IP Library › Patent Application 10489804
Patent Application
App. No. 10/489,804

Assessment of neurons in the arcuate nucleus to screen for agents that modify feeding behavior

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Quick Facts
Patent No.
US None
App. No.
10/489,804
Abstract

Screening methods of use in identifying agents that affect caloric intake, food intake, appetite, and energy expenditure are disclosed herein. These methods are used to identify agents of use in treating obesity, or that can be used to decrease the weight of a subject. These methods can also be used to identify agents of use in treating anorexia or cachexia and can be used to increase appetite and to increase the weight and lean body mass of a subject.

Claims (89)

1 . A method for screening for an agent that affects caloric intake, comprising

contacting a histological section of an arcuate nucleus from a mouse expressing a marker in proopiomelanocortin neurons with an agent to be tested, wherein the mouse comprises a transgene comprising a nucleic acid encoding the marker operably linked to a proopiomelanocortin nucleic acid sequence, wherein the proopiomelanocortin nucleic acid sequence directs expression of the marker in proopiomelanocortin neurons in the arcuate nucleus of the mouse; and

assaying for an electrophysiological response of a proopiomelanocortin neuron in the histological section, thereby determining if the agent affects caloric intake.

2 . The method of claim 1 , wherein the agent specifically binds a receptor on the proopiomelanocortin neuron.

3 . The method of claim 1 , wherein the agent specifically binds a melanocortin receptor or a μ-opioid receptor.

4 . The method of claim 3 , wherein the agent specifically binds the melanocortin 3 receptor.

5 . The method of claim 1 , wherein the agent specifically binds a receptor on a neuropeptide Y neuron.

6 . The method of claim 5 , wherein the agent specifically binds the Y2 receptor.

7 . The method of claim 1 , wherein the electrophysiological response comprises induction of current or a change in the membrane potential of the proopiomelanocortin neuron.

8 . The method of claim 1 , wherein the electrophysiological response comprises depolarization of the proopiomelanocortin neuron.

9 . The method of claim 1 , wherein the marker is a fluorescent protein.

10 . The method of claim 9 , wherein the fluorescent protein is green fluorescent protein.

11 . The method of claim 1 , wherein assaying an electrophysiological response comprises a whole cell recording.

12 . The method of claim 1 , wherein assaying an electrophysiological response comprises determining a resting membrane potential of a proopiomelanocortin neuron.

13 . The method of claim 1 , wherein assaying an electrophysiological response comprises determining a GABA-mediated inhibitory postsynaptic current or determining the action potential frequency of a proopiomelanocortin neuron.

14 . The method of claim 1 , wherein the proopiomelanocortin nucleic acid sequences comprises a proopiomelanocortin regulatory nucleic acid sequence and a nucleic acid sequence encoding a marker.

15 . The method of claim 1 , wherein the agent is a polypeptide, a chemical compound, a salt, or a neurotransmitter.

16 . The method of claim 1 , wherein the agent is not PYY and is not a polypeptide fragment of PYY that is more than 10 amino acids in length.

17 . The method of claim 1 , wherein the agent is not a polypeptide.

18 . A compound identified by the method of claim 16 .

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

20 . A method for screening for an agent that affects appetite, comprising

contacting a histological section of an arcuate nucleus from a mouse expressing a marker in proopiomelanocortin neurons with an agent to be tested, wherein the mouse comprises a transgene comprising a nucleic acid encoding the marker operably linked to a proopiomelanocortin nucleic acid sequence, wherein the proopiomelanocortin nucleic acid sequence directs expression of the marker in proopiomelanocortin neurons in the arcuate nucleus of the mouse; and

assaying for an electrophysiological response of a proopiomelanocortin neuron in the histological section, thereby determining if the agent affects appetite.

21 . The method of claim 20 , wherein the agent specifically binds a receptor on the proopiomelanocortin neuron.

22 . The method of claim 20 , wherein the agent specifically binds a melanocortin receptor or a μ-opioid receptor.

23 . The method of claim 22 , wherein the agent specifically binds the melanocortin 3 receptor.

24 . The method of claim 20 , wherein the agent specifically binds a receptor on a neuropeptide Y neuron.

25 . The method of claim 24 , wherein the agent specifically binds the Y2 receptor.

26 . The method of claim 20 , wherein the electrophysiological response comprises induction of current or a change in the membrane potential of the proopiomelanocortin neuron.

27 . The method of claim 20 , wherein the electrophysiological response comprises depolarization of the proopiomelanocortin neuron.

28 . The method of claim 20 , wherein the marker is a fluorescent protein.

29 . The method of claim 28 , wherein the fluorescent protein is green fluorescent protein.

30 . The method of claim 20 , wherein assaying an electrophysiological response comprises a whole cell recording.

31 . The method of claim 20 , wherein assaying an electrophysiological response comprises determining a resting membrane potential of a proopiomelanocortin neuron.

32 . The method of claim 20 , wherein assaying an electrophysiological response comprises determining a GABA-mediated inhibitory postsynaptic current or determining the action potential frequency of a proopiomelanocortin neuron.

33 . The method of claim 20 , wherein the proopiomelanocortin nucleic acid sequences comprises a proopiomelanocortin regulatory nucleic acid sequence and a nucleic acid sequence encoding a marker.

34 . The method of claim 20 , wherein the agent is a polypeptide, a chemical compound, a salt, or a neurotransmitter.

35 . The method of claim 20 , wherein the agent is not PYY and is not a polypeptide fragment of PYY that is more than 10 amino acids in length.

36 . The method of claim 20 , wherein the agent is not a polypeptide.

37 . A compound identified by the method of claim 35 .

38 . A compound identified by the method of claim 36 .

