Abstract
The excessive accumulation of adipocytes contributes to the development of obesity and obesity-related diseases. The interactions of several transcription factors, such as C/EBPβ, PPARγ, C/EBPα, Nrf2, and STAT3, are required for adipogenic differentiation. Dimethylfumarate (DMF), an immune modulator and antioxidant, may function as an inhibitor of STAT3 and an activator of Nrf2. This study examined whether DMF inhibits adipogenic differentiation of 3T3-L1 preadipocytes by inhibiting STAT3 or activating Nrf2. DMF suppressed 3T3-L1 preadipocyte differentiation to mature adipocytes in a dose-dependent manner as determined by Oil Red O staining. The mRNA and protein levels of adipogenic genes, including C/EBPβ, C/EBPα, PPARγ, SREBP-1c, FAS, and aP2, were significantly lower in DMF-treated 3T3-L1 preadipocytes. Suppression of adipogenic differentiation by DMF treatment resulted primarily from inhibition of the early stages of differentiation. DMF inhibits clonal expansion during adipogenic differentiation through induction of a G1 cell cycle arrest. Additionally, DMF regulates cell cycle-related proteins, such as p21, pRb, and cyclin D. DMF treatment markedly inhibited differentiation medium-induced STAT3 phosphorylation and inhibited STAT3 transcriptional activation of a reporter construct composed of four synthetic STAT3-response elements. Moreover, inhibition of endogenous Nrf2 activity using a dominant negative Nrf2 did not abolish the DMF-induced inhibition of adipogenic differentiation of 3T3-L1 preadipocytes. In summary, DMF is a negative regulator of adipogenic differentiation based on its regulation of adipogenic transcription factors and cell cycle proteins. This negative regulation by DMF is mediated by STAT3 inhibition, but is unlikely to involve Nrf2 activation.
Highlights
Adipose tissue contributes to the maintenance of energy homeostasis [1] and is considered to be an endocrine organ that contributes to the pathogenesis of obesity and obesity-related metabolic complications [1]
Post-confluent 3T3-L1 preadipocytes treated with differentiation medium (MDI), which contains a mixture of IBMX, dexamethasone, and insulin, initiated adipogenic differentiation and Oil Red O staining showed that intracellular lipid accumulation was marked by day 8, suggesting that 3T3-L1 preadipocytes differentiate into mature adipocytes
The protein levels of C/EBPa, peroxisome proliferator-activated receptor gamma (PPARc), SREBP-1c, and FAS in DMF-treated 3T3-L1 preadipocytes were decreased by DMF treatment in a dose-dependent manner (Fig. 2B)
Summary
Adipose tissue contributes to the maintenance of energy homeostasis [1] and is considered to be an endocrine organ that contributes to the pathogenesis of obesity and obesity-related metabolic complications [1]. Excessive accumulation of adipose tissue in the body may cause the development of obesity and obesity-related diseases [2]. Recent evidence has demonstrated that accelerated adipogenic differentiation is implicated in the excessive accumulation of body fat [4]. Adipogenic differentiation is a complex process accompanied by changes in cytoarchitecture, signaling pathways, and transcriptional regulation. The interactions of several transcription factors, such as peroxisome proliferator-activated receptor gamma (PPARc), CCAATT enhancer binding proteins (C/EBP), and SREBP-1c, are required for adipogenic differentiation [4,5]
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