Carbamazepine directly inhibits adipocyte differentiation through activation of the ERK 1/2 pathway.
OBJECTIVE
Carbamazepine (CBZ), known for its anti-epileptic, analgesic and mood-stabilizing properties, is also known to induce weight gain but the pathophysiology of this adverse effect is still largely unknown. We tested the hypothesis that CBZ could have a direct effect on adipocyte development and metabolism. EXPERIMENTAL RESEARCH: We studied the effects of CBZ on morphological biochemical and molecular markers of adipogenesis, using several pre-adipocyte murine cell lines (3T3-L1, 3T3-F442A and T37i cells) and primary cultures of human pre-adipocytes. To delineate the mechanisms underlying the effect of CBZ, clonal expansion of pre-adipocytes, pro-adipogenic transcription factors, glucose uptake and lipolysis were also examined.


RESULTS
CBZ strongly inhibited pre-adipocyte differentiation and triglyceride accumulation in a time- and dose-dependent manner in all models. Pleiotropic mechanisms were at the basis of the inhibitory effects of CBZ on adipogenesis and cell lipid accumulation. They included suppression of both clonal expansion and major adipogenic transcription factors such as PPAR-γ and CCAAT/enhancer binding protein-α, activation of basal lipolysis and decrease in insulin-stimulated glucose transport.


CONCLUSIONS
The effect of CBZ on adipogenesis involves activation of the ERK1/2 pathway. Our results show that CBZ acts directly on pre-adipocytes and adipocytes to alter adipose tissue development and metabolism.
INSERM, U, Le Kremlin-Bicêtre, France.
E
E
Turpin
A
A
Muscat
C
C
Vatier
G
G
Chetrite
E
E
Corruble
M
M
Moldes
B
B
Fève
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002220:Carbamazepine / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D005947:Glucose / Q000493:pharmacokinetics; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; D007328:Insulin; D047495:PPAR gamma; D014157:Transcription Factors; D014280:Triglycerides; D002220:Carbamazepine; D005947:Glucose