PMID- 30253111 OWN - NLM STAT- MEDLINE DCOM- 20190826 LR - 20200309 IS - 1522-1555 (Electronic) IS - 0193-1849 (Print) IS - 0193-1849 (Linking) VI - 315 IP - 6 DP - 2018 Dec 1 TI - Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice. PG - E1168-E1184 LID - 10.1152/ajpendo.00205.2018 [doi] AB - Brain-derived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that encode a common protein. We sought to assess the phenotypic outcomes of disrupting BDNF production from individual Bdnf promoters. Mice with an intact coding region but selective disruption of BDNF production from Bdnf promoters I, II, IV, or VI (Bdnf-e1(-/-), -e2(-/-), -e4(-/-), and -e6(-/-)) were created by inserting an enhanced green fluorescent protein-STOP cassette upstream of the targeted promoter splice donor site. Body composition was measured by MRI weekly from age 4 to 22 wk. Energy expenditure was measured by indirect calorimetry at 18 wk. Food intake was measured in Bdnf-e1(-/-) and Bdnf-e2(-/-) mice, and pair feeding was conducted. Weight gain, lean mass, fat mass, and percent fat of Bdnf-e1(-/-) and Bdnf-e2(-/-) mice (both sexes) were significantly increased compared with wild-type littermates. For Bdnf-e4(-/-) and Bdnf-e6(-/-) mice, obesity was not observed with either chow or high-fat diet. Food intake was increased in Bdnf-e1(-/-) and Bdnf-e2(-/-) mice, and pair feeding prevented obesity. Mutant and wild-type littermates for each strain (both sexes) had similar total energy expenditure after adjustment for body composition. These findings suggest that the obesity phenotype observed in Bdnf-e1(-/-) and Bdnf-e2(-/-) mice is attributable to hyperphagia and not altered energy expenditure. Our findings show that disruption of BDNF from specific promoters leads to distinct body composition effects, with disruption from promoters I or II, but not IV or VI, inducing obesity. FAU - McAllan, Liam AU - McAllan L AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. FAU - Maynard, Kristen R AU - Maynard KR AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland. FAU - Kardian, Alisha S AU - Kardian AS AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland. FAU - Stayton, Amanda S AU - Stayton AS AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. FAU - Fox, Shelby L AU - Fox SL AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. FAU - Stephenson, Erin J AU - Stephenson EJ AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. FAU - Kinney, Clint E AU - Kinney CE AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. FAU - Alshibli, Noor K AU - Alshibli NK AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. FAU - Gomes, Charles K AU - Gomes CK AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. FAU - Pierre, Joseph F AU - Pierre JF AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. FAU - Puchowicz, Michelle A AU - Puchowicz MA AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. FAU - Bridges, Dave AU - Bridges D AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. AD - Department of Physiology, University of Tennessee Health Science Center , Memphis, Tennessee. FAU - Martinowich, Keri AU - Martinowich K AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland. AD - Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , Baltimore, Maryland. AD - Department of Neuroscience, Johns Hopkins University School of Medicine , Baltimore, Maryland. FAU - Han, Joan C AU - Han JC AUID- ORCID: 0000-0003-4252-2678 AD - Department of Pediatrics, University of Tennessee Health Science Center , Memphis, Tennessee. AD - Children's Foundation Research Institute, Le Bonheur Children's Hospital , Memphis, Tennessee. AD - Department of Physiology, University of Tennessee Health Science Center , Memphis, Tennessee. LA - eng GR - P30 DK020572/DK/NIDDK NIH HHS/United States GR - R01 DK107535/DK/NIDDK NIH HHS/United States GR - R01 MH105592/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180925 PL - United States TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226 RN - 0 (Brain-Derived Neurotrophic Factor) MH - Animals MH - Body Composition/*genetics MH - Body Weight/*genetics MH - Brain-Derived Neurotrophic Factor/*genetics/metabolism MH - Calorimetry, Indirect MH - Eating/genetics MH - Energy Metabolism/genetics MH - Mice MH - Mice, Transgenic MH - Obesity/*genetics/metabolism MH - Phenotype MH - *Promoter Regions, Genetic PMC - PMC6336959 OTO - NOTNLM OT - BDNF OT - hyperphagia OT - obesity OT - promoter EDAT- 2018/09/27 06:00 MHDA- 2019/08/27 06:00 PMCR- 2019/12/01 CRDT- 2018/09/26 06:00 PHST- 2018/09/27 06:00 [pubmed] PHST- 2019/08/27 06:00 [medline] PHST- 2018/09/26 06:00 [entrez] PHST- 2019/12/01 00:00 [pmc-release] AID - E-00205-2018 [pii] AID - 10.1152/ajpendo.00205.2018 [doi] PST - ppublish SO - Am J Physiol Endocrinol Metab. 2018 Dec 1;315(6):E1168-E1184. doi: 10.1152/ajpendo.00205.2018. Epub 2018 Sep 25.