Abstract
The role of inducible nitric oxide synthase (iNOS) in the modulation of adipocyte lipolysis was investigated. Treatment of white and brown adipose cell lines and mouse adipose explants with a mixture of tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide (LPS) doubled the lipolytic rate, and this was associated with marked induction of iNOS expression and nitric oxide (NO) production. iNOS inhibition by 1400W, aminoguanidine, or L-NIL pretreatment further increased the cytokine/LPS-mediated lipolysis by 30% (P < 0.05) in cultured adipocytes and in adipose explants. However, this potentiating effect of iNOS inhibition was abolished in adipose explants isolated from iNOS knockout mice. Pharmacological inhibitors of adenylyl cyclase or protein kinase A reduced cytokine/LPS-induced lipolysis and also blunted the potentiating effect of iNOS inhibition on the lipolytic rate. Furthermore, addition of the antioxidants l-cystine and l-glutathione to cytokine/LPS-stimulated adipocytes mimicked the lipolytic effect of iNOS inhibition. In conclusion, inhibition of iNOS activity in adipocytes potentiates cytokine/LPS-induced lipolysis. This effect was fully reversed by adenylyl cyclase and protein kinase A inhibitors but was mimicked by cellular antioxidants. These data suggest that iNOS-mediated NO production counteracts cytokine/LPS-mediated lipolysis in adipocytes and that this feedback mechanism involves an oxidative process upstream of cAMP production in the signaling pathway.
Highlights
The role of inducible nitric oxide synthase in the modulation of adipocyte lipolysis was investigated
Adipose tissue lipolysis is mediated by Hormone-sensitive lipase (HSL), the end-limiting enzyme of the lipolytic process, which is regulated by both changes in gene expression and phosphorylation by protein kinase A (PKA)
We found that treatment with TNF-␣, IFN-␥, and LPS caused a marked decrease in HSL in both white and brown adipocytes, which is consistent with previous studies in 3T3-L1 adipocytes [22]
Summary
The role of inducible nitric oxide synthase (iNOS) in the modulation of adipocyte lipolysis was investigated. Inhibition of iNOS activity in adipocytes potentiates cytokine/LPS-induced lipolysis This effect was fully reversed by adenylyl cyclase and protein kinase A inhibitors but was mimicked by cellular antioxidants. Adipose tissue represents a major site of iNOS expression in endotoxemia, and its induction involves the combined actions of LPS and proinflammatory cytokines (e.g., TNF-␣ and IFN-␥) [13] This cytokine-inducible isoform produces large amounts of nitric oxide (NO; up to the micromolar range) and for a longer period of time (several hours) compared with the other members of the NOS family [endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) isoforms].
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