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The Journal of Neuroscience, July 4, 2007, 27(27):7125-7129; doi:10.1523/JNEUROSCI.1025-07.2007

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Brief Communications
Glucagon-Like Peptide 1 Stimulates Hypothalamic Proopiomelanocortin Neurons

Xiaosong Ma,¹ Jens Bruning,² and Frances M. Ashcroft¹

¹University Laboratory of Physiology, Oxford OX1 3PT, United Kingdom, and ²Institute for Genetics, Department of Mouse Genetics and Metabolism, 50674 Köln, Germany

Correspondence should be addressed to Prof. Frances Ashcroft, University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK. Email: frances.ashcroft{at}physiol.ox.ac.uk

Glucagon-like peptide 1 (GLP-1) is a potent inhibitor of food intake. GLP-1 receptor mRNA is densely expressed in hypothalamic arcuate nucleus (ARC) and precisely overlaps the area occupied by proopiomelanocortin (POMC) neurons. Activation of POMC neurons suppresses appetite, and lack of POMC-derived peptides or inhibition of POMC neuronal firing causes obesity. Here, we identify living POMC cells in mouse ARC brain slices by targeted expression of green fluorescent protein. Using whole-cell patch-clamp recordings, we show that GLP-1 increases the spontaneous action-potential firing of POMC neurons. The stimulatory effect of GLP-1 was mimicked by GLP-1 receptor agonist exendin-4 and abolished by the receptor antagonist exendin 9-39. The effect of GLP-1 was unchanged in the presence of the synaptic blockers DAP5 (D(-)-2-amino-5-phosphonopentanoic acid)/CNQX (6-cyano-7-nitroquinoxaline-2,3-dione disodium salt) and picrotoxin. These results suggest that GLP-1 excites POMC neurons postsynaptically, via interaction with GLP-1 receptors on POMC cells. Whole-cell Ca²⁺ currents increased 70% in the presence of GLP-1, and this effect was abolished by L-type Ca²⁺ channel antagonist nifedipine. Forskolin (which activates cAMP) mimicked the effects of GLP-1 and the PKA inhibitor Rp-8-Bromo-cAMPS (8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer) blocked GLP-1 action. These data indicate that GLP-1 stimulates the electrical activity of hypothalamic POMC neurons by activation of PKA and a subsequent increase in L-type Ca²⁺ current. This effect may contribute to the anorectic action of GLP-1, because excitation of POMC cells is well established to reduce food intake.

Key words: GLP-1; POMC neurons; L-type Ca²⁺ channel; PKA; appetite; obesity

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Received March 7, 2007; revised May 14, 2007; accepted May 30, 2007.

Correspondence should be addressed to Prof. Frances Ashcroft, University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK. Email: frances.ashcroft{at}physiol.ox.ac.uk

This article has been cited by other articles:

				M. R. Hayes, K. P. Skibicka, and H. J. Grill Caudal Brainstem Processing Is Sufficient for Behavioral, Sympathetic, and Parasympathetic Responses Driven by Peripheral and Hindbrain Glucagon-Like-Peptide-1 Receptor Stimulation Endocrinology, August 1, 2008; 149(8): 4059 - 4068. [Abstract] [Full Text] [PDF]

				D. A. Sandoval, D. Bagnol, S. C. Woods, D. A. D'Alessio, and R. J. Seeley Arcuate Glucagon-Like Peptide 1 Receptors Regulate Glucose Homeostasis but Not Food Intake Diabetes, August 1, 2008; 57(8): 2046 - 2054. [Abstract] [Full Text] [PDF]

				X. Ma, L. Zubcevic, and F. M. Ashcroft Glucose regulates the effects of leptin on hypothalamic POMC neurons PNAS, July 15, 2008; 105(28): 9811 - 9816. [Abstract] [Full Text] [PDF]

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