Inhibitor kappaB kinase is involved in the paracrine crosstalk between human fat and muscle cells.
OBJECTIVE
Adipose tissue is now considered as an endocrine and secretory organ, and some adipocyte factors are thought to play a major role in the induction of insulin resistance in skeletal muscle. Here we tested the hypothesis that the crosstalk between fat and muscle involves activation of inhibitor kappaB Kinase (IKK) in the myocytes.


METHODS
Adipocyte-conditioned culture medium was added to the muscle cells overnight, or human fat and muscle cells were kept in co-culture. Insulin signalling was subsequently analysed in the myocytes. Involvement of IKK was assessed using I229, a highly specific inhibitor of the IKK complex.


RESULTS
Adipocyte-conditioned medium strongly inhibited insulin-induced serine phosphorylation of Akt in myocytes with a rapid parallel activation of the nuclear factor kappaB pathway in these cells. Conditioned medium lacking the perturbation of insulin signalling did not activate NF-kappaB. Insulin signalling to Akt was completely abrogated under co-culture conditions. The IKK inhibitor I229 did not affect protein expression of Akt, but fully restored insulin action in myocytes subjected to co-culture.


CONCLUSIONS
These data show that the release of fat cell factors may rapidly induce insulin resistance in human skeletal muscle cells. This process appears to be mediated by an IKK/NF-kappaB dependent pathway. We suggest that inhibitors of IKK would be of use to counteract the negative crosstalk between fat and muscle.
Dietze
D
D
Department of Clinical Biochemistry and Pathobiochemistry, German Diabetes Research Institute, Düsseldorf, Germany.
Ramrath
S
S
Ritzeler
O
O
Tennagels
N
N
Hauner
H
H
Eckel
J
J
D017667:Adipocytes / Q000378:metabolism*; D000704:Analysis of Variance; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D007328:Insulin; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human