Pre- and post-translational negative effect of beta-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies.
The adipose-derived hormone, adiponectin (ApN), has a role in fuel homoeostasis, insulin action and atherosclerosis. Regulation of ApN by catecholamines has scarcely been investigated. We examined the effects of beta-adrenergic agonists (and their second messenger, cAMP) on ApN gene expression, production and secretion in mouse in vitro and in vivo; their effects in human fat were also briefly studied in vitro. beta-Adrenergic agonists and cAMP inhibited ApN gene expression in human visceral adipose tissue. Likewise, cAMP down-regulated ApN mRNAs in cultured mouse explants from visceral and subcutaneous regions. The amount of ApN released into the medium decreased concomitantly. cAMP also caused qualitative changes in ApN secretion. Under basal conditions, ApN was secreted as a single 32 kDa species. In the presence of cAMP, an additional and probably immature (not modified post-translationally) 30 kDa species was also sorted. This altered secretion resulted from cAMP-induced quantitative and qualitative changes of ApN within the adipocyte. Under basal conditions, the 32 kDa form of ApN was mainly associated with high-density microsomes (HDMs), while the 30 kDa species was confined to a pool recovered with the cytosol fraction. cAMP depleted intracellular ApN at the expense of both HDM and cytosol fractions, and abnormally targeted ApN species to the different subcellular compartments as a result of impaired maturation. beta-Adrenergic agonists mimicked the inhibitory effects of cAMP on ApN mRNA and secretion, the beta(3)-agonist BRL37344 being the most potent. Administration of BRL37344 to mice reduced ApN mRNAs in both adipose regions, and ApN levels in plasma. In conclusion, beta-agonists inhibited ApN production and maturation, and thus exerted a dual (pre- and post-translational) negative effect on ApN secretion by cultured mouse adipose explants. ApN inhibition by beta-agonists was reproduced in mouse in vivo and in humans in vitro. ApN down-regulation may have an important role in fuel homoeostasis, insulin resistance and stress-induced atherosclerosis.
Delporte
Marie-Laure
ML
Unit of Endocrinology and Metabolism, University of Louvain, Faculty of Medicine, UCL 5530 Avenue Hippocrate, 55, B-1200 Brussels, Belgium.
Funahashi
Tohru
T
Takahashi
Masahiko
M
Matsuzawa
Yuji
Y
Brichard
Sonia M
SM
D052242:Adiponectin; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D000242:Cyclic AMP / Q000494:pharmacology; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
D052242:Adiponectin; D000318:Adrenergic beta-Agonists; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D000242:Cyclic AMP