PMID- 23139814
OWN - NLM
STAT- MEDLINE
DCOM- 20130423
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 11
DP  - 2012
TI  - In a model of Batten disease, palmitoyl protein thioesterase-1 deficiency is 
      associated with brown adipose tissue and thermoregulation abnormalities.
PG  - e48733
LID - 10.1371/journal.pone.0048733 [doi]
LID - e48733
AB  - Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative 
      disorder caused by a deficiency of palmitoyl-protein thioesterase-1 (PPT1). We 
      have previously shown that children with INCL have increased risk of hypothermia 
      during anesthesia and that PPT1-deficiency in mice is associated with disruption 
      of adaptive energy metabolism, downregulation of peroxisome 
      proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), and mitochondrial 
      dysfunction. Here we hypothesized that Ppt1-knockout mice, a well-studied model 
      of INCL that shows many of the neurologic manifestations of the disease, would 
      recapitulate the thermoregulation impairment observed in children with INCL. We 
      also hypothesized that when exposed to cold, Ppt1-knockout mice would be unable 
      to maintain body temperature as in mice thermogenesis requires upregulation of 
      Pgc-1alpha and uncoupling protein 1 (Ucp-1) in brown adipose tissue. We found that 
      the Ppt1-KO mice had lower basal body temperature as they aged and developed 
      hypothermia during cold exposure. Surprisingly, this inability to maintain body 
      temperature during cold exposure in Ppt1-KO mice was associated with an adequate 
      upregulation of Pgc-1alpha and Ucp-1 but with lower levels of sympathetic 
      neurotransmitters in brown adipose tissue. In addition, during baseline 
      conditions, brown adipose tissue of Ppt1-KO mice had less vacuolization (lipid 
      droplets) compared to wild-type animals. After cold stress, wild-type animals had 
      significant decreases whereas Ppt1-KO had insignificant changes in lipid droplets 
      compared with baseline measurements, thus suggesting that Ppt1-KO had less 
      lipolysis in response to cold stress. These results uncover a previously unknown 
      phenotype associated with PPT1 deficiency, that of altered thermoregulation, 
      which is associated with impaired lipolysis and neurotransmitter release to brown 
      adipose tissue during cold exposure. These findings suggest that INCL should be 
      added to the list of neurodegenerative diseases that are linked to alterations in 
      peripheral metabolic processes. In addition, extrapolating these findings 
      clinically, impaired thermoregulation and hypothermia are potential risks in 
      patients with INCL.
FAU - Khaibullina, Alfia
AU  - Khaibullina A
AD  - Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National 
      Medical Center, Washington District of Colmbia, USA.
FAU - Kenyon, Nicholas
AU  - Kenyon N
FAU - Guptill, Virginia
AU  - Guptill V
FAU - Quezado, Martha M
AU  - Quezado MM
FAU - Wang, Li
AU  - Wang L
FAU - Koziol, Deloris
AU  - Koziol D
FAU - Wesley, Robert
AU  - Wesley R
FAU - Moya, Pablo R
AU  - Moya PR
FAU - Zhang, Zhongjian
AU  - Zhang Z
FAU - Saha, Arjun
AU  - Saha A
FAU - Mukherjee, Anil B
AU  - Mukherjee AB
FAU - Quezado, Zenaide M N
AU  - Quezado ZM
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121106
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Ion Channels)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Proto-Oncogene Proteins c-fos)
RN  - 0 (Receptors, Adrenergic, beta)
RN  - 0 (Ucp1 protein, mouse)
RN  - 0 (Uncoupling Protein 1)
RN  - 0U46U6E8UK (NAD)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Adipose Tissue, Brown/*abnormalities/metabolism/pathology/*physiopathology
MH  - Animals
MH  - Body Temperature Regulation/*physiology
MH  - Cold Temperature
MH  - Disease Models, Animal
MH  - Female
MH  - Hot Temperature
MH  - Ion Channels/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mitochondrial Proteins/metabolism
MH  - NAD/metabolism
MH  - Neuronal Ceroid-Lipofuscinoses/*enzymology/pathology/*physiopathology
MH  - Neurotransmitter Agents/metabolism
MH  - Proto-Oncogene Proteins c-fos/metabolism
MH  - Receptors, Adrenergic, beta/metabolism
MH  - Thiolester Hydrolases/*deficiency/metabolism
MH  - Uncoupling Protein 1
MH  - Ventromedial Hypothalamic Nucleus/metabolism/pathology/physiopathology
PMC - PMC3490854
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/11/10 06:00
MHDA- 2013/04/24 06:00
PMCR- 2012/11/06
CRDT- 2012/11/10 06:00
PHST- 2012/07/07 00:00 [received]
PHST- 2012/09/28 00:00 [accepted]
PHST- 2012/11/10 06:00 [entrez]
PHST- 2012/11/10 06:00 [pubmed]
PHST- 2013/04/24 06:00 [medline]
PHST- 2012/11/06 00:00 [pmc-release]
AID - PONE-D-12-20782 [pii]
AID - 10.1371/journal.pone.0048733 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(11):e48733. doi: 10.1371/journal.pone.0048733. Epub 2012 Nov 6.