Melatonin enhances leptin expression by rat adipocytes in the presence of insulin.
Leptin and melatonin play an important role in the regulation of body mass and energy balance. Both hormones show a circadian rhythm, with increasing values at night. In addition, melatonin receptors were recently described in adipocytes, where leptin is synthesized. Here, we investigated the influence of melatonin and its interaction with insulin and dexamethasone on leptin expression. Isolated rat adipocytes were incubated with melatonin (1 nM) alone or in combination with insulin (5 nM) and/or dexamethasone (7 nM) for 6 h. Melatonin or insulin alone did not affect leptin expression, but together they increased it by 120%. Dexamethasone increased leptin mRNA content (105%), and this effect was not enhanced by melatonin. Simultaneous treatment with the three hormones provoked a further increase in leptin release (250%) and leptin mRNA (100%). Melatonin prevented the forskolin-induced inhibition (95%) of leptin expression. In addition, melatonin's ability to stimulate leptin release (in the presence of insulin) was completely blocked by pertussis toxin and luzindole. To gain further insight into the molecular basis of melatonin and insulin synergism, the insulin-signaling pathway was investigated. Melatonin increased the insulin-induced insulin receptor-beta tyrosine phosphorylation, which led to an increased serine phosphorylation of the downstream convergent protein Akt. We concluded that melatonin interacts with insulin and upregulates insulin-stimulated leptin expression. These effects are caused by melatonin binding to the pertussis toxin-sensitive G(i) protein-coupled membrane receptor (MT1 subtype) and the cross talk with insulin, since insulin receptor and its convergent target Akt are coactivated by melatonin.
Alonso-Vale
Maria Isabel Cardoso
MI
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil.
Andreotti
Sandra
S
Peres
Sidney Barnabé
SB
Anhê
Gabriel Forato
GF
das Neves Borges-Silva
Cristina
C
Neto
José Cipolla
JC
Lima
Fabio Bessa
FB
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000494:pharmacology*; D020738:Leptin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014363:Tryptamines / Q000494:pharmacology
D005938:Glucocorticoids; D007328:Insulin; D020738:Leptin; D011518:Proto-Oncogene Proteins; D044122:Receptor, Melatonin, MT1; D014363:Tryptamines; C057154:luzindole; D005576:Colforsin; D012313:RNA; D003907:Dexamethasone; D037342:Pertussis Toxin; D011972:Receptor, Insulin; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin