thereof is administered to a patient to be inhibited from visceral fat accumulation.
In the aforementioned uses and methods of the present invention, preferred embodiments of the compound represented by the aforementioned general formula (1) are the same as those invented in the second aspect of the present application.
The visceral fat accumulation inhibitor of the present invention and the food or beverage containing the same can be safely taken or ingested and have an effect of effectively inhibiting visceral fat accumulation. In addition, the active ingredient of the visceral fat accumulation inhibitor of the present invention can be safely ingested and can be easily prepared from readily available liliaceae plants such as Aloe barbadensis Miller.
Detailed Description
Next, preferred embodiments of the present invention are described in detail. However, the present invention is not limited to the following preferred embodiments, and modifications can be freely made within the scope of the present invention. Note that the percentages used herein represent mass percentages unless otherwise indicated.
In the present invention, the effect of inhibiting visceral fat accumulation means an effect of reducing the amount of fat accumulated in the abdominal cavity. Therefore, the effect of inhibiting visceral fat accumulation can be evaluated by measuring the amount of fat in the abdominal cavity (e.g., the weight of mesenteric fat).
The compound used as an active ingredient of the visceral fat accumulation inhibitor of the present invention (hereinafter also referred to as "the drug of the present invention") is a compound having a structure represented by the aforementioned general formula (1), and any derivative or the like of the compound is also included as an active ingredient as long as it is a compound having an effect of inhibiting visceral fat accumulation (hereinafter also referred to as "the compound of the present invention").
Most preferably, the purity of the compound of the present invention used as an active ingredient of the visceral fat accumulation inhibitor of the present invention is 100%. However, the purity may be appropriately set within a range in which the compound exerts an effect of inhibiting visceral fat accumulation.
In addition, the composition used as an active ingredient of the visceral fat accumulation inhibitor of the present invention (hereinafter also referred to as "the composition of the present invention") is an extract of a liliaceae plant or a fraction thereof containing at least the aforementioned compound in an amount of 0.001% by dry mass, preferably 0.01% by dry mass or more, more preferably 0.1% by dry mass or more. The upper limit of the content of the compound of the present invention is, but not particularly limited to and is preferably, for example, 10 dry mass%, 50 dry mass%, 70 dry mass%, or 90 dry mass%.
"Dry mass" as used in the present invention means a mass measured after a compound is dried by a drying method defined by "drying loss test" described in general test method in Japanese Pharmacopeapoeia, 14 th edition (3/30/2001, Japan healthcare labor province, bulletin No. 111). For example, the mass of the compound of the present invention can be determined in such a manner that: about 1g of the compound of the invention is measured and dried at 105 ℃ for 4 hours; cooling the resultant by standing in a desiccator; the mass of the compound was weighed using a scale.
In the general formula (1), R1 represents a straight-chain or branched alkyl group having 5 to 16 carbon atoms or an alkenyl group having 1 or 2 double bonds. Note that the aforementioned alkyl group and alkenyl group may be a substituted alkyl group and alkenyl group having a hydroxyl group and/or a carbonyl group, respectively. R2 and R3 each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a substituted alkyl group, and R4 forms C ═ O with the carbon atoms constituting the ring or represents-OH or-OCOCH3. As the aforementioned alkyl group having 1 to 3 carbon atoms, a methyl group, an ethyl group and the like are preferable, and a methyl group is particularly preferable.
R1 is preferably any one of groups represented by the following formulae.
(i)-CH2-CH2-CH(-CH2-CH3)-CH(CH3)2
(ii)-CH2-CH2-CH＝C(CH3)2
(iii)-CH2-CH＝C(CH3)-CH(CH3)2
(iv)-CH2-CH2-C(＝CH-CH3)-CH(CH3)2
(v)-CH2-CH2-CH(Ra)＝C(CH3)Rb
(wherein Ra and Rb are-H, -OH or-CH3Any one of them)
(vi)-CH2-CH2-CH(Rc)-CH(CH3)Rd
(wherein Rc and Rd are-H, -OH or-CH3Any of the above).
Further, it is preferable that one of R2 or R3 is a hydrogen atom and the other is a methyl group. Further, R4 is preferably a hydroxyl group.
