title: MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus.
abstract: Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however, the identity, location, and axonal projections of the neurons bearing MC4Rs that control feeding remain unknown. Reexpression of MC4Rs on single-minded 1 (SIM1)(+) neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia. Thus, MC4Rs on SIM1(+) neurons, possibly in the paraventricular hypothalamus (PVH) and/or amygdala, regulate food intake. It is unknown, however, whether they are also necessary, a distinction required for excluding redundant sites of action. Hence, the location and nature of obesity-preventing MC4R-expressing neurons are unknown. Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both necessity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1(+), located in the PVH, glutamatergic and not GABAergic, and do not express oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin. Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected to neurons in the parabrachial nucleus, which relays visceral information to the forebrain. This suggests a basis for the feeding-regulating effects of MC4Rs.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.
authors.forename: Bhavik P
authors.initials: BP
authors.lastname: Shah
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.
authors.forename: Linh
authors.initials: L
authors.lastname: Vong
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.
authors.forename: David P
authors.initials: DP
authors.lastname: Olson
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Koda
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krashes
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.
authors.forename: Chianping
authors.initials: C
authors.lastname: Ye
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.
authors.forename: Zongfang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, and.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Fuller
authors.affiliation: Division of Hypothalamic Research, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 blowell@bidmc.harvard.edu joel.elmquist@utsouthwestern.edu.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Program in Neuroscience, Harvard Medical School, Boston, MA 02115; and blowell@bidmc.harvard.edu joel.elmquist@utsouthwestern.edu.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001835:Body Weight; D000229:Dependovirus / Q000378:metabolism; D004734:Energy Metabolism; D005247:Feeding Behavior; D059330:GABAergic Neurons / Q000378:metabolism; D017353:Gene Deletion; D005971:Glutamates / Q000378:metabolism*; D007267:Injections; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D065823:Parabrachial Nucleus / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D013238:Stereotaxic Techniques; D013569:Synapses / Q000378:metabolism*; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005971:Glutamates; D019426:Integrases; D009479:Neuropeptides; D044105:Receptor, Melanocortin, Type 4; D012097:Repressor Proteins; D050599:Vesicular Glutamate Transport Protein 2; C101750:Sim1 protein, mouse; C493477:Slc17a6 protein, mouse; C045073:Cre recombinase