PMID- 19543218
OWN - NLM
STAT- MEDLINE
DCOM- 20100126
LR  - 20240109
IS  - 1930-7381 (Print)
IS  - 1930-7381 (Linking)
VI  - 17
IP  - 10
DP  - 2009 Oct
TI  - Central administration of an endoplasmic reticulum stress inducer inhibits the 
      anorexigenic effects of leptin and insulin.
PG  - 1861-5
LID - 10.1038/oby.2009.194 [doi]
AB  - Leptin and insulin are important anorexigenic hormones acting on the 
      hypothalamus. However, most obese humans and animals have reduced hypothalamic 
      responses to leptin and insulin. Increased endoplasmic reticulum (ER) stress has 
      been shown to cause insulin resistance in the livers of obese animals. In the 
      present study, we investigated a role of ER stress in the development of central 
      leptin and insulin resistance. Intracerebroventricular (ICV) administration of 
      the ER stress inducer thapsigargin (TG) increased food intake and body weight. 
      Furthermore, ICV or intra-hypothalamic administration of TG inhibited the 
      anorexigenic and weight-reducing effects of leptin and insulin. ICV 
      administration of TG by itself activated 
      signal-transduction-activated-transcript-3 (STAT3) and Akt in the hypothalamus, 
      but prevented a further activation of hypothalamic STAT3 and Akt by leptin and 
      insulin. We also found that the expression of the ER stress markers such as 
      phosphorylation of the inositol-requiring kinase-1 (IRE1), spliced form of 
      X-box-binding protein-1 (XBP-1s), glucose-regulated/binding immunoglobulin 
      protein-78, and C/EBP homology protein (CHOP) increased in the hypothalami of 
      diet-induced obese (DIO) mice. Furthermore, treatment of chemical chaperone 
      4-phenyl butylic acid significantly improved central leptin resistance in DIO 
      mice. These findings suggest that increased hypothalamic ER stress in obese 
      animals may induce central leptin and insulin resistance.
FAU - Won, Jong Chul
AU  - Won JC
AD  - Department of Internal Medicine, Mitochondrial Research Group, Inje University 
      College of Medicine, Seoul, Korea.
FAU - Jang, Pil-Geum
AU  - Jang PG
FAU - Namkoong, Churl
AU  - Namkoong C
FAU - Koh, Eun Hee
AU  - Koh EH
FAU - Kim, Suk Kyeoug
AU  - Kim SK
FAU - Park, Joong-Yeol
AU  - Park JY
FAU - Lee, Ki-Up
AU  - Lee KU
FAU - Kim, Min-Seon
AU  - Kim MS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090618
PL  - United States
TA  - Obesity (Silver Spring)
JT  - Obesity (Silver Spring, Md.)
JID - 101264860
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Insulin)
RN  - 0 (Leptin)
RN  - 0 (Regulatory Factor X Transcription Factors)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Stat3 protein, mouse)
RN  - 0 (Transcription Factors)
RN  - 0 (X-Box Binding Protein 1)
RN  - 0 (XBP1 protein, human)
RN  - 0 (Xbp1 protein, mouse)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 63231-63-0 (RNA)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - DNA-Binding Proteins/physiology
MH  - Endoplasmic Reticulum/*drug effects/physiology
MH  - Enzyme Inhibitors/*administration & dosage
MH  - Hypothalamus/*drug effects/physiopathology
MH  - Insulin/*physiology
MH  - Leptin/antagonists & inhibitors/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Obesity/drug therapy/*physiopathology
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - RNA/chemistry/genetics
MH  - Regulatory Factor X Transcription Factors
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - STAT3 Transcription Factor/physiology
MH  - Thapsigargin/*administration & dosage
MH  - Transcription Factor CHOP/genetics/physiology
MH  - Transcription Factors/physiology
MH  - X-Box Binding Protein 1
EDAT- 2009/06/23 09:00
MHDA- 2010/01/27 06:00
CRDT- 2009/06/23 09:00
PHST- 2009/06/23 09:00 [entrez]
PHST- 2009/06/23 09:00 [pubmed]
PHST- 2010/01/27 06:00 [medline]
AID - oby2009194 [pii]
AID - 10.1038/oby.2009.194 [doi]
PST - ppublish
SO  - Obesity (Silver Spring). 2009 Oct;17(10):1861-5. doi: 10.1038/oby.2009.194. Epub 
      2009 Jun 18.