The most preferred compounds as the aforementioned compounds are those represented by the formula: 4-methylcholest-7-en-3-ol (formula (2)), 4-methylergost-7-en-3-ol (formula (3)), and 4-methylcoumarin-7-en-3-ol (formula (4)).
Namely, 4-methylcholest-7-en-3-ol is a compound represented by the aforementioned general formula (1): wherein one of R2 and R3 is a hydrogen atom and the other is a methyl group, R4 is a hydroxyl group, R1 is a group represented by the aforementioned formula (vi) (Rc represents-H, Rd represents-CH)3). Further, 4-methylergosta-7-en-3-ol is a compound represented by the aforementioned general formula (1): wherein one of R2 and R3 is a hydrogen atom and the other is a methyl group, R4 is a hydroxyl group, and R1 is a group represented by the aforementioned formula (vi) (Rc and Rd each represent-CH)3). Further, 4-Methylostigmasta-7-en-3-ol is a compound represented by the aforementioned general formula (1): wherein one of R2 and R3 is a hydrogen atom and the other is a methyl group, R4 is a hydroxyl group, and R1 is a group represented by the aforementioned formula (i).
The medicament, food or drink of the present invention may contain one, two or more of any of the foregoing compounds.
It is known that 4-methyl-7-cholestanol is contained in plants, and the compound of the present invention can be prepared according to known methods for preparing 4-methyl-7-cholestanol (shantan hong, "biochemical test method", volume 24, fatty lipid metabolism test method, page 174, academic press, 1989). The compounds of the invention can be obtained, for example, by: the compound is extracted from the plant containing the compound using a method such as extraction with an organic solvent or extraction with hot water and purification of the resulting extract. In the present invention, although the compound of the present invention can be purified, a composition such as a plant extract or a fraction thereof can also be used as long as it contains an effective amount of the compound.
The compounds of the invention or compositions comprising them may be prepared in the following manner: for example, from a plant belonging to the family Liliaceae, a part thereof or a pulverized product thereof containing the compound of the present invention, a fraction containing the compound is extracted with an organic solvent or hot water and concentrated.
Examples of the aforementioned plants belonging to the Liliaceae family include plants belonging to the genus Aloe or Allium. Examples of plants of the genus aloe include: aloe barbadensis Miller, Aloe ferox Miller, Aloe africana Miller, Aloe arborescens Berger, Aloe spicata Baker, and the like. In the preparation of the compound of the present invention or the composition comprising the same, although the whole of the aforementioned plants may be used, it is preferable to use mesophyll (transparent gel fraction) thereof. It is preferable that the plant or a part thereof is crushed and thereby liquefied by using a homogenizer or the like, and the compound of the present invention or the composition comprising the same is extracted from the crushed product by using an organic solvent or hot water. Examples of the organic solvent include alcohols such as methanol, ethanol and butanol; esters such as methyl acetate, ethyl acetate, propyl acetate, and butyl acetate; ketones such as acetone and methyl isobutyl ketone; ethers such as diethyl ether and petroleum ether; hydrocarbons such as hexane, cyclohexane, toluene and benzene; halogenated hydrocarbons such as carbon tetrachloride, methylene chloride and chloroform; heterocyclic compounds such as pyridine; glycols such as ethylene glycol; polyols such as polyethylene glycol; nitrile solvents such as acetonitrile, mixtures of these solvents, and the like. In addition, these solvents may be anhydrous or aqueous. Of these solvents, particular preference is given to using ethyl acetate/butanol mixtures (3: 1) and chloroform/methanol mixtures (2: 1).
As the extraction method, a method conventionally used for extracting plant components can be used. For example, a method of heating and refluxing 1 to 300 parts by mass of an organic solvent and 1 part by mass of a fresh plant or a dried plant at a temperature lower than the boiling point of the solvent while stirring or shaking, or a method of ultrasonic extraction at room temperature is conventionally used. The crude extract may be obtained by separating insoluble materials from the extract by a suitable method such as filtration or centrifugation.
The crude extract can be purified by various chromatographies such as normal phase or reverse phase silica gel column chromatography. When a gradient chloroform/methanol mixture is used as an elution solvent in normal phase silica gel column chromatography, the compound of the present invention is eluted with a mixing ratio of chloroform: methanol of about 25: 1. In addition, when a hexane/ethyl acetate mixture (4: 1) was used as an elution solvent in reverse phase silica gel column chromatography, the compound of the present invention was eluted in an elution fraction at an early stage. The obtained fraction can be further purified by HPLC or the like.
