title: Hypothalamic Non-AgRP, Non-POMC GABAergic Neurons Are Required for Postweaning Feeding and NPY Hyperphagia.
abstract: The hypothalamus is critical for feeding and body weight regulation. Prevailing studies focus on hypothalamic neurons that are defined by selectively expressing transcription factors or neuropeptides including those expressing proopiomelanocortin (POMC) and agouti-related peptides (AgRP). The Cre expression driven by the pancreas-duodenum homeobox 1 promoter is abundant in several hypothalamic nuclei but not in AgRP or POMC neurons. Using this line, we generated mice with disruption of GABA release from a major subset of non-POMC, non-AgRP GABAergic neurons in the hypothalamus. These mice exhibited a reduction in postweaning feeding and growth, and disrupted hyperphagic responses to NPY. Disruption of GABA release severely diminished GABAergic input to the paraventricular hypothalamic nucleus (PVH). Furthermore, disruption of GABA-A receptor function in the PVH also reduced postweaning feeding and blunted NPY-induced hyperphagia. Given the limited knowledge on postweaning feeding, our results are significant in identifying GABA release from a major subset of less appreciated hypothalamic neurons as a key mediator for postweaning feeding and NPY hyperphagia, and the PVH as one major downstream site that contributes significantly to the GABA action. Significance statement: Prevalent studies on feeding in the hypothalamus focus on well characterized, selective groups neurons [e.g., proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons], and as a result, the role of the majority of other hypothalamic neurons is largely neglected. Here, we demonstrated an important role for GABAergic projections from non-POMC non-AgRP neurons to the paraventricular hypothalamic nucleus in promoting postweaning (mainly nocturnal) feeding and mediating NPY-induced hyperphagia. Thus, these results signify an importance to study those yet to be defined hypothalamic neurons in the regulation of energy balance and reveal a neural basis for postweaning (nocturnal) feeding and NPY-mediated hyperphagia.
authors.affiliation: Brown Foundation Institute of Molecular Medicine and.
authors.forename: Eun Ran
authors.initials: ER
authors.lastname: Kim
authors.affiliation: Brown Foundation Institute of Molecular Medicine and.
authors.forename: Zhaofei
authors.identifier: http://orcid.org/0000-0002-2463-242X
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Brown Foundation Institute of Molecular Medicine and.
authors.forename: Hao
authors.identifier: http://orcid.org/0000-0001-9388-9176
authors.initials: H
authors.lastname: Sun
authors.affiliation: Brown Foundation Institute of Molecular Medicine and.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Brown Foundation Institute of Molecular Medicine and Graduate Program in Neuroscience of Graduate School of Biological Sciences, the University of Texas Medical School at Houston, Houston, Texas 77030, and.
authors.forename: Leandra R
authors.initials: LR
authors.lastname: Mangieri
authors.affiliation: Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Brown Foundation Institute of Molecular Medicine and Graduate Program in Neuroscience of Graduate School of Biological Sciences, the University of Texas Medical School at Houston, Houston, Texas 77030, and qingchun.tong@uth.tmc.edu.
authors.forename: Qingchun
authors.identifier: http://orcid.org/0000-0002-4561-2540
authors.initials: Q
authors.lastname: Tong
mesh_terms: D054369:Agouti-Related Protein / Q000096:biosynthesis; D000818:Animals; D005247:Feeding Behavior / Q000502:physiology*; D059330:GABAergic Neurons / Q000502:physiology*; D006963:Hyperphagia / Q000503:physiopathology*; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D009478:Neuropeptide Y / Q000378:metabolism; D009924:Organ Culture Techniques; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis
chemical_list: D054369:Agouti-Related Protein; D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin
keywords: AgRP; GABA; NPY; PVH; Pdx1-Cre; feeding