title: Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite.
abstract: Disruption of finely coordinated neuropeptide signals in the hypothalamus can result in altered food intake and body weight. We identified neuron-derived neurotrophic factor (NENF) as a novel secreted protein through a large-scale screen aimed at identifying novel secreted hypothalamic proteins that regulate food intake. We observed robust Nenf expression in hypothalamic nuclei known to regulate food intake, and its expression was altered under the diet-induced obese (DIO) condition relative to the fed state. Hypothalamic Nenf mRNA was regulated by brain-derived neurotrophic factor (BDNF) signaling, itself an important regulator of appetite. Delivery of purified recombinant BDNF into the lateral cerebral ventricle decreased hypothalamic Nenf expression, while pharmacological inhibition of trkB signaling increased Nenf mRNA expression. Furthermore, recombinant NENF administered via an intracerebroventricular cannula decreased food intake and body weight and increased hypothalamic Pomc and Mc4r mRNA expression. Importantly, the appetite-suppressing effect of NENF was abrogated in obese mice fed a high-fat diet, demonstrating a diet-dependent modulation of NENF function. We propose the existence of a regulatory circuit involving BDNF, NENF, and melanocortin signaling. Our study validates the power of using an integrated experimental and bioinformatic approach to identify novel CNS-derived proteins with appetite-modulating function and reveals NENF as an important central modulator of food intake.
authors.affiliation: Department of Physiology and Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. mardibyerly@gmail.com
authors.forename: Mardi S
authors.initials: MS
authors.lastname: Byerly
authors.forename: Roy D
authors.initials: RD
authors.lastname: Swanson
authors.forename: Nina N
authors.initials: NN
authors.lastname: Semsarzadeh
authors.forename: Patrick S
authors.initials: PS
authors.lastname: McCulloh
authors.forename: Kiwook
authors.initials: K
authors.lastname: Kwon
authors.forename: Susan
authors.initials: S
authors.lastname: Aja
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
mesh_terms: D000818:Animals; D001066:Appetite / Q000187:drug effects / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C574273:MC4R protein, mouse; D009419:Nerve Tissue Proteins; D044105:Receptor, Melanocortin, Type 4; D011994:Recombinant Proteins; C500817:neudesin protein, mouse; D011333:Pro-Opiomelanocortin
keywords: agouti-related protein; brain-derived neurotrophic factor; melanocortin; neural circuitry; whole-body energy balance