In addition, the compound used in the present invention can also be prepared by a chemical synthesis method or a biological or enzymatic method using a microorganism, an enzyme or the like.
It can be confirmed by, for example, Mass Spectrometry (MS), Nuclear Magnetic Resonance (NMR) spectroscopy, or the like that the compound obtained as described above or a composition containing the same is the compound of the present invention or contains the compound of the present invention.
The compound of the present invention has an effect of inhibiting visceral fat accumulation, and thus can prevent visceral fat obesity. Therefore, the compound of the present invention can be used as an active ingredient of a visceral fat accumulation inhibitor, food or drink.
Furthermore, since the leaf skin of aloe barbadensis contains barbaloin and aloe-emodin having laxative effects, these components are considered to be disadvantageous for use in drugs or foods or beverages in which laxative effects are not desired. Thus, it is preferred that compositions comprising the compounds of the present invention do not comprise the aforementioned components. In addition, mesophyll of aloe vera or a pulverized product thereof can be used as an active ingredient of the visceral fat accumulation inhibitor.
The compound of the present invention has an effect of inhibiting visceral fat accumulation, and thus can prevent visceral fat obesity. Therefore, the compound of the present invention itself can be used as an active ingredient of the visceral fat accumulation inhibitor of the present invention and food or drink containing the same. In addition, an organic solvent extract or a hot water extract of a plant containing the compound of the present invention or a fraction thereof (hereinafter referred to as "extract or the like") can also be used as an active ingredient of the medicine or food or drink. In this case, the aforementioned extract and the like contained in the drug preferably contain at least 0.001 dry mass%, more preferably 0.01 to 1 dry mass%, particularly preferably 0.05 to 1 dry mass% of the compound of the present invention. The extract and the like contained in the food or drink preferably contain the compound of the present invention in an amount of at least 0.0001% by dry mass, more preferably 0.001 to 1% by dry mass, and particularly preferably 0.005 to 1% by dry mass. The aforementioned extracts and the like may contain two or more compounds of the present invention. In addition, the aforementioned extract and the like may be a solution, or may also be lyophilized or spray-dried by a conventional manner, and stored or used as a powder.
As the visceral fat accumulation inhibitor of the present invention, a compound of the present invention or a composition containing the same may be administered to mammals (including humans) orally or non-orally either directly or in combination with a pharmaceutically acceptable carrier. In the visceral fat accumulation inhibitor of the present invention, the compound of the present invention may be a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include metal salts (inorganic salts) and organic salts such as those listed in "Remington's Pharmaceutical Sciences", 17 th edition, p 1418, 1985. Specific examples thereof include, but are not limited to, inorganic acid salts such as hydrochloride, sulfate, phosphate, diphosphate and hydrobromide; and organic acid salts such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, pamoate (pamoate), salicylate and stearate. Further, the salt may be a salt with a metal such as sodium, potassium, calcium, magnesium, and aluminum or a salt with an amino acid such as lysine. Furthermore, solvates such as hydrates of the aforementioned compounds or pharmaceutically acceptable salts thereof also fall within the scope of the present invention.
The dosage form of the visceral fat accumulation inhibitor of the present invention is not particularly limited and may be appropriately selected depending on the purpose of treatment. Specific examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, syrups, suppositories, injections, ointments, patches, eye drops, nasal drops and the like. For the preparation, additives generally used as pharmaceutical carriers in general preventives for inhibiting visceral fat accumulation, such as excipients, binders, disintegrants, lubricants, stabilizers, flavors, diluents, surfactants, and solvents for injections, and the like, can be used. Further, as long as the effect of the present invention is not deteriorated, the compound of the present invention or an extract containing the same may be used in combination with another drug having an effect of inhibiting visceral fat accumulation.
Although the content of the compound of the present invention or an extract containing the same or the like in the visceral fat accumulation inhibitor of the present invention is not particularly limited and may be suitably selected, the amount of the compound of the present invention may be, for example, at least 0.001 mass%, preferably 0.01 to 1 mass%, particularly preferably 0.05 to 1 mass%.
