PMID- 26042202
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150604
LR  - 20181113
IS  - 2212-8778 (Print)
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 4
IP  - 6
DP  - 2015 Jun
TI  - Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose 
      tissue metabolism.
PG  - 483-92
LID - 10.1016/j.molmet.2015.03.006 [doi]
AB  - OBJECTIVE: Brown adipose tissue (BAT) thermogenesis is critical in maintaining 
      body temperature. The dorsomedial hypothalamus (DMH) integrates cutaneous 
      thermosensory signals and regulates adaptive thermogenesis. Here, we study the 
      function and synaptic connectivity of input from DMH cholinergic neurons to 
      sympathetic premotor neurons in the raphe pallidus (Rpa). METHODS: In order to 
      selectively manipulate DMH cholinergic neuron activity, we generated transgenic 
      mice expressing channelrhodopsin fused to yellow fluorescent protein (YFP) in 
      cholinergic neurons (choline acetyltransferase (ChAT)-Cre::ChR2-YFP) with the 
      Cre-LoxP technique. In addition, we used an adeno-associated virus carrying the 
      Cre recombinase gene to delete the floxed Chat gene in the DMH. Physiological 
      studies in response to optogenetic stimulation of DMH cholinergic neurons were 
      combined with gene expression and immunocytochemical analyses. RESULTS: A subset 
      of DMH neurons are ChAT-immunopositive neurons. The activity of these neurons is 
      elevated by warm ambient temperature. A phenotype-specific neuronal tracing shows 
      that DMH cholinergic neurons directly project to serotonergic neurons in the Rpa. 
      Optical stimulation of DMH cholinergic neurons decreases BAT activity, which is 
      associated with reduced body core temperature. Furthermore, elevated DMH 
      cholinergic neuron activity decreases the expression of BAT uncoupling protein 1 
      (Ucp1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc1alpha) 
      mRNAs, markers of BAT activity. Injection of M2-selective muscarinic receptor 
      antagonists into the 4th ventricle abolishes the effect of optical stimulation. 
      Single cell qRT-PCR analysis of retrogradely identified BAT-projecting neurons in 
      the Rpa shows that all M2 receptor-expressing neurons contain tryptophan 
      hydroxylase 2. In animals lacking the Chat gene in the DMH, exposure to warm 
      temperature reduces neither BAT Ucp1 nor Pgc1alpha mRNA expression. CONCLUSION: DMH 
      cholinergic neurons directly send efferent signals to sympathetic premotor 
      neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity 
      through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct 
      DMH(ACh)-Rpa(5-HT) pathway may mediate physiological heat-defense responses to 
      elevated environmental temperature.
FAU - Jeong, Jae Hoon
AU  - Jeong JH
AD  - Division of Endocrinology, Department of Medicine, Albert Einstein College of 
      Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
FAU - Lee, Dong Kun
AU  - Lee DK
AD  - Division of Endocrinology, Department of Medicine, Albert Einstein College of 
      Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
FAU - Blouet, Clemence
AU  - Blouet C
AD  - Medical Research Council Metabolic Diseases Unit, University of Cambridge 
      Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of 
      Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
FAU - Ruiz, Henry H
AU  - Ruiz HH
AD  - Diabetes, Obesity & Metabolism Institute and Department of Medicine, Mount Sinai 
      School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA ; 
      Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy 
      Place, New York, NY 10029, USA.
FAU - Buettner, Christoph
AU  - Buettner C
AD  - Diabetes, Obesity & Metabolism Institute and Department of Medicine, Mount Sinai 
      School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA ; 
      Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy 
      Place, New York, NY 10029, USA.
FAU - Chua, Streamson Jr
AU  - Chua S Jr
AD  - Division of Endocrinology, Department of Medicine, Albert Einstein College of 
      Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
FAU - Schwartz, Gary J
AU  - Schwartz GJ
AD  - Division of Endocrinology, Department of Medicine, Albert Einstein College of 
      Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
FAU - Jo, Young-Hwan
AU  - Jo YH
AD  - Division of Endocrinology, Department of Medicine, Albert Einstein College of 
      Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA ; 
      Department of Molecular Pharmacology, Albert Einstein College of Medicine of 
      Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
LA  - eng
GR  - P30 DK020541/DK/NIDDK NIH HHS/United States
GR  - P50 AG005138/AG/NIA NIH HHS/United States
GR  - P30 DK026687/DK/NIDDK NIH HHS/United States
GR  - R01 DK092246/DK/NIDDK NIH HHS/United States
GR  - P60 DK020541/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20150411
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
PMC - PMC4443291
OTO - NOTNLM
OT  - Acetylcholine
OT  - Hypothalamus
OT  - Muscarinic
OT  - Neuronal tracing
OT  - Nicotinic
OT  - Serotonin
EDAT- 2015/06/05 06:00
MHDA- 2015/06/05 06:01
PMCR- 2015/04/11
CRDT- 2015/06/05 06:00
PHST- 2015/03/17 00:00 [received]
PHST- 2015/03/27 00:00 [revised]
PHST- 2015/03/31 00:00 [accepted]
PHST- 2015/06/05 06:00 [entrez]
PHST- 2015/06/05 06:00 [pubmed]
PHST- 2015/06/05 06:01 [medline]
PHST- 2015/04/11 00:00 [pmc-release]
AID - S2212-8778(15)00061-7 [pii]
AID - 10.1016/j.molmet.2015.03.006 [doi]
PST - epublish
SO  - Mol Metab. 2015 Apr 11;4(6):483-92. doi: 10.1016/j.molmet.2015.03.006. 
      eCollection 2015 Jun.