Direct effects of leptin on brown and white adipose tissue.
Leptin is thought to exert its actions on energy homeostasis through the long form of the leptin receptor (OB-Rb), which is present in the hypothalamus and in certain peripheral organs, including adipose tissue. In this study, we examined whether leptin has direct effects on the function of brown and white adipose tissue (BAT and WAT, respectively) at the metabolic and molecular levels. The chronic peripheral intravenous administration of leptin in vivo for 4 d resulted in a 1.6-fold increase in the in vivo glucose utilization index of BAT, whereas no significant change was found after intracerebroventricular administration compared with pair-fed control rats, compatible with a direct effect of leptin on BAT. The effect of leptin on WAT fat pads from lean Zucker Fa/ fa rats was assessed ex vivo, where a 9- and 16-fold increase in the rate of lipolysis was observed after 2 h of exposure to 0.1 and 10 nM leptin, respectively. In contrast, no increase in lipolysis was observed in the fat pads from obese fa/fa rats, which harbor an inactivating mutation in the OB-Rb. At the level of gene expression, leptin treatment for 24 h increased malic enzyme and lipoprotein lipase RNA 1.8+/-0.17 and 1.9+/-0.14-fold, respectively, while aP2 mRNA levels were unaltered in primary cultures of brown adipocytes from lean Fa/fa rats. Importantly, however, no significant effect of leptin was observed on these genes in brown adipocytes from obese fa/fa animals. The presence of OB-Rb receptors in adipose tissue was substantiated by the detection of its transcripts by RT-PCR, and leptin treatment in vivo and in vitro activated the specific STATs implicated in the signaling pathway of the OB-Rb. Taken together, our data strongly suggest that leptin has direct effects on BAT and WAT, resulting in the activation of the Jak/STAT pathway and the increased expression of certain target genes, which may partially account for the observed increase in glucose utilization and lipolysis in leptin-treated adipose tissue.
Siegrist-Kaiser
C A
CA
Unité de Thyroïde, Division d'Endocrinologie et Diabétologie, Hôpital Universitaire de Genève, Geneva, Switzerland.
Pauli
V
V
Juge-Aubry
C E
CE
Boss
O
O
Pernin
A
A
Chin
W W
WW
Cusin
I
I
Rohner-Jeanrenaud
F
F
Burger
A G
AG
Zapf
J
J
Meier
C A
CA
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D053613:Janus Kinase 1; D020738:Leptin; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000235:genetics; D008291:Malate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D018996:Myelin P2 Protein / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D000077154:Rosiglitazone; D050794:STAT1 Transcription Factor; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D015534:Trans-Activators / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D007004:Hypoglycemic Agents; D020738:Leptin; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050794:STAT1 Transcription Factor; D013844:Thiazoles; D045162:Thiazolidinediones; D015534:Trans-Activators; C515447:leptin receptor, mouse; D000077154:Rosiglitazone; D008291:Malate Dehydrogenase; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D008071:Lipoprotein Lipase; D005947:Glucose