The visceral fat accumulation inhibitor of the present invention has an effect of inhibiting visceral fat accumulation, and thus can prevent visceral fat obesity. Visceral fat type obesity generally means that the visceral fat area is 100cm2Or more, and according to the diagnostic criteria for metabolic syndrome, visceral fat obesity refers to a case where a japanese male has a waist circumference of 85cm or more or a japanese female has a waist circumference of 90cm or more (Internal Medicine, vol. 94, p. 188-203, 2005). In addition, the visceral fat accumulation inhibitor of the present invention is preferably used for treating a patient having a larger amount of accumulated visceral fat than a healthy person.
In addition, the visceral fat accumulation inhibitor of the present invention can ameliorate or prevent diseases, complications, and the like caused by visceral fat accumulation, such as abnormal lipid metabolism and cardiovascular diseases, and can also reduce the risk of these diseases, complications, and the like. Examples of various diseases caused by visceral fat accumulation include obesity (particularly visceral fat type obesity), hyperlipidemia, diabetes, hypertension, and arteriosclerosis. Examples of complications caused by these diseases include: diabetic retinopathy, nephropathy, neuropathy and diabetic gangrene caused by diabetes; stroke, nephrosclerosis and renal failure due to hypertension; and cardiovascular diseases such as cerebral apoplexy, cerebral infarction, angina pectoris, myocardial infarction, etc., caused by arteriosclerotic diseases, and renal diseases such as uremia, nephrosclerosis and renal failure. In addition, the present inventors found that the compound of the present invention has an effect of improving hyperglycemia by decreasing hemoglobin Alc level (WO 2005/094838). It is preferable that the diseases using the visceral fat accumulation inhibitor of the present invention are not accompanied by a state of higher than hemoglobin Alc level in a healthy human.
In addition, the visceral fat accumulation inhibitor of the present invention can be used for preventing the onset of metabolic syndrome. The effect of the agent for inhibiting or reducing visceral fat accumulation as described above is very effective for preventing the onset of metabolic syndrome and metabolic syndrome-related arteriosclerotic diseases and lifestyle-related diseases such as diabetes, hypertension and hyperlipidemia which are indicative of risk factors thereof, and complications associated with these diseases. Further, the "metabolic syndrome" used in the present invention refers to a state in which arteriosclerosis is likely to occur and there are pathological risk factors regarded as multiple risk factor syndromes, such as hyperinsulinemia, abnormal glucose tolerance or hyperglycemia, abnormal lipid metabolism, hyperlipidemia (hypertriglyceridemia and low-HDL-cholesterolemia), hypertension, obesity, and visceral fat accumulation, which are complicated with symptoms.
The administration time of the drug of the present invention is not particularly limited and may be appropriately selected depending on the method for treating the target disease. Further, it is preferable to determine the administration route according to the dosage form, the age, sex and other conditions of the patient, the severity of the patient's symptoms, and the like. The dosage of the present drug is selected according to the usage, age, sex of the patient, severity of the disease, other conditions of the patient, and the like. The amount of the compound of the present invention as an active ingredient is usually selected from the range of preferably 0.001 to 50 mg/kg/day, more preferably 0.01 to 1 mg/kg/day. Further, when an extract or the like containing the compound of the present invention is used, the dry weight of the extract or the like is selected from the range of preferably 0.1 to 1000 mg/kg/day, more preferably 1 to 100 mg/kg/day, for the test dose. In any case, the dose may be administered once or divided into several doses during the day.
The compound of the present invention or a composition containing the same may be added to food or drink (beverage or food) to prepare food or drink having an effect of inhibiting visceral fat accumulation. There is no particular limitation on the form and properties of the food or drink as long as the effect of the effective ingredient is not deteriorated and the food or drink can be taken orally, and it can be prepared in a conventional manner by using the raw materials generally used for food or drink in addition to the aforementioned effective ingredient. The content of the compound of the present invention or the extract or the like containing the same contained in the food or drink of the present invention is not particularly limited and may be appropriately selected. For example, the present compound or an extract containing the same or the like is contained in the food or drink in an amount of at least 0.0001% by mass, preferably 0.001 to 1% by mass, particularly preferably 0.005 to 1% by mass, based on the amount of the present compound.
The food or drink of the present invention can be used for various purposes utilizing the visceral fat reducing effect. For example, it can be used as food or drink suitable for people who are beginning to worry about their waist size, food or drink suitable for people who are beginning to worry about blood lipids, food or drink for reducing or eliminating risk factors of metabolic syndrome, and the like.
