PMID- 23576617 OWN - NLM STAT- MEDLINE DCOM- 20130830 LR - 20220408 IS - 1522-1490 (Electronic) IS - 0363-6119 (Print) IS - 0363-6119 (Linking) VI - 304 IP - 12 DP - 2013 Jun 15 TI - Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite. PG - R1085-95 LID - 10.1152/ajpregu.00368.2012 [doi] AB - 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. FAU - Byerly, Mardi S AU - Byerly MS AD - Department of Physiology and Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. mardibyerly@gmail.com FAU - Swanson, Roy D AU - Swanson RD FAU - Semsarzadeh, Nina N AU - Semsarzadeh NN FAU - McCulloh, Patrick S AU - McCulloh PS FAU - Kwon, Kiwook AU - Kwon K FAU - Aja, Susan AU - Aja S FAU - Moran, Timothy H AU - Moran TH FAU - Wong, G William AU - Wong GW FAU - Blackshaw, Seth AU - Blackshaw S LA - eng GR - P30 DK079637/DK/NIDDK NIH HHS/United States GR - R01 DK084171/DK/NIDDK NIH HHS/United States GR - T32DK007751/DK/NIDDK NIH HHS/United States GR - DK084171/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130410 PL - United States TA - Am J Physiol Regul Integr Comp Physiol JT - American journal of physiology. Regulatory, integrative and comparative physiology JID - 100901230 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (MC4R protein, mouse) RN - 0 (Nerve Tissue Proteins) RN - 0 (Receptor, Melanocortin, Type 4) RN - 0 (Recombinant Proteins) RN - 0 (neudesin protein, mouse) RN - 66796-54-1 (Pro-Opiomelanocortin) SB - IM MH - Animals MH - Appetite/drug effects/*physiology MH - Brain-Derived Neurotrophic Factor/administration & dosage/pharmacology MH - Diet, High-Fat/adverse effects MH - Disease Models, Animal MH - Energy Metabolism/drug effects/physiology MH - Hypothalamus/*metabolism MH - Injections, Intraventricular MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Nerve Tissue Proteins/administration & dosage/*metabolism/pharmacology MH - Obesity/chemically induced/metabolism/*physiopathology MH - Pro-Opiomelanocortin/metabolism MH - Receptor, Melanocortin, Type 4/metabolism MH - Recombinant Proteins/administration & dosage/pharmacology MH - Signal Transduction/drug effects/*physiology PMC - PMC3680792 OTO - NOTNLM OT - agouti-related protein OT - brain-derived neurotrophic factor OT - melanocortin OT - neural circuitry OT - whole-body energy balance EDAT- 2013/04/12 06:00 MHDA- 2013/08/31 06:00 PMCR- 2014/06/15 CRDT- 2013/04/12 06:00 PHST- 2013/04/12 06:00 [entrez] PHST- 2013/04/12 06:00 [pubmed] PHST- 2013/08/31 06:00 [medline] PHST- 2014/06/15 00:00 [pmc-release] AID - ajpregu.00368.2012 [pii] AID - R-00368-2012 [pii] AID - 10.1152/ajpregu.00368.2012 [doi] PST - ppublish SO - Am J Physiol Regul Integr Comp Physiol. 2013 Jun 15;304(12):R1085-95. doi: 10.1152/ajpregu.00368.2012. Epub 2013 Apr 10.