title: Effects of Trecadrine, a beta3-adrenergic agonist, on leptin secretion, glucose and lipid metabolism in isolated rat adipocytes.
abstract: OBJECTIVE
  Leptin, a hormone produced in adipocytes, is a key signal in the regulation of food intake and energy expenditure. Beta-adrenergic agonists have been shown to inhibit leptin gene expression and leptin secretion. The mechanisms underlying the inhibitory effects of beta-adrenergic agonists have not been established. In this study, we examined the effects of Trecadrine, a novel beta3-adrenergic agonist, on basal and insulin-stimulated leptin secretion in isolated rat adipocytes. Because insulin-stimulated glucose metabolism is an important regulator of leptin expression and secretion by the adipocytes, the effects of Trecadrine on indices of adipocyte metabolism were also examined.
  
  
  METHODS
  Isolated adipocytes were incubated with Trecadrine (10(-8)-10(-4) M) in the absence or presence of insulin (1.6 nM). Leptin secretion, glucose utilization, lactate production, glucose incorporation into CO(2) and triglyceride, as well as lipolysis (glycerol release) were determined.
  
  
  RESULTS
  Trecadrine induced a concentration-dependent inhibition of basal leptin secretion. Trecadrine also decreased insulin-stimulated leptin secretion; however, the effect was not as pronounced as in the absence of insulin. Treatment of adipocytes with Trecadrine increased basal glucose utilization and produced a further increase in insulin-stimulated glucose utilization. Basal lactate production was also increased by Trecadrine; however, the proportion (percentage) of glucose carbon released as lactate was unaffected. In the presence of insulin, absolute lactate production was unaffected by Trecadrine at 96 h. However, the percentage of glucose carbon released as lactate was significantly decreased by insulin treatment, and was further decreased by the co-treatment with Trecadrine. Trecadrine induced a dose-dependent increase of the absolute amount of glucose incorporated into triglyceride. However, the percentage of glucose utilized that was incorporated into triglyceride was unaffected by Trecadrine. Trecadrine did not modify the proportion of glucose utilized that was oxidized to CO(2). Trecadrine increased glycerol release after 96 h of treatment. Glycerol release was negatively correlated with leptin secretion.
  
  
  CONCLUSIONS
  These results suggest that alterations of glucose metabolism are not directly involved in the effects of beta3-adrenergic agonists to inhibit leptin expression and secretion. The inverse relationship between leptin secretion and the increase of glycerol levels, which is an index of the activation of cAMP-dependent protein kinases, suggests that activation of the cAMP signaling pathway mediates the inhibitory effects of Trecadrine on leptin gene expression and secretion.
authors.affiliation: Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Moreno-Aliaga
authors.forename: J A
authors.initials: JA
authors.lastname: Martínez
authors.forename: K L
authors.initials: KL
authors.lastname: Stanhope
authors.forename: M P
authors.initials: MP
authors.lastname: Fernández-Otero
authors.forename: P J
authors.initials: PJ
authors.lastname: Havel
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001592:Benzyl Alcohols / Q000494:pharmacology*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D019344:Lactic Acid / Q000096:biosynthesis; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D001592:Benzyl Alcohols; D020738:Leptin; D012333:RNA, Messenger; D022702:Receptors, Adrenergic, beta-3; D014280:Triglycerides; D019344:Lactic Acid; C101319:trecadrine; D005947:Glucose