Regulation of food intake and glucose production by modulation of long-chain fatty acyl-coa levels in the hypothalamus

• US 20070093434A1
• Filed: 02/12/2004
• Published: 04/26/2007
• Est. Priority Date: 02/13/2003
• Status: Active Grant

• Current Assignee: National Institutes of Health (NIH) (Government of the United States of America)
• Original Assignee: Albert Einstein College of Medicine of Yeshiva University
• Inventors: Rossetti, Luciano, Obici, Silvana
• Granted Patent: US 7,705,016 B2
• Time in Patent Office: Days
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/12 catalytic nucleic acids, e.g. ribozymes
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2799/04 in vivo
• CPC Class Codes: C12N 9/1029 transferring groups other than amino-acyl groups (2.3.1)
• CPC Class Codes: C12Y 203/01021 : Carnitine O-palmitoyltransferase (2.3.1.21)

Abstract

Methods of reducing food intake and glucose production in a mammal, or restoring hepatic autoregulation are provided. The methods involve increasing long-chain fatty acyl-Co-A (LC-CoA) levels in the hypothalamus, or stimulating efferent fibers in the hepatic branch of the vagus nerve. Also provided are methods of increasing food intake and glucose production in a mammal. The methods involve decreasing long-chain fatty acyl-Co-A (LC-CoA) levels in the hypothalamus of the mammal.

Claims

1. A method of reducing food intake and glucose production in a mammal, the method comprising increasing long-chain fatty acyl-Co-A (LC-CoA) levels in the hypothalamus of the mammal,

wherein the mammal has at least one condition selected from the group consisting of obesity, type 2 diabetes, leptin resistance, insulin resistance, gonadotropin deficiency, amenorrhea, and polycystic ovary syndrome.

2. The method of claim 1, wherein the LC-CoA is increased by decreasing the activity of an LC-CoA-decreasing molecule in the hypothalamus.

3. The method of claim 2, wherein the LC-CoA-decreasing molecule is selected from the group consisting of carnitine palmitoyl transferase 1 (CPT1), malonyl-CoA decarboxylase, carnitine acylcarnitine translocase, acyl-CoA dehydrogenase, 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, 3-oxyacyl-CoA thiolase, and acyl-CoA hydrolase.

4. The method of claim 2, wherein the LC-CoA-decreasing molecule is CPT 1.

5. The method of claim 4, wherein the CPT1 is carnitine palmitoyl transferase-1, liver isoform (CPT1L).

6. The method of claim 2, wherein the activity of the LC-CoA-decreasing molecule is decreased by administering a pharmaceutical composition to the brain of the mammal, the pharmaceutical composition comprising a small molecule capable of decreasing the activity of the LC-CoA-decreasing molecule.

7. The method of claim 6, wherein the pharmaceutical composition is administered to the brain of the mammal by direct administration of the composition to the brain.

8. The method of claim 6, wherein the small molecule is capable of crossing the blood-brain barrier when present in the pharmaceutical composition.

9. The method of claim 2, wherein the activity of the LC-CoA-decreasing molecule is decreased by administering an antibody or antibody fragment comprising an antibody binding site to the brain of the mammal, wherein the antibody or antibody fragment is capable of binding to the LC-CoA-decreasing molecule to inhibit the activity of the molecule.

10. The method of claim 2, wherein the activity of the LC-CoA-decreasing molecule is decreased by administering an inhibitory nucleic acid or mimetic to the brain of the mammal.

11. The method of claim 10, wherein the inhibitory nucleic acid or mimetic is selected from the group consisting of a ribozyme, an antisense compound, an aptamer and an iRNA.

12. The method of claim 10, wherein the inhibitory nucleic acid or mimetic is a ribozyme.

13. The method of claim 12, wherein the LC-CoA-decreasing molecule is CPT1L and the ribozyme comprises the sequence 5′

-ACAGCACGCCGCUCUGAUGAGUCCGUGAGGACGAAACCACGUUCUUCGUC-3′

14. The method of claim 1, wherein the LC-CoA levels are increased by increasing the activity of an LC-CoA-increasing molecule in the hypothalamus.

15. The method of claim 14, wherein the LC-CoA-increasing molecule is selected from the group consisting of acetyl-CoA carboxylase, fatty acid transporter molecule, acyl-CoA synthetase, carnitine palmitoyl transferase 11, and acyl-CoA thioesterase.

