Carbamazepine directly inhibits adipocyte differentiation through activation of the ERK 1/2 pathway

Abstract

BACKGROUND AND PURPOSECarbamazepine (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 RESEARCHWe 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. KEY RESULTSCBZ 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-g and CCAAT/enhancer binding protein-a, activation of basal lipolysis and decrease in insulin-stimulated glucose transport. CONCLUSIONS AND IMPLICATIONSThe 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. AbbreviationsACC, acetyl-CoA carboxylase; C/EBP-a, CCAAT/enhancer binding protein-a; C/EBP-b, CCAAT/enhancer binding protein-b; CBZ, carbamazepine; DOG, deoxyglucose; FAS, fatty acid synthase; G3PDH, glycerol-3-phosphate dehydrogenase; HSL, hormone-sensitive lipase; MEK, MAPK/ERK kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; SREBP-1c, sterol regulatory element-binding protein 1c

Chemerin induces lipolysis through ERK1/2 pathway in intramuscular mature adipocytes of dairy bull calves

“…In our current study, we observed that Chemerin induces higher protein expressions of HSL, LPL and PPARα through the ERK1/2 signaling pathway in mature adipocyte metabolism. The result is similar to the role of Carbamazepine in 3T3‐L1 cells . PPARγ and C/EBPα are particularly important in the regulation of adipogenesis, and are highly expressed in mature adipocytes .…”

“…The result is similar to the role of Carbamazepine in 3T3-L1 cells. 29 PPARγ and C/ EBPα are particularly important in the regulation of adipogenesis, and are highly expressed in mature adipocytes. 30 Here, we observed that Chemerin induces higher expression of the lipolytic-related critical factors HSL, leptin, and LPL, and down-regulate lipogenic-related genes PPARγ and C/EBPα in mature adipocyte metabolism.…”

Involvement of the L-arginine/Nitric Oxide/Cyclic GMP/KATP Channel Pathway and PPARγ Receptors in the Peripheral Antinociceptive Effect of Carbamazepine

“…Moreover, we previously reported that the role of PPARγ receptors in the antinociceptive effects of some drugs [17,18]. On the other hand, Turpin et al (2013) indicated that carbamazepine may alter cell metabolism through PPARγ receptors in mice cells [19].…”

Carbamazepine Enhances Adipogenesis by Inhibiting Wnt/β-Catenin Expression

“…Moreover, the expression levels of adipogenic genes (such as SREBP ) , genes related to lipid synthesis (such as FASN , SCD1 , MGAT1 , and DGAT1 ) , and adipokine genes (including Adipoq , leptin , and FABP4 ) were increased after carbamazepine treatment. In contrast, Turpin et al [42] have reported that carbamazepine treatment at a concentration of 500 μM inhibits adipocyte differentiation and suppresses the expression levels of adipogenic transcription factors (such as PPARγ , C/EBPα , and C/EBPβ ) and lipogenic enzymes (such as ACC , and FASN ) in 3T3-L1, 3T3-F442A, and T37i cells. However, the concentration of carbamazepine used in their study was very high (500 μM).…”