As used in the food or drink of the present invention, "inhibiting visceral fat accumulation" means improving or preventing various adverse effects on health caused by visceral fat accumulation. In the present invention, "improving visceral fat type obesity", "preventing visceral fat type obesity", "reducing visceral fat", "preventing visceral fat accumulation" and the like can also be exemplified as having the same meaning as the aforementioned term "inhibiting visceral fat accumulation".
The food or drink of the present invention is useful for ameliorating or preventing diseases caused by visceral fat accumulation, such as abnormal lipid metabolism including hyperlipidemia and cardiovascular diseases. The food or drink of the present invention can also be used for preventing the onset of visceral fat obesity, metabolic syndrome, and the like. In addition, the food or drink of the present invention can treat or prevent various diseases, complications, and the like caused by visceral fat accumulation, and can reduce the risk of diseases, complications, and the like such as those mentioned above for the inventive medicament.
The food or beverage of the present invention is preferably sold as a food or beverage to which a label for inhibiting visceral fat accumulation is attached, and examples of the label include "a food or beverage containing a compound having an effect of inhibiting visceral fat accumulation" labeled as "for inhibiting visceral fat accumulation", and "a food or beverage containing a plant extract" labeled as "for inhibiting visceral fat accumulation". Further, since the compound of the present invention or a composition containing the same has an effect of inhibiting visceral fat accumulation, the indication that the food or drink is used for inhibiting visceral fat accumulation may mean that visceral fat obesity is improved. Therefore, the food or drink of the present invention can also be labeled as "for improving visceral fat obesity". In other words, the aforementioned indication that the food or drink is used for inhibiting visceral fat accumulation may be replaced with the indication of "for improving visceral fat obesity".
The terms used for these designations as described above are not limited to the terms "for inhibiting visceral fat accumulation" or "for improving visceral fat obesity", and it is not necessary to indicate that other terms are included within the scope of the present invention as long as the terms indicate the effect of inhibiting visceral fat accumulation, or preventing or improving visceral fat obesity. Such terms may be various usage-based labels that allow consumers to recognize the effect of inhibiting visceral fat accumulation or ameliorating visceral fat obesity. Examples of the markers include "a person who is fit for starting to worry about waist size", "a person who has a tendency to become visceral fat type obesity", and "a risk factor (risk) that can be used to reduce or eliminate metabolic syndrome".
The aforementioned term "identification" includes all actions for making consumers aware of the aforementioned use, and any identification reminding or analogizing the aforementioned use falls within the scope of "identification" of the present invention, regardless of the purpose, contents, objective objects, media, and the like of the identification. However, it is preferable to use the expression for identification that enables the consumer to directly recognize the aforementioned use. Specific examples include: the act of identifying the aforementioned use on the commodity or commodity package related to the food or beverage of the present invention, the act of transferring, delivering, and displaying for the purpose of transferring, delivering, or importing the commodity or commodity package identified by the aforementioned use such as the present invention, the act of displaying or distributing an advertisement, a price list, or a commercial document related to the commodity identified by the aforementioned use, or the act of providing information including the content identified by the aforementioned use or the like by an electromagnetic method (the internet or the like). On the other hand, the identification is preferably an identification approved by an administrative agency or the like (for example, identification in an approval-based form which is approved based on various systems specified by the administrative agency), and particularly preferably an identification on advertising materials such as packages, containers, catalogs, brochures and POPs, other texts, and the like at the point of sale.
Examples of markers further include markers that are health foods, functional foods, enteral nutrition foods, special purpose foods, foods with nutritional function instructions, quasi-drugs, etc., as well as markers approved by health, labor, and welfare departments, such as markers approved based on specific health food systems and the like. Examples of the latter include a logo as a specific health food, a logo as a specific health food with a restricted health description, a logo affecting the structure and function of the human body, a logo reducing the disease risk description, and more specifically, typical examples include a logo (in particular, a health-use logo) and the like as a logo for a specific health food prescribed in the health promotion act enforcement regulations (japan heisheng labour province No. 86, 30/4 2003).
The present invention will be explained more specifically with reference to the following examples. However, the scope of the present invention is not limited to the following examples.
First, the preparation examples describe that the compound or composition of the present invention can be prepared from a plant belonging to the liliaceae family.
