title: Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor.
abstract: Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.
authors.affiliation: Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics.
authors.forename: Sun-Gyun
authors.initials: SG
authors.lastname: Kim
authors.forename: Bora
authors.initials: B
authors.lastname: Lee
authors.forename: Dae-Hwan
authors.initials: DH
authors.lastname: Kim
authors.forename: Juhee
authors.initials: J
authors.lastname: Kim
authors.forename: Seunghee
authors.initials: S
authors.lastname: Lee
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020738:Leptin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054369:Agouti-Related Protein; D004268:DNA-Binding Proteins; D020738:Leptin; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; C490411:Nr4a3 protein, mouse; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone
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