PMID- 21962636
OWN - NLM
STAT- MEDLINE
DCOM- 20120307
LR  - 20111024
IS  - 1618-1298 (Electronic)
IS  - 0171-9335 (Linking)
VI  - 90
IP  - 12
DP  - 2011 Dec
TI  - Conditioned medium from hypoxia-treated adipocytes renders muscle cells insulin 
      resistant.
PG  - 1000-15
LID - 10.1016/j.ejcb.2011.06.004 [doi]
AB  - Adipose tissue hypoxia is an early phenotype in obesity, associated with 
      macrophage infiltration and local inflammation. Here we test the hypothesis that 
      adipocytes in culture respond to a hypoxic environment with the release of 
      pro-inflammatory factors that stimulate macrophage migration and cause muscle 
      insulin resistance. 3T3-L1 adipocytes cultured in a 1% O2 atmosphere responded 
      with a classic hypoxia response by elevating protein expression of HIF-1alpha. This 
      was associated with elevated mRNA expression and peptide release of cytokines 
      TNFalpha, IL-6 and the chemokine monocyte chemoattractant protein-1 (MCP-1). The mRNA 
      and protein expression of the anti-inflammatory adipokine adiponectin was 
      reduced. Conditioned medium from hypoxia-treated adipocytes (CM-H), inhibited 
      insulin-stimulated and raised basal cell surface levels of GLUT4myc stably 
      expressed in C2C12 myotubes. Insulin stimulation of Akt and AS160 
      phosphorylation, key regulators of GLUT4myc exocytosis, was markedly impaired. 
      CM-H also caused activation of JNK and S6K, and elevated serine phosphorylation 
      of IRS1 in the C2C12 myotubes. These effects were implicated in reducing 
      propagation of insulin signaling to Akt and AS160. Heat inactivation of CM-H 
      reversed its dual effects on GLUT4myc traffic in muscle cells. Interestingly, 
      antibody-mediated neutralization of IL-6 in CM-H lowered its effect on both the 
      basal and insulin-stimulated cell surface GLUT4myc compared to unmodified CM-H. 
      IL-6 may have regulated GLUT4myc traffic through its action on AMPK. 
      Additionally, antibody-mediated neutralization of MCP-1 partly reversed the 
      inhibition of insulin-stimulated GLUT4myc exocytosis caused by unmodified CM-H. 
      In Transwell co-culture, hypoxia-challenged adipocytes attracted RAW 264.7 
      macrophages, consistent with elevated release of MCP-1 from adipocytes during 
      hypoxia. Neutralization of MCP-1 in adipocyte CM-H prevented macrophage migration 
      towards it and partly reversed the effect of CM-H on insulin response in muscle 
      cells. We conclude that adipose tissue hypoxia may be an important trigger of its 
      inflammatory response observed in obesity, and the elevated chemokine MCP-1 may 
      contribute to increased macrophage migration towards adipose tissue and 
      subsequent decreased insulin responsiveness of glucose uptake in muscle.
CI  - Copyright (c) 2011 Elsevier GmbH. All rights reserved.
FAU - Yu, Junna
AU  - Yu J
AD  - Department of Immunology, Key Laboratory of Immuno Microenvironment and Disease 
      of the Educational Ministry of China, Tianjin Medical University, Tianjin 300070, 
      China.
FAU - Shi, Lihuan
AU  - Shi L
FAU - Wang, Hui
AU  - Wang H
FAU - Bilan, Philip J
AU  - Bilan PJ
FAU - Yao, Zhi
AU  - Yao Z
FAU - Samaan, M Constantine
AU  - Samaan MC
FAU - He, Qing
AU  - He Q
FAU - Klip, Amira
AU  - Klip A
FAU - Niu, Wenyan
AU  - Niu W
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111001
PL  - Germany
TA  - Eur J Cell Biol
JT  - European journal of cell biology
JID - 7906240
RN  - 0 (Adiponectin)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Cytokines)
RN  - 0 (Glucose Transporter Type 4)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Insulin)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adipocytes/cytology/*metabolism
MH  - Adiponectin/metabolism
MH  - Animals
MH  - Cell Hypoxia/physiology
MH  - Culture Media, Conditioned
MH  - Cytokines/metabolism
MH  - Glucose Transporter Type 4/biosynthesis
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis
MH  - Insulin/*metabolism/pharmacology
MH  - *Insulin Resistance
MH  - Macrophages/cytology/drug effects/metabolism
MH  - Mice
MH  - Muscle Fibers, Skeletal/cytology/drug effects/metabolism
MH  - Muscle, Skeletal/cytology/drug effects/*metabolism
MH  - Signal Transduction
EDAT- 2011/10/04 06:00
MHDA- 2012/03/08 06:00
CRDT- 2011/10/04 06:00
PHST- 2011/01/18 00:00 [received]
PHST- 2011/06/24 00:00 [revised]
PHST- 2011/06/24 00:00 [accepted]
PHST- 2011/10/04 06:00 [entrez]
PHST- 2011/10/04 06:00 [pubmed]
PHST- 2012/03/08 06:00 [medline]
AID - S0171-9335(11)00126-9 [pii]
AID - 10.1016/j.ejcb.2011.06.004 [doi]
PST - ppublish
SO  - Eur J Cell Biol. 2011 Dec;90(12):1000-15. doi: 10.1016/j.ejcb.2011.06.004. Epub 
      2011 Oct 1.