[ preparation example 1]
100kg of aloe vera mesophyll (clear gel fraction) was liquefied by using a homogenizer, and 100L of an ethyl acetate/butanol mixture (3: 1) was added and stirred.
The mixture was allowed to stand overnight, and then the ethyl acetate/butanol mixture and the aqueous layer were separated to recover the ethyl acetate/butanol mixture. The ethyl acetate/butanol mixture extract obtained by concentrating the ethyl acetate/butanol mixture under reduced pressure weighed 13.5 g. A solution obtained by dissolving 13g of the extract in 1mL of chloroform/methanol mixture (1: 1) was loaded on a column packed with 400g of silica Gel 60(Merck corporation), the components were adsorbed on the column, and then the components were eluted with chloroform/methanol mixture by a gradient method in which the methanol concentration was gradually increased (the mixing ratio of chloroform to methanol was 100: 1, 25: 1, 10: 1, 5: 1 and 1: 1), and the eluate was separated for each mixing ratio of the above-mentioned mixtures. Of these fractions, the presence of the compound of the invention was confirmed in fractions eluted with a mixture of chloroform: methanol ═ 25: 1, by normal and reverse phase thin layer chromatography (Merck, Silica Gel 60F254 and RP-18F 2543).
The crude purified material (crude purified 1) containing the compound of the present invention weighed 3 g. In addition, yields of the crude purified product obtained from fractions eluted with a mixture of chloroform: methanol at 10: 1 and 1: 1 in the above procedure were 1.17 and 2.27g, respectively. The solvent of these fractions was removed, then each extract was dissolved in 1mL of chloroform/methanol mixture (1: 1), loaded on a column filled with 100g of silica Gel 60, the components were adsorbed on the column, and then the components were eluted with 1100mL of hexane/ethyl acetate mixture (4: 1). The eluted fractions were collected separately in the order of 300mL (fraction A), 300mL (fraction B) and 500mL (fraction C). Yields obtained after removal of solvent from fractions A, B and C were 0.6g, 1.35g and 0.15g, respectively. Concentration of the compound of the invention in fraction a (crude purification 2) was confirmed by normal phase and reverse phase thin layer chromatography. This crude purified compound 2 was further isolated by HPLC using COSMOSIL C18(Nacalai Tesque, Inc.) with the aid of a chloroform/hexane mixture (85: 15) to give 1.3mg of compound 3 (4-methylcholest-7-en-3-ol), 1.2mg of compound 4 (4-methylergost-7-en-3-ol) and 1mg of compound 5 (4-methylcoustan-7-en-3-ol). The structures of these compounds were confirmed by MS and NMR.
Example 1
In example 1, the inhibitory effect of a compound having a 4-methyl-7-ene cholestanol skeleton on visceral fat accumulation was studied using zdf (zuckerdiabeta fatty) rats, which are animal models of obese diabetes.
(1) Preparation of samples
Compound 3 (4-methylcholest-7-en-3-ol), compound 4 (4-methylergost-7-en-3-ol) and compound 5 (4-methylstiglin-7-en-3-ol) prepared in preparation example 1 were used as test samples 1, 2 and 3, respectively. Test samples 1-1, 2-1 and 3-1 were prepared by dissolving each test sample in DMSO and adjusting the concentration of each compound in each test sample to 10. mu.g/ml with distilled water. Test samples 1-2, 2-2 and 3-2 having a compound concentration of 1. mu.g/ml were prepared. In addition, the final concentration of DMSO was adjusted to 0.2%. In addition, a solution containing no test sample was prepared as a negative sample.
(2) Test method
Male ZDF rats (purchased from Charles River Laboratories, Inc., US) 6 weeks old were previously fed with a high fat Diet (Research Diet Inc.) for 1 month, and then the rats were divided into groups of 6 rats each. Solutions of the negative sample, test samples 1-1, 1-2, 2-1, 2-2, 3-1 and 3-2 were orally administered to each group of rats once a day using a probe at 1ml per 400g of rat weight for 44 consecutive days. On the 45 th day from the start of administration, the weight of mesenteric fat was measured as visceral fat.