16. The method of claim 14, wherein the activity of the LC-CoA-increasing molecule is increased by administering a pharmaceutical composition to the brain of the mammal, the pharmaceutical composition comprising a small molecule capable of stimulating production or activity of the LC-CoA-increasing molecule.

17. The method of claim 16, wherein the pharmaceutical composition is administered to the brain of the mammal by direct administration to the brain.

18. The method of claim 16, wherein the pharmaceutical composition is capable of crossing the blood-brain barrier.

19. The method of claim 14, wherein the activity of the LC-CoA-increasing molecule is increased by administering the molecule or a vector encoding the molecule to the hypothalamus.

20. The method of claim 19, wherein the molecule is administered to the hypothalamus in a pharmaceutically acceptable carrier.

21. The method of claim 19, wherein a vector encoding the molecule is administered to the hypothalamus.

22. The method of claim 21, wherein the vector is a viral vector.

23. The method of claim 1, wherein the LC-CoA is increased by directly administering LC-CoA to the brain.

24. The method of claim 1, wherein the mammal is a rodent.

25. The method of claim 1, wherein the mammal is a human.

26. The method of claim 1, wherein the mammal is diabetic.

27. The method of claim 1, wherein the mammal is at least 5% over normal body weight.

28. The method of claim 1, wherein the mammal is at least 20% over normal body weight.

29. The method of claim 1, wherein food intake is decreased by at least 5%.

30. The method of claim 1, wherein food intake is decreased by at least 20%.

31. The method of claim 1, wherein food intake is decreased by at least 40%.

32. A method of increasing food intake and glucose production in an mammal suffering from a condition characterized by insufficient food intake or glucose production, the method comprising decreasing long-chain fatty acyl-Co-A (LC-CoA) levels in the hypothalamus of the mammal.

33. The method of claim 32, wherein the LC-CoA levels are decreased by decreasing the activity of an LC-CoA-increasing molecule in the hypothalamus.

34. The method of claim 33, wherein the LC-CoA-increasing molecule is selected from the group consisting of acetyl-CoA carboxylase, fatty acid transporter molecule, acyl-CoA synthetase, carnitine palmitoyl transferase II, and acyl-CoA thioesterase.

35. The method of claim 33, wherein the activity of the LC-CoA-increasing molecule is decreased by administering a pharmaceutical composition to the brain of the mammal, the pharmaceutical composition comprising a small molecule capable of inhibiting the activity of the LC-CoA-decreasing molecule.

36. The method of claim 35, wherein the pharmaceutical composition is administered to the brain of the mammal by directly administering the composition to the brain of the mammal.

37. The method of claim 35, wherein the small molecule is capable of crossing the blood-brain barrier when present in the pharmaceutical composition.

38. The method of claim 33, wherein the activity of the LC-CoA-increasing molecule is decreased by administering an antibody or antibody fragment comprising an antibody binding site to the brain of the mammal, wherein the antibody or antibody fragment is capable of binding to the LC-CoA-increasing molecule to inhibit the activity of the molecule.

39. The method of claim 33, wherein the activity of the LC-CoA-increasing molecule is decreased by administering an inhibitory nucleic acid or mimetic to the brain of the mammal.

40. The method of claim 39, wherein the inhibitory nucleic acid or mimetic is selected from the group consisting of a ribozyme, an antisense compound, an aptamer and an iRNA.

41. The method of claim 39, wherein the inhibitory nucleic acid or mimetic is a ribozyme.

42. The method of claim 32, wherein the LC-CoA levels are decreased by increasing the activity of an LC-CoA-decreasing molecule in the hypothalamus.

43. The method of claim 42, wherein the LC-CoA-decreasing molecule is selected from the group consisting of carnitine palmitoyl transferase 1 (CPT1), malonyl-CoA decarboxylase, carnitine acylcarnitine translocase, acyl-CoA dehydrogenase, 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, 3-oxyacyl-CoA thiolase, and acyl-CoA hydrolase.

44. The method of claim 42, wherein the LC-CoA-decreasing molecule is CPT1.

45. The method of claim 44, wherein the CPT1 is carnitine palmitoyl transferase-1, liver isoform (CPT1L).

46. The method of claim 42, wherein the activity of the LC-CoA-decreasing molecule is increased by administering a pharmaceutical composition to the brain of the mammal, the pharmaceutical composition comprising a small molecule capable of increasing activity of the LC-CoA-increasing molecule.

