PMID- 12351429
OWN - NLM
STAT- MEDLINE
DCOM- 20021203
LR  - 20220318
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 51
IP  - 10
DP  - 2002 Oct
TI  - Tumor necrosis factor-alpha stimulates lipolysis in differentiated human 
      adipocytes through activation of extracellular signal-related kinase and 
      elevation of intracellular cAMP.
PG  - 2929-35
AB  - Tumor necrosis factor-alpha (TNF-alpha) stimulates lipolysis in human adipocytes. 
      However, the mechanisms regulating this process are largely unknown. We 
      demonstrate that TNF-alpha increases lipolysis in differentiated human adipocytes 
      by activation of mitogen-activated protein kinase kinase (MEK), extracellular 
      signal-related kinase (ERK), and elevation of intracellular cAMP. TNF-alpha 
      activated ERK and increased lipolysis; these effects were inhibited by two 
      specific MEK inhibitors, PD98059 and U0126. TNF-alpha treatment caused an 
      electrophoretic shift of perilipin from 65 to 67 kDa, consistent with perilipin 
      hyperphosphorylation by activated cAMP-dependent protein kinase A (PKA). 
      Coincubation with TNF-alpha and MEK inhibitors caused perilipin to migrate as a 
      single 65-kDa band. Consistent with the hypothesis that TNF-alpha induces 
      perilipin hyperphosphorylation by activating PKA, TNF-alpha increased 
      intracellular cAMP approximately 1.7-fold, and the increase was abrogated by 
      PD98059. Furthermore, H89, a specific PKA inhibitor, blocked TNF-alpha-induced 
      lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA 
      in TNF-alpha-induced lipolysis. Finally, TNF-alpha decreased the expression of 
      cyclic-nucleotide phosphodiesterase 3B (PDE3B) by approximately 50%, delineating 
      a mechanism by which TNF-alpha could increase intracellular cAMP. Cotreatment 
      with PD98059 restored PDE3B expression. These studies suggest that in human 
      adipocytes, TNF-alpha stimulates lipolysis through activation of MEK-ERK and 
      subsequent increase in intracellular cAMP.
FAU - Zhang, Hui H
AU  - Zhang HH
AD  - Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on 
      Aging at Tufts University, Boston, MA 02111, USA.
FAU - Halbleib, Melanie
AU  - Halbleib M
FAU - Ahmad, Faiyaz
AU  - Ahmad F
FAU - Manganiello, Vincent C
AU  - Manganiello VC
FAU - Greenberg, Andrew S
AU  - Greenberg AS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Butadienes)
RN  - 0 (Carrier Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Flavonoids)
RN  - 0 (Isoquinolines)
RN  - 0 (Nitriles)
RN  - 0 (Perilipin-1)
RN  - 0 (Phosphoproteins)
RN  - 0 (Sulfonamides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (U 0126)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.1.- (MAP2K2 protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 2)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
RN  - EC 3.1.4.17 (PDE3B protein, human)
RN  - M876330O56 (N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
SB  - IM
MH  - 3',5'-Cyclic-AMP Phosphodiesterases/metabolism
MH  - Adipocytes/cytology/drug effects/*enzymology
MH  - Adult
MH  - Antineoplastic Agents/*pharmacology
MH  - Butadienes/pharmacology
MH  - Carrier Proteins
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Cyclic AMP/*metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/metabolism
MH  - Cyclic Nucleotide Phosphodiesterases, Type 3
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Flavonoids/pharmacology
MH  - Humans
MH  - Isoquinolines/pharmacology
MH  - Lipolysis/*drug effects
MH  - MAP Kinase Kinase 2
MH  - MAP Kinase Signaling System/*physiology
MH  - Male
MH  - Middle Aged
MH  - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Nitriles/pharmacology
MH  - Perilipin-1
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism
MH  - *Sulfonamides
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2002/09/28 04:00
MHDA- 2002/12/04 04:00
CRDT- 2002/09/28 04:00
PHST- 2002/09/28 04:00 [pubmed]
PHST- 2002/12/04 04:00 [medline]
PHST- 2002/09/28 04:00 [entrez]
AID - 10.2337/diabetes.51.10.2929 [doi]
PST - ppublish
SO  - Diabetes. 2002 Oct;51(10):2929-35. doi: 10.2337/diabetes.51.10.2929.