Compositions and methods relating to glucose metabolism, weight control, and food intake

• US 20030032595A1
• Filed: 06/11/2002
• Published: 02/13/2003
• Est. Priority Date: 06/12/2001
• Status: Active Grant

• Current Assignee: Yale University
• Original Assignee: Yale University
• Inventors: Xu, Jianchao, Desir, Gary
• Granted Patent: US 6,861,405 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0362 Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/14 Quaternary ammonium compounds, e.g. edrophonium, choline betaines A61K31/205
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/4422 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C12N 15/8509 : for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: G01N 33/5008 : for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/502 : for testing non-proliferative effects
• CPC Class Codes: G01N 33/5044 : involving specific cell types
• CPC Class Codes: G01N 33/5061 : Muscle cells

Abstract

The present invention relates to weight control, control of body fat and food intake, and provides useful methods for treating, inter alia, obesity, diabetes and insulin insensitivity, and conditions, diseases, and disorders relating thereto. The invention also relates to methods of identifying useful compounds relating to weight loss, food intake, diabetes, and obesity, among other things, based on the discovery that inhibiting Kv1.3 activity mediates decreased food intake, weight loss, decreased body fat, increase glucose uptake, and increased insulin sensitivity, among other things.

Claims

1. A method for inducing weight loss in an animal, said method comprising administering to an animal a voltage-gated potassium channel Kv1.3 inhibiting amount of a Kv1.3 inhibitor, thereby inducing weight loss in said animal.

2. The method of claim 1, wherein said Kv1.3 inhibitor is selected from the group consisting of a ribozyme, an antisense nucleic acid, an antibody, a peptide and a chemical compound.

3. The method of claim 2, wherein said chemical compound is selected from the group consisting of 4-aminopyridine, H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide), Hstx1, ShK-Dap²², a short scorpion toxin, clotrimazole, paxilline, stichodactyla toxin, melatonin, tetraethylammonium chloride, α

-dendrotoxin, β

-dendrotoxin, tityustoxin-Kα

, noxiustoxin, agitoxin-2, κ

-conotoxin, hanatoxin, hongotoxin, correolide, WIN 17317-3 (1-Benzyl-7-chloro-4-n-propylimino-1,4-dihydroquiniline), UK78282 (4-[(Diphenylmethoxy)methyl]-1-[3-(4-methyoxyphenyl)propyl]-piperidine), CP 339818 hydrochloride (N-[1-(Phenylmethyl)-4( 1H)-quinolinylidene]-1 pentanamine hydrochloride), iberiotoxin, verapamil, nifedipine, fluxetime, a serotonin uptake inhibitor, and a serotonin agonist.

4. The method of claim 3, wherein said short scorpion toxin is selected from the group consisting of bmtx1, bmktx, bmtx2, bmp02, neurotoxin, tstx-k alpha, margatoxin, noxiustoxin, maurotoxin, charybdotoxin, scyllatoxin, agitoxin, chlorootoxin, butantoxin, toxin ts kappa, toxin I5a, toxin analog, toxin analog P01, OSK1 toxin, kaliotoxin, LQ2 toxin, and pandinus toxin.

5. A method for decreasing body fat in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to said animal, thereby decreasing body fat in said animal.

6. The method of claim 5, wherein said animal is selected from the group consisting of a bird, a rodent, and a mammal, and further wherein said mammal is selected from the group consisting of a cow, a pig, a sheep, a buffalo, a beefalo, a bison, a deer, a goat, and a human.

7. A method for increasing insulin sensitivity in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to an animal, thereby increasing insulin sensitivity in said animal.

8. A method for decreasing food intake in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to an animal, thereby decreasing food intake in said animal.

9. A method for affecting appetite in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to an animal, thereby affecting appetite in said animal.

10. A method for treating obesity in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to an animal, thereby treating obesity in said animal.

11. A method for preventing obesity in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to an animal, thereby preventing obesity in said animal.

12. A method for treating a glucose-metabolism disease or disorder in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to an animal, thereby treating a glucose-metabolism disorder in said animal.

13. The method of claim 12, wherein said glucose-metabolism disease or disorder is selected from the group consisting of obesity, diabetes, insulin resistance, glucose intolerance, hyerinsulinemia, Syndrome X, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, atherosclerosis, and diabetic renal disease.

14. A method of producing a transgenic non-human mammal having a decreased body fat content compared with the body fat content of an otherwise identical non-transgenic mammal, said method comprising producing a transgenic non-human mammal lacking Kv1.3 activity, thereby producing a transgenic non-human mammal having decreased body fat content compared with said body fat content of said otherwise identical non-transgenic mammal.

15. A method for affecting physical activity in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to an animal, thereby affecting physical activity in said animal.

16. A method for affecting metabolic rate in an animal, said method comprising administering a Kv1.3 inhibiting amount of a Kv1.3 inhibitor to an animal, thereby affecting metabolic rate in said animal.