(3) Test results
Table 1 shows the mesenteric fat weight at day 45 from the start of administration. The group of rats to which the negative samples were applied had a mesenteric fat weight of 6.83. + -. 1.10g, and the groups of test samples 1-1, 2-1 and 3-1 to which the compound concentration was 10. mu.g/ml had mesenteric fat weights of 4.48. + -. 1.34g, 3.78. + -. 0.26g and 3.36. + -. 1.67g, respectively, which were 65.0%, 54.9% and 48.7% of the group to which the negative samples were applied. Thus, it was confirmed that the test samples 1-1, 2-1 and 3-1 had a significant visceral fat accumulation-inhibiting effect. On the other hand, the test samples 1-2, 2-2 and 3-2, each administered with a compound concentration of 1. mu.g/ml, tended to decrease visceral fat, but no significant effect was observed. Moreover, no side effects are observed from a pathological point of view. In addition, the p-values in Table 1 represent the significance probability of Tukey-Kramer test.
[ Table 1]
In the table, "*"indicates that there is a statistically significant effect of inhibiting visceral fat accumulation.
Example 2
In example 2, the effect of a compound having a 4-methyl-7-cholestanol skeleton on food intake (food intake) and body weight gain (body weight gain) in rats was investigated.
(1) Preparation of samples
The test samples 1-1, 2-1 and 3-1 used in example 1 were used as test samples. In addition, a solution containing no test sample was prepared as a negative sample.
(2) Test method
Male ZDF rats (purchased from Charles River Laboratories, Inc., US) 6 weeks old were previously fed with a high fat Diet (Research Diet Inc.) for 1 month, the body weights of the rats were measured, and the rats were divided into groups of 6 rats, respectively. The solutions of test samples 1-1, 2-1, 3-1 and negative samples were orally administered to each group of rats once a day using a probe at 1ml per 400g of rat body weight for 44 consecutive days. The body weight of the rats was measured on the 42 th day after the start of the administration, and the difference between the body weight on the 42 th day and those measured before the start of the administration was taken as the body weight increase amount. In addition, the amount of food taken per day was measured approximately once a week from the beginning of the day, and the weight average value was taken as the amount of food taken per day.
(3) Test results
Table 2 shows the daily food intake and the body weight gain over a 42 day period for each rat. It was observed that the groups to which the test samples 1-1, 2-1 and 3-1 were applied, respectively, did not show a significant increase or decrease in the amount of food intake compared to the group to which the negative sample was applied. In addition, the increase in body weight (body weight gain) of the groups to which the test samples 1-1, 2-1 and 3-1 were applied, respectively, was almost the same as that of the group to which the negative sample was applied. Therefore, it was found that the compound having 4-methyl-7-cholestanol skeleton did not affect the food intake and body weight gain of rats.
[ Table 2]
Industrial applicability
According to the present invention, it is possible to provide a visceral fat accumulation inhibitor which can maintain a standard body weight without reducing the body weight and is effective for inhibiting the development of obesity without excessive dietary restrictions and the like, and a physiologically functional food or beverage (e.g., a specific health food) containing the visceral fat accumulation inhibitor. Therefore, diseases, complications, and the like (such as abnormal lipid metabolism and cardiovascular diseases) caused by visceral fat accumulation can be ameliorated or prevented, and the risk of these diseases, complications, and the like can also be reduced. In addition, the present invention also has an effect of preventing the onset of metabolic syndrome and lifestyle-related diseases (such as diabetes, hypertension and hyperlipidemia) which are considered as risk factors for metabolic syndrome.
Claims (2)
1. Use of a compound selected from the group consisting of 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstiglin-7-en-3-ol for the preparation of an inhibitor of visceral fat accumulation.
2. Use of a compound selected from the group consisting of 4-methylcholest-7-en-3-ol, 4-methylergost-7-en-3-ol and 4-methylstiglin-7-en-3-ol for the preparation of a food or beverage for inhibiting visceral fat accumulation.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005275172 | 2005-09-22 | ||
| JP275172/2005 | 2005-09-22 | ||
| JP287888/2005 | 2005-09-30 | ||
| JP2005287888 | 2005-09-30 | ||
| PCT/JP2006/318686 WO2007043294A1 (en) | 2005-09-22 | 2006-09-21 | Visceral fat accumulation inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1119403A1 HK1119403A1 (en) | 2009-03-06 |
| HK1119403B true HK1119403B (en) | 2011-05-13 |
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