47. The method of claim 46, wherein the pharmaceutical composition is administered to the brain by direct administration to the brain.

48. The method of claim 46, wherein the pharmaceutical composition is capable of crossing the blood-brain barrier.

49. The method of claim 42, wherein the activity of the LC-CoA-increasing molecule is increased by administering the molecule or a vector encoding the molecule to the hypothalamus.

50. The method of claim 49, wherein the molecule is administered to the hypothalamus in a pharmaceutically acceptable carrier.

51. The method of claim 49, wherein a vector encoding the molecule is administered to the hypothalamus.

52. The method of claim 51, wherein the vector is a viral vector.

53. The method of claim 32, wherein the mammal is a rodent.

54. The method of claim 32, wherein the mammal is a human.

55. The method of claim 32, wherein the mammal is at least 10% below normal body weight.

56. The method of claim 32, wherein the mammal is at least 20% below normal body weight.

57. The method of claim 32, wherein food intake is increased by at least 5%.

58. The method of claim 32, wherein food intake is increased by at least 20%.

59. The method of claim 32, wherein food intake is increased by at least 40%.

60. The method of claim 32, wherein the mammal is undergoing a treatment that causes insufficient food intake or glucose production.

61. The method of claim 60, wherein the treatment is administration of a cancer chemotherapy.

62. The method of claim 32, wherein the mammal has a viral infection that causes insufficient food intake or glucose production.

63. The method of claim 62, wherein the mammal is a human and the infection is with HIV-1.

64. The method of claim 32, wherein the mammal is hypoglycemic.

65. A method of restoring hepatic autoregulation in a mammal with inadequate hepatic autoregulation, the method comprising increasing long-chain fatty acyl-Co-A (LC-CoA) levels in the hypothalamus of the mammal.

66. The method of claim 65, wherein the LC-CoA is increased by decreasing the activity of an LC-CoA-decreasing molecule in the hypothalamus.

67. The method of claim 66, wherein the LC-CoA-decreasing molecule is CPT1.

68. The method of claim 67, wherein the CPT1 is carnitine palmitoyl transferase-1, liver isoform (CPT1L).

69. The method of claim 66, wherein the activity of the LC-CoA-decreasing molecule is decreased by administering a pharmaceutical composition to the brain of the mammal, the pharmaceutical composition comprising a small molecule capable of decreasing the activity of the LC-CoA-decreasing molecule.

70. The method of claim 66, wherein the activity of the LC-CoA-decreasing molecule is decreased by administering an antibody or antibody fragment comprising an antibody binding site to the brain of the mammal, wherein the antibody or antibody fragment is capable of binding to the LC-CoA-decreasing molecule to inhibit the activity of the molecule.

71. The method of claim 66, wherein the activity of the LC-CoA-decreasing molecule is decreased by administering an inhibitory nucleic acid or mimetic to the brain of the mammal.

72. The method of claim 71, wherein the inhibitory nucleic acid or mimetic is a ribozyme.

73. The method of claim 65, wherein the LC-CoA levels are increased by increasing the activity of an LC-CoA-increasing molecule in the hypothalamus.

74. The method of claim 65, wherein the LC-CoA is increased by directly administering LC-CoA to the brain.

75. The method of claim 65, wherein the mammal is a rodent.

76. The method of claim 65, wherein the mammal is a human.

77. The method of claim 65, wherein the mammal is diabetic.

78. A method of reducing food intake and glucose production in a mammal, the method comprising stimulating an efferent hepatic vagus nerve fiber, wherein the mammal has at least one condition selected from the group consisting of obesity, type 2 diabetes, leptin resistance, insulin resistance, gonadotropin deficiency, amenorrhea, and polycystic ovary syndrome.

79. The method of claim 78, wherein the efferent hepatic vagus nerve fiber is stimulated electrically.

80. The method of claim 78, wherein the afferent hepatic vagus nerve fibers are not stimulated.

81. The method of claim 78, wherein the efferent hepatic vagus nerve fiber is stimulated by directly stimulating the liver.

82. A method of restoring hepatic autoregulation in a mammal with inadequate hepatic autoregulation, the method comprising stimulating an efferent hepatic vagus nerve fiber.