Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation.
Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.
Wu
Qi
Q
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Boyle
Maureen P
MP
Palmiter
Richard D
RD
D000818:Animals; D000855:Anorexia / Q000503:physiopathology*; D001253:Astrocytes / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D005968:Glutamate Decarboxylase; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012249:Rhombencephalon / Q000378:metabolism*; D015398:Signal Transduction; D013217:Starvation / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D058785:GABA-A Receptor Agonists; D016760:Proto-Oncogene Proteins c-fos; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1