PMID- 11978627
OWN - NLM
STAT- MEDLINE
DCOM- 20020523
LR  - 20220222
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 51
IP  - 5
DP  - 2002 May
TI  - Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates 
      expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB 
      activation by TNF-alpha is obligatory.
PG  - 1319-36
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a contributing cause of the insulin 
      resistance seen in obesity and obesity-linked type 2 diabetes, but the 
      mechanism(s) by which TNF-alpha induces insulin resistance is not understood. By 
      using 3T3-L1 adipocytes and oligonucleotide microarrays, we identified 142 known 
      genes reproducibly upregulated by at least threefold after 4 h and/or 24 h of 
      TNF-alpha treatment, and 78 known genes downregulated by at least twofold after 
      24 h of TNF-alpha incubation. TNF-alpha-induced genes include transcription 
      factors implicated in preadipocyte gene expression or NF-kappaB activation, 
      cytokines and cytokine-induced proteins, growth factors, enzymes, and signaling 
      molecules. Importantly, a number of adipocyte-abundant genes, including GLUT4, 
      hormone sensitive lipase, long-chain fatty acyl-CoA synthase, adipocyte 
      complement-related protein of 30 kDa, and transcription factors CCAAT/enhancer 
      binding protein-alpha, receptor retinoid X receptor-alpha, and peroxisome 
      profilerator-activated receptor gamma were significantly downregulated by 
      TNF-alpha treatment. Correspondingly, 24-h exposure of 3T3-L1 adipocytes to 
      TNF-alpha resulted in reduced protein levels of GLUT4 and several insulin 
      signaling proteins, including the insulin receptor, insulin receptor substrate 1 
      (IRS-1), and protein kinase B (AKT). Nuclear factor-kappaB (NF-kappaB) was 
      activated within 15 min of TNF-alpha addition. 3T3-L1 adipocytes expressing 
      IkappaBalpha-DN, a nondegradable NF-kappaB inhibitor, exhibited normal 
      morphology, global gene expression, and insulin responses. However, absence of 
      NF-kappaB activation abolished suppression of >98% of the genes normally 
      suppressed by TNF-alpha and induction of 60-70% of the genes normally induced by 
      TNF-alpha. Moreover, extensive cell death occurred in IkappaBalpha-DN-expressing 
      adipocytes after 2 h of TNF-alpha treatment. Thus the changes in adipocyte gene 
      expression induced by TNF-alpha could lead to insulin resistance. Further, 
      NF-kappaB is an obligatory mediator of most of these TNF-alpha responses.
FAU - Ruan, Hong
AU  - Ruan H
AD  - Whitehead Institute for Biomedical Research, Massachusetts Institute of 
      Technology, Cambridge, Massachusetts 02142, USA.
FAU - Hacohen, Nir
AU  - Hacohen N
FAU - Golub, Todd R
AU  - Golub TR
FAU - Van Parijs, Luk
AU  - Van Parijs L
FAU - Lodish, Harvey F
AU  - Lodish HF
LA  - eng
GR  - R37-DK-47618/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Glucose Transporter Type 4)
RN  - 0 (Insulin)
RN  - 0 (Monosaccharide Transport Proteins)
RN  - 0 (Muscle Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Messenger)
RN  - 0 (Slc2a4 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - 3T3 Cells
MH  - Adipocytes/cytology/drug effects/*physiology
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Cycle/physiology
MH  - Cell Differentiation/physiology
MH  - Cell Nucleus/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression/*drug effects/immunology
MH  - Glucose Transporter Type 4
MH  - Insulin/metabolism
MH  - Insulin Resistance/physiology
MH  - Mice
MH  - Monosaccharide Transport Proteins/genetics/metabolism
MH  - *Muscle Proteins
MH  - NF-kappa B/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - RNA, Messenger/analysis
MH  - Signal Transduction/drug effects/immunology
MH  - Stem Cells/cytology/drug effects/physiology
MH  - Transcriptional Activation/drug effects/immunology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2002/04/30 10:00
MHDA- 2002/05/25 10:01
CRDT- 2002/04/30 10:00
PHST- 2002/04/30 10:00 [pubmed]
PHST- 2002/05/25 10:01 [medline]
PHST- 2002/04/30 10:00 [entrez]
AID - 10.2337/diabetes.51.5.1319 [doi]
PST - ppublish
SO  - Diabetes. 2002 May;51(5):1319-36. doi: 10.2337/diabetes.51.5.1319.