title: GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism.
abstract: The hypothalamic arcuate nucleus contains two anatomically and functionally distinct populations of neurons-the agouti-related peptide (AgRP)- and pro-opiomelanocortin (POMC)-expressing neurons that integrate various nutritional, hormonal, and neuronal signals to regulate food intake and energy expenditure, and thereby help achieve energy homeostasis. AgRP neurons, also co-release neuropeptide Y (NPY) and γ-aminobutyric acid (GABA) to promote feeding and inhibit metabolism through at least three possible mechanisms: (1) suppression of the melanocortin signaling system through competitive binding of AgRP with the melanocortin 4 receptors; (2) NPY-mediated inhibition of post-synaptic neurons that reside in hypothalamic nuclei; (3) GABAergic inhibition of POMC neurons in their post-synaptic targets including the parabrachial nucleus (PBN), a brainstem structure that relays gustatory and visceral sensory information. Acute ablation of AgRP neurons in adult mice by the action of diphtheria toxin (DT) results in precipitous reduction of food intake, and eventually leads to starvation within 6days of DT treatment. Chronic delivery of bretazenil, a GABA(A) receptor partial agonist, into the PBN is sufficient to restore feeding and body weight when AgRP neurons are ablated, whereas chronic blockade of melanocortin 4 receptor signaling is inadequate. This review summarizes the physiological roles of a neural circuitry regulated by AgRP neurons in control of feeding behavior with particular emphasis of the GABA output to the parabrachial nucleus. We also describe a compensatory mechanism that is gradually engaged after ablation of AgRP neurons that allows mice to continue eating without them.
authors.affiliation: Howard Hughes Medical Institute and Departments of Biochemistry, University of Washington, Seattle, WA 98195, USA. qiwu@uw.edu
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D000855:Anorexia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D004734:Energy Metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D044101:Receptors, Melanocortin; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D054369:Agouti-Related Protein; D010446:Peptide Fragments; D044101:Receptors, Melanocortin; C412618:agouti-related peptide, (Yc(CRFFNAFC)Y); D005680:gamma-Aminobutyric Acid