17. A method of identifying a compound useful for treatment of obesity in an animal, said method comprising administering a compound to an animal and comparing the level of Kv1.3 activity in said animal with the level of Kv1.3 activity in an otherwise identical animal to which said compound is not administered, wherein a lower level of Kv1.3 activity in said animal to which said compound was administered compared with said level of Kv1.3 activity in said otherwise identical animal is an indication that said compound is useful for treatment of obesity, thereby identifying a compound useful for treatment of obesity in said animal.

18. A compound identified by the method of claim 17.

19. A method of identifying a compound useful for treatment of obesity, said method comprising contacting a cell with a compound and comparing the level of Kv1.3 activity in said cell contacted with said compound with the level of Kv1.3 activity in an otherwise identical cell not contacted with said compound, wherein a lower level of Kv1.3 activity in said cell contacted with said compound compared with said level of Kv1.3 activity in said otherwise identical cell not contacted with said compound is an indication that said compound is useful for treatment of obesity, thereby identifying a compound useful for treatment of obesity.

20. The method of claim 19, wherein said cell is selected from the group consisting of a skeletal muscle cell, a fat cell, a liver cell, a brain cell, a kidney cell, and a pancreas cell.

21. The method of claim 20, wherein said skeletal muscle cell is a rat L6 cell.

22. A method of identifying a compound that inhibits Kv1.3 activity in an animal, said method comprising administering a compound to an animal and comparing the level of Kv1.3 activity in said animal with the level of Kv1.3 activity in said animal prior to administration of said compound, wherein said Kv1.3 activity is selected from the group consisting of increased cellular glucose uptake, decreased food intake, decreased percent body fat, increased insulin sensitivity, increased physical activity, and increased metabolic rate, wherein a decrease in said level of Kv1.3 activity in said animal compared with said level of Kv1.3 activity in said animal prior to administration of said compound is an indication that said compound inhibits Kv1.3, thereby identifying a compound that inhibits Kv1.3 activity in said mammal.

23. A compound identified by the method of claim 22.

24. A kit for treating obesity in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.

25. A kit for decreasing body fat in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.

26. A kit for inducing weight loss in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.

27. A kit for increasing insulin sensitivity in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.

28. A kit for decreasing food intake in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.

29. A kit for preventing obesity in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof .

30. The kit of claim 29, wherein said inhibitor is selected from the group consisting of 4-aminopyridine, H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide), Hstx1, ShK-Dap²², a short scorpion toxin, clotrimazole, paxilline, stichodactyla toxin, melatonin, tetraethylammonium chloride, α

-dendrotoxin, β

-dendrotoxin, tityustoxin-Kα

, noxiustoxin, agitoxin-2, κ

-conotoxin, hanatoxin, hongotoxin, correolide, WIN 17317-3 (1-Benzyl-7-chloro-4-n-propylimino-1,4-dihydroquiniline), UK78282 (4-[(Diphenylmethoxy)methyl]-1-[3-(4-methyoxyphenyl)propyl]-piperidine), CP 339818 hydrochloride (N-[1-(Phenylmethyl)-4(1H)-quinolinylidene]-1 pentanamine hydrochloride), iberiotoxin, verapamil, nifedipine, fluxetime, a serotonin uptake inhibitor, and a serotonin agonist.

31. The method of claim 30, wherein said short scorpion toxin is selected from the group consisting of bmtx1, bmktx, bmtx2, bmp02, neurotoxin, tstx-k alpha, margatoxin, noxiustoxin, maurotoxin, charybdotoxin, scyllatoxin, agitoxin, chlorootoxin, butantoxin, toxin ts kappa, toxin I5a, toxin analog, toxin analog P01, OSK1 toxin, kaliotoxin, LQ2 toxin, and pandinus toxin.

32. A kit for treating a glucose-metabolism disease or disorder in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.

33. The kit of claim 32, wherein said inhibitor is selected from the group consisting of 4-aminopyridine, H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide), Hstx1, ShK-Dap²², a short scorpion toxin, clotrimazole, paxilline, stichodactyla toxin, melatonin, tetraethylammonium chloride, α

-dendrotoxin, β

-dendrotoxin, tityustoxin-Kα

, noxiustoxin, agitoxin-2, κ

-conotoxin, hanatoxin, hongotoxin, correolide, WIN 17317-3 (1-Benzyl-7-chloro-4-n-propylimino-1,4-dihydroquiniline), UK78282 (4-[(Diphenylmethoxy)methyl]-1-[3-(4-methyoxyphenyl)propyl]-piperidine), CP 339818 hydrochloride (N-[1-(Phenylmethyl)-4(1H)-quinolinylidene]-1 pentanamine hydrochloride), iberiotoxin, verapamil, nifedipine, fluxetime, a serotonin uptake inhibitor, and a serotonin agonist.

34. A kit for affecting appetite in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.

35. A kit for affecting physical activity in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.

36. A kit for affecting metabolic rate in an animal, said kit comprising an effective amount of a Kv1.3 inhibitor, said kit further comprising an applicator and an instructional material for the use thereof.