(-)-Ternatin inhibits adipogenesis and lipid metabolism in 3T3-L1 cells.
(-)-Ternatin, a highly N-methylated cyclic peptide, inhibits fat accumulation in 3T3-L1 cells and reduces fat mass in mice. However, the mechanism for its anti-adipogenic effect has remained unknown. To examine the mechanism used by (-)-ternatin to inhibit adipocyte differentiation, we examined the effects of (-)-ternatin and [l-Ala(4)]ternatin, an inactive analog of (-)-ternatin, on the expression of adipocyte markers and lipogenic enzymes. We found that (-)-ternatin potently reduced mRNA expression of several adipocyte markers in a dose-dependent manner, whereas [l-Ala(4)]ternatin showed no effects. At the immediate early phase, (-)-ternatin, but not [l-Ala(4)]ternatin, reduced the expression of Srebp1c, Fas, Acc2 and C/EBP-alpha while showing no effects on C/EBP-beta and C/EBP-delta. These results suggest that (-)-ternatin affects the mid-to late differentiation stages of adipocytes. Consistent with the decreased expression of lipogenic enzymes, (-)-ternatin potently inhibited triglyceride synthesis. Intriguingly, (-)-ternatin also inhibited triglyceride synthesis in rat primary hepatocytes, suggesting that the potential action sites for (-)-ternatin are shared by adipocytes and liver. Although the target molecule of (-)-ternatin remains unknown, our data suggest that (-)-ternatin and its potential target might provide a new therapeutic approach to metabolic disorders.
Ito
Masahiko
M
Tsukuba Research Institute, BANYU Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan.
Ito
Junko
J
Kitazawa
Hidefumi
H
Shimamura
Ken
K
Fukami
Takehiro
T
Tokita
Shigeru
S
Shimokawa
Kenichiro
K
Yamada
Kaoru
K
Kanatani
Akio
A
Uemura
Daisuke
D
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D015415:Biomarkers; D005419:Flavonoids; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D014280:Triglycerides; C051080:ternatin (flavonoid)