title: Nitric oxide production from rat adipocytes is modulated by beta3-adrenergic receptor agonists and is involved in a cyclic AMP-dependent lipolysis in adipocytes.
abstract: It is established that the modulation of beta(3)-adrenoceptor function could be associated with impairment of lipolysis in white fat and be responsible for disturbed lipid metabolism. Though two isoforms of nitric oxide synthase (NOS) were reported in adipocytes, the role of nitric oxide (NO) in adipose tissue is still ambiguous. The present work was directed to study the interplay between NO production and beta-adrenoceptor/cyclic AMP (cAMP) pathway on lipid mobilization (glycerol and nonesterified fatty acids, NEFA) in cultures of rat adipocytes isolated from epididymal white adipose tissue. beta-Nonselective (isoprenaline) and beta(3)-selective (BRL-37344) agonists and the postadrenoceptor agents such as dibutyryl-cAMP, forskolin, and 3-isobutyl-1-methylxanthine significantly increased nitrite, glycerol, and NEFA levels with BRL-37344 being the most potent. Conversely, addition of beta-nonselective (propranolol) or beta(3)-selective (bupranolol) antagonist or the adenylyl cyclase inhibitor (SQ 22,536) significantly reduced beta-agonist-induced NO production and lipolysis. For beta-adrenoceptor agonists, antagonists, and their pairs, there was a positive correlation between medium nitrite and glycerol or NEFA with r(2) being 0.90 and 0.84, respectively. The possible relationship between NO and lipolysis was revealed after adipocyte treatment with nonspecific (N(omega)-nitro-l-arginine methyl ester, l-NAME) and specific (aminoguanidine) NOS inhibitors. Both l-NAME and aminoguanidine significantly inhibited the lipolytic effect of BRL-37344. Moreover, NO-donor (S-nitroso-N-acetylpenicillamine) at higher concentration increased basal glycerol and NEFA levels. 8-bromo-cyclic GMP had no effect on adipocyte lipolysis. These data suggest that beta-adrenergic lipolysis, specifically beta(3)-adrenoceptor effect, which is realized via the adenylyl cyclase/cAMP/protein kinase A signaling cascade, involves NO production downstream of beta(3)-adrenoceptor/cAMP pathway.
authors.affiliation: Institute of Pharmacology, 1st Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague 2, Czech Republic.
authors.forename: Nikolina Kutinová
authors.initials: NK
authors.lastname: Canová
authors.forename: Dagmar
authors.initials: D
authors.lastname: Lincová
authors.forename: Eva
authors.initials: E
authors.lastname: Kmonícková
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kameníková
authors.forename: Hassan
authors.initials: H
authors.lastname: Farghali
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000322:Adrenergic Agonists / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000322:Adrenergic Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D020030:Nitric Oxide Donors; C017759:9-(tetrahydro-2-furyl)-adenine; D005576:Colforsin; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D000242:Cyclic AMP; D006152:Cyclic GMP; D000225:Adenine; D015056:1-Methyl-3-isobutylxanthine