PMID- 29650350
OWN - NLM
STAT- MEDLINE
DCOM- 20190411
LR  - 20210109
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 11
DP  - 2018 May
TI  - Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and 
      increases adiposity.
PG  - 33-46
LID - S2212-8778(18)30143-1 [pii]
LID - 10.1016/j.molmet.2018.03.008 [doi]
AB  - OBJECTIVE: Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely 
      innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in 
      body weight regulation and the sympathetic control of brown adipose tissue (BAT) 
      thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to 
      regulate energy balance by controlling sympathetic outflow and BAT function. 
      METHODS: We investigate this possibility in adult male rats by using direct 
      administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with 
      viral-mediated RNA interference, and by examining the neurochemical phenotype of 
      GLP-1R expressing cells in the DMH using in situ hybridization. RESULTS: GLP-1 
      administered into the DMH increased BAT thermogenesis and hepatic triglyceride 
      (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased 
      body weight gain and adiposity, with a concomitant reduction in energy 
      expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. 
      Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and 
      elevated liver specific de-novo lipogenesis, effects that collectively 
      contributed to insulin resistance. Interestingly, DMH Glp1r KD increased 
      neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, 
      was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent 
      inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, 
      DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, 
      highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies. 
      CONCLUSIONS: Collectively, our data show that DMH GLP-1R signaling plays a key 
      role for BAT thermogenesis and adiposity.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
FAU - Lee, Shin J
AU  - Lee SJ
AD  - Physiology and Behavior Laboratory, ETH Zurich, 8603 Schwerzenbach, Switzerland. 
      Electronic address: shin-lee@ethz.ch.
FAU - Sanchez-Watts, Graciela
AU  - Sanchez-Watts G
AD  - Department of Biological Sciences, University of Southern California, Los 
      Angeles, CA 90089, USA.
FAU - Krieger, Jean-Philippe
AU  - Krieger JP
AD  - Physiology and Behavior Laboratory, ETH Zurich, 8603 Schwerzenbach, Switzerland.
FAU - Pignalosa, Angelica
AU  - Pignalosa A
AD  - Physiology and Behavior Laboratory, ETH Zurich, 8603 Schwerzenbach, Switzerland.
FAU - Norell, Puck N
AU  - Norell PN
AD  - Physiology and Behavior Laboratory, ETH Zurich, 8603 Schwerzenbach, Switzerland.
FAU - Cortella, Alyssa
AU  - Cortella A
AD  - Department of Biological Sciences, University of Southern California, Los 
      Angeles, CA 90089, USA.
FAU - Pettersen, Klaus G
AU  - Pettersen KG
AD  - Physiology and Behavior Laboratory, ETH Zurich, 8603 Schwerzenbach, Switzerland.
FAU - Vrdoljak, Dubravka
AU  - Vrdoljak D
AD  - Physiology and Behavior Laboratory, ETH Zurich, 8603 Schwerzenbach, Switzerland.
FAU - Hayes, Matthew R
AU  - Hayes MR
AD  - Department of Psychiatry, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA, USA.
FAU - Kanoski, Scott E
AU  - Kanoski SE
AD  - Department of Biological Sciences, University of Southern California, Los 
      Angeles, CA 90089, USA.
FAU - Langhans, Wolfgang
AU  - Langhans W
AD  - Physiology and Behavior Laboratory, ETH Zurich, 8603 Schwerzenbach, Switzerland.
FAU - Watts, Alan G
AU  - Watts AG
AD  - Department of Biological Sciences, University of Southern California, Los 
      Angeles, CA 90089, USA.
LA  - eng
GR  - R01 DK104897/DK/NIDDK NIH HHS/United States
GR  - R01 NS029728/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180321
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (Glp1r protein, rat)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - 0 (Neuropeptide Y)
RN  - 0 (Ucp1 protein, rat)
RN  - 0 (Uncoupling Protein 1)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 9P1872D4OL (Exenatide)
SB  - IM
MH  - Adipose Tissue, Brown/*metabolism
MH  - *Adiposity
MH  - Animals
MH  - Exenatide/metabolism
MH  - GABAergic Neurons/metabolism
MH  - Glucagon-Like Peptide 1/metabolism
MH  - Glucagon-Like Peptide-1 Receptor/genetics/*metabolism
MH  - Hypothalamus/*metabolism
MH  - Insulin Resistance
MH  - Lipogenesis
MH  - Male
MH  - Neuropeptide Y/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - *Thermogenesis
MH  - Uncoupling Protein 1/metabolism
PMC - PMC6001878
OTO - NOTNLM
OT  - Adipose tissue
OT  - Hypothalamus
OT  - Neuropeptide
OT  - Obesity
OT  - Sympathetic nerve
EDAT- 2018/04/14 06:00
MHDA- 2019/04/12 06:00
PMCR- 2018/03/21
CRDT- 2018/04/14 06:00
PHST- 2018/02/06 00:00 [received]
PHST- 2018/03/09 00:00 [revised]
PHST- 2018/03/14 00:00 [accepted]
PHST- 2018/04/14 06:00 [pubmed]
PHST- 2019/04/12 06:00 [medline]
PHST- 2018/04/14 06:00 [entrez]
PHST- 2018/03/21 00:00 [pmc-release]
AID - S2212-8778(18)30143-1 [pii]
AID - 10.1016/j.molmet.2018.03.008 [doi]
PST - ppublish
SO  - Mol Metab. 2018 May;11:33-46. doi: 10.1016/j.molmet.2018.03.008. Epub 2018 Mar 
      21.