Cytokine-induced metabolic effects in human adipocytes are independent of endogenous nitric oxide.
Nitric oxide (NO) has been recognized as a potential mediator of inflammation-induced metabolic alterations, including insulin resistance. However, expression mechanisms and potential roles of endothelial and inducible NO synthases (eNOS and iNOS, respectively) in human adipocytes are poorly understood. In the present study, we aimed to analyze several aspects of NO-related gene expression and metabolite synthesis in basal and inflammation-activated human adipocyte models. eNOS mRNA was highly expressed in omental and to a lesser extent in human subcutaneous adipose tissue biopsies, but not in purified adipocytes, in mesenchymal stem cell (MSC)- and in preadipocyte-derived adipocytes, respectively. Trace amounts of iNOS mRNA were detected in adipose tissue samples of donors with abdominal infection, as opposed to noninfected subjects. Interferon-gamma, in combination with interleukin-1beta or lipopolysaccharide, evoked a transient (4 h < time < 24 h) iNOS mRNA expression in human MSC and preadipocyte-derived adipocytes, respectively. This induction was preceded by cytokine-specific mRNAs. In addition, it was accompanied by an activation of the tetrahydrobiopterin synthesis pathway and by inhibition of peroxisome proliferator-activated receptor-gamma2. In contrast to murine 3T3-L1-derived adipocytes, iNOS protein and NO oxidation products remained undetectable in iNOS mRNA-positive human adipocytes. Accordingly, coadministration of NOS inhibitors (i.e., Nomega-nitro-L-arginine methyl ester, Nomega-monomethyl-L-arginine, and 1400W) had no effects on insulin-mediated glucose uptake and lipolysis. We conclude that, in human adipocytes, endogenous NO is not involved in metabolic regulation during either basal or cytokine-activated conditions.
Linscheid
Philippe
P
Dept. of Research, Univ. Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Philippe.Linscheid@unibas.ch
Seboek
Dalma
D
Zulewski
Henryk
H
Scherberich
Arnaud
A
Blau
Nenad
N
Keller
Ulrich
U
Müller
Beat
B
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D001708:Biopterins / Q000031:analogs & derivatives / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism
D016207:Cytokines; D007328:Insulin; D047495:PPAR gamma; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C003402:sapropterin; D005990:Glycerol