PMID- 24403154
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20221221
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 34
IP  - 2
DP  - 2014 Jan 8
TI  - Hypothalamic dysfunction of the thrombospondin receptor alpha2delta-1 underlies the 
      overeating and obesity triggered by brain-derived neurotrophic factor deficiency.
PG  - 554-65
LID - 10.1523/JNEUROSCI.1572-13.2014 [doi]
AB  - Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are critical 
      components of the neural circuitry controlling appetite and body weight. 
      Diminished BDNF signaling in mice results in severe hyperphagia and obesity. In 
      humans, BDNF haploinsufficiency and the functional Bdnf Val66Met polymorphism 
      have been linked to elevated food intake and body weight. The mechanisms 
      underlying this dysfunction are poorly defined. We demonstrate a chief role of 
      alpha2delta-1, a calcium channel subunit and thrombospondin receptor, in triggering 
      overeating in mice with central BDNF depletion. We show reduced alpha2delta-1 
      cell-surface expression in the BDNF mutant ventromedial hypothalamus (VMH), an 
      energy balance-regulating center. This deficit contributes to the hyperphagia 
      exhibited by BDNF mutant mice because selective inhibition of alpha2delta-1 by gabapentin 
      infusion into wild-type VMH significantly increases feeding and body weight gain. 
      Importantly, viral-mediated alpha2delta-1 rescue in BDNF mutant VMH significantly 
      mitigates their hyperphagia, obesity, and liver steatosis and normalizes deficits 
      in glucose homeostasis. Whole-cell recordings in BDNF mutant VMH neurons revealed 
      normal calcium currents but reduced frequency of EPSCs. These results suggest 
      calcium channel-independent effects of alpha2delta-1 on feeding and implicate 
      alpha2delta-1-thrombospondin interactions known to facilitate excitatory synapse 
      assembly. Our findings identify a central mechanism mediating the inhibitory 
      effects of BDNF on feeding. They also demonstrate a novel and critical role for 
      alpha2delta-1 in appetite control and suggest a mechanism underlying weight gain in 
      humans treated with gabapentinoid drugs.
FAU - Cordeira, Joshua W
AU  - Cordeira JW
AD  - Department of Neuroscience and Graduate Program in Neuroscience, Sackler School 
      of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, 
      Massachusetts 02111, Graduate Program in Biochemical and Molecular Nutrition, 
      Gerald J. and Dorothy R. Friedman School of Nutrition and Science Policy, Tufts 
      University, Boston, Massachusetts 02111, and Department of Neurology and Gene 
      Therapy Center, University of Massachusetts Medical School, Worcester, 
      Massachusetts 01605.
FAU - Felsted, Jennifer A
AU  - Felsted JA
FAU - Teillon, Sarah
AU  - Teillon S
FAU - Daftary, Shabrine
AU  - Daftary S
FAU - Panessiti, Micaella
AU  - Panessiti M
FAU - Wirth, Jena
AU  - Wirth J
FAU - Sena-Esteves, Miguel
AU  - Sena-Esteves M
FAU - Rios, Maribel
AU  - Rios M
LA  - eng
GR  - T32 DK124170/DK/NIDDK NIH HHS/United States
GR  - T32 DK07542/DK/NIDDK NIH HHS/United States
GR  - T32 DK062032/DK/NIDDK NIH HHS/United States
GR  - R01 DK073311/DK/NIDDK NIH HHS/United States
GR  - DK073311/DK/NIDDK NIH HHS/United States
GR  - P30 NS047243/NS/NINDS NIH HHS/United States
GR  - T32 DK007542/DK/NIDDK NIH HHS/United States
GR  - T32 NS061764/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (CACNA2D1 protein, mouse)
RN  - 0 (CD36 Antigens)
RN  - 0 (Calcium Channels)
SB  - IM
CIN - Am J Manag Care. 2014 Jan;20(1 Spec No.):E11. PMID: 25928938
MH  - Animals
MH  - Blotting, Western
MH  - Brain-Derived Neurotrophic Factor/*deficiency
MH  - CD36 Antigens/metabolism
MH  - Calcium Channels/*metabolism
MH  - Feeding Behavior/*physiology
MH  - Hypothalamus/*metabolism
MH  - In Situ Hybridization
MH  - Male
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Neurons/metabolism
MH  - Obesity/*metabolism
MH  - Patch-Clamp Techniques
MH  - Reverse Transcriptase Polymerase Chain Reaction
PMC - PMC3870936
EDAT- 2014/01/10 06:00
MHDA- 2014/03/04 06:00
PMCR- 2014/07/08
CRDT- 2014/01/10 06:00
PHST- 2014/01/10 06:00 [entrez]
PHST- 2014/01/10 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
PHST- 2014/07/08 00:00 [pmc-release]
AID - 34/2/554 [pii]
AID - 1572-13 [pii]
AID - 10.1523/JNEUROSCI.1572-13.2014 [doi]
PST - ppublish
SO  - J Neurosci. 2014 Jan 8;34(2):554-65. doi: 10.1523/JNEUROSCI.1572-13.2014.