title: Leptin acts via lateral hypothalamic area neurotensin neurons to inhibit orexin neurons by multiple GABA-independent mechanisms.
abstract: The adipocyte-derived hormone leptin modulates neural systems appropriately for the status of body energy stores. Leptin inhibits lateral hypothalamic area (LHA) orexin (OX; also known as hypocretin)-producing neurons, which control feeding, activity, and energy expenditure, among other parameters. Our previous results suggest that GABAergic LHA leptin receptor (LepRb)-containing and neurotensin (Nts)-containing (LepRb(Nts)) neurons lie in close apposition with OX neurons and control Ox mRNA expression. Here, we show that, similar to leptin, activation of LHA Nts neurons by the excitatory hM3Dq DREADD (designer receptor exclusively activated by designer drugs) hyperpolarizes membrane potential and suppresses action potential firing in OX neurons in mouse hypothalamic slices. Furthermore, ablation of LepRb from Nts neurons abrogated the leptin-mediated inhibition, demonstrating that LepRb(Nts) neurons mediate the inhibition of OX neurons by leptin. Leptin did not significantly enhance GABAA-mediated inhibitory synaptic transmission, and GABA receptor antagonists did not block leptin-mediated inhibition of OX neuron activity. Rather, leptin diminished the frequency of spontaneous EPSCs onto OX neurons. Furthermore, leptin indirectly activated an ATP-sensitive potassium (K(ATP)) channel in OX neurons, which was required for the hyperpolarization of OX neurons by leptin. Although Nts did not alter OX activity, galanin, which is coexpressed in LepRb(Nts) neurons, inhibited OX neurons, whereas the galanin receptor antagonist M40 (galanin-(1-12)-Pro3-(Ala-Leu)2-Ala amide) prevented the leptin-induced hyperpolarization of OX cells. These findings demonstrate that leptin indirectly inhibits OX neurons by acting on LHA LepRb(Nts) neurons to mediate two distinct GABA-independent mechanisms of inhibition: the presynaptic inhibition of excitatory neurotransmission and the opening of K(ATP) channels.
authors.affiliation: Departments of Pharmacology and.
authors.forename: Paulette B
authors.initials: PB
authors.lastname: Goforth
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, and Department of Physiology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Leinninger
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, and.
authors.forename: Christa M
authors.initials: CM
authors.lastname: Patterson
authors.affiliation: Departments of Pharmacology and mgmyers@umich.edu lsatin@umich.edu.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.affiliation: Molecular and Integrative Physiology, and Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, and mgmyers@umich.edu lsatin@umich.edu.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D007026:Hypothalamic Area, Lateral / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism*; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009479:Neuropeptides; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D054411:Receptors, Leptin; D009496:Neurotensin; D005680:gamma-Aminobutyric Acid
keywords: EPSC; GABA; LHA; leptin; neurotensin; orexin