39 . A method for screening for an agent that affects food intake, comprising

contacting a histological section of an arcuate nucleus from a mouse expressing a marker in proopiomelanocortin neurons with an agent to be tested, wherein the mouse comprises a transgene comprising a nucleic acid encoding the marker operably linked to a proopiomelanocortin nucleic acid sequence, wherein the proopiomelanocortin nucleic acid sequence directs expression of the marker in proopiomelanocortin neurons in the arcuate nucleus of the mouse; and

assaying for an electrophysiological response of a proopiomelanocortin neuron in the histological section, thereby determining if the agent affects food intake.

40 . The method of claim 39 , wherein the agent specifically binds a receptor on the proopiomelanocortin neuron.

41 . The method of claim 39 , wherein the agent specifically binds a melanocortin receptor or a μ-opioid receptor.

42 . The method of claim 41 , wherein the agent specifically binds the melanocortin 3 receptor.

43 . The method of claim 39 , wherein the agent specifically binds a receptor on a neuropeptide Y neuron.

44 . The method of claim 43 , wherein the agent specifically binds the Y2 receptor.

45 . The method of claim 39 , wherein the electrophysiological response comprises induction of current or a change in the membrane potential of the proopiomelanocortin neuron.

46 . The method of claim 39 , wherein the electrophysiological response comprises depolarization of the proopiomelanocortin neuron.

47 . The method of claim 39 , wherein the marker is a fluorescent protein.

48 . The method of claim 47 , wherein the fluorescent protein is green fluorescent protein.

49 . The method of claim 39 , wherein assaying an electrophysiological response comprises a whole cell recording.

50 . The method of claim 39 , wherein assaying an electrophysiological response comprises determining a resting membrane potential of a proopiomelanocortin neuron.

51 . The method of claim 39 , wherein assaying an electrophysiological response comprises determining a GABA-mediated inhibitory postsynaptic current or determining the action potential frequency of a proopiomelanocortin neuron.

52 . The method of claim 39 , wherein the proopiomelanocortin nucleic acid sequences comprises a proopiomelanocortin regulatory nucleic acid sequence and a nucleic acid sequence encoding a marker.

53 . The method of claim 39 , wherein the agent is a polypeptide, a chemical compound, a salt, or a neurotransmitter.

54 . The method of claim 39 , wherein the agent is not PYY and is not a polypeptide fragment of PYY that is more than 10 amino acids in length.

55 . The method of claim 39 , wherein the agent is not a polypeptide.

56 . A compound identified by the method of claim 53 .

57 . A compound identified by the method of claim 54 .

58 . A method for screening for an agent that affects caloric intake, energy expenditure, appetite, or food intake, comprising

contacting a histological section of an arcuate nucleus, with an agent to be tested, wherein proopiomelanocortin neurons in the histological section express a heterologous marker that distinguishes the proopiomelanocortin neurons from other cells in the histological section; and

assaying for an electrophysiological response of a proopiomelanocortin neuron in the histological section, thereby determining if the agent affects caloric intake, appetite, energy expenditure, or food intake.

59 . The method of claim 58 , wherein the heterologous marker is expressed from a transgene.

60 . The method of claim 58 , wherein the agent specifically binds a receptor on the proopiomelanocortin neuron.

61 . The method of claim 58 , wherein the agent specifically binds a melanocortin receptor or a μ-opioid receptor.

62 . (canceled).

62 . The method of claim 58 , wherein the agent specifically binds a receptor on a neuropeptide Y neuron.

63 . The method of claim 62 , wherein the agent specifically binds the Y2 receptor.

64 . The method of claim 58 , wherein the electrophysiological response comprises induction of current or a change in the membrane potential of the proopiomelanocortin neuron.

65 . The method of claim 58 , wherein the electrophysiological response comprises depolarization of the proopiomelanocortin neuron.

66 . The method of claim 58 , wherein the heterologous marker is a fluorescent protein.

67 . The method of claim 66 , wherein the fluorescent protein is green fluorescent protein.

68 . The method of claim 58 , wherein assaying an electrophysiological response comprises a whole cell recording.

69 . The method of claim 58 , wherein assaying an electrophysiological response comprises determining a resting membrane potential of a proopiomelanocortin neuron.

70 . The method of claim 58 , wherein assaying an electrophysiological response comprises determining a GABA-mediated inhibitory postsynaptic current or determining the action potential frequency of a proopiomelanocortin neuron.

71 . The method of claim 58 , wherein the proopiomelanocortin nucleic acid sequences comprises a proopiomelanocortin regulatory nucleic acid sequence and a nucleic acid sequence encoding proopiomelanocortin.

72 . The method of claim 58 , wherein the agent is not PYY and is not a polypeptide fragment of PYY that is more than 10 amino acids in length.

73 . The method of claim 58 , wherein the agent is not a polypeptide.

74 . A compound identified by the method of claim 72 .

75 . A compound identified by the method of claim 73 .

76 . The method of claim 1 , wherein assaying for an electrophysiological response of a proopiomelanocortin neuron comprises a loose cell attached patch recording.

77 . The method of claim 20 , wherein assaying for an electrophysiological response of a proopiomelanocortin neuron comprises a loose cell attached patch recording.

78 . The method of claim 39 , wherein assaying for an electrophysiological response of a proopiomelanocortin neuron comprises a loose cell attached patch recording.

79 . The method of claim 58 , wherein assaying for an electrophysiological response of a proopiomelanocortin neuron comprises a loose cell attached patch recording.

80 . The method of claim 61 , wherein the agent specifically binds the melanocortin 3 receptor.

Assignments (1)
EXECUTIVE ORDER 9424, CONFIRMATORY LICENSE Recorded Mar 12, 2009
From: OREGON HEALTH AND SCIENCE UNIVERSITY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
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