E2F1 Regulates Adipocyte Differentiation and Adipogenesis by Activating ICAT

Abstract

Wnt/β-catenin is a crucial repressor of adipogenesis. We have shown that E2 promoter binding factor 1 (E2F1) suppresses Wnt/β-catenin activity through transactivation of β-catenin interacting protein 1 (CTNNBIP1), also known as inhibitor of β-catenin and TCF4 (ICAT) in human colorectal cancers. However, it remains unknown whether ICAT is required for E2F1 to promote differentiation by inhibiting β-catenin activity in pre-adipocytes. In the present study, we found that 1-methyl-3-isobutylxanthine, dexamethasone, and insulin (MDI)-induced differentiation and lipid accumulation in 3T3-L1 pre-adipocytes was reversed by activation of β-catenin triggered by CHIR99021, a GSK3β inhibitor. Intriguingly, we observed a reduced protein level of E2F1 and ICAT at a later stage of pre-adipocytes differentiation. Importantly, overexpression of ICAT in 3T3-L1 pre-adipocytes markedly promote the adipogenesis and partially reversed the inhibitory effect of CHIR99021 on MDI-induced adipogenesis and lipid accumulation by regulating adipogenic regulators and Wnt/β-catenin targets. Moreover, pre-adipocytes differentiation induced by MDI were markedly inhibited in siE2F1 or siICAT transfected 3T3-L1 cells. Gene silencing of ICAT in the E2F1 overexpressed adipocytes also inhibited the adipogenesis. These data indicated that E2F1 is a metabolic regulator with an ability to promote pre-adipocyte differentiation by activating ICAT, therefore represses Wnt/β-catenin activity in 3T3-L1 cells. We also demonstrated that ICAT overexpression did not affect oleic acid-induced lipid accumulation at the surface of Hela and HepG2 cells. In conclusion, we show that E2F1 is a critical regulator with an ability to promote differentiation and adipogenesis by activating ICAT in pre-adipocytes.Cells 2020, 9, 1024 2 of 15 generally believed that the increased number of adipocytes is mainly determined by the adipocyte differentiation process, termed adipogenesis [3]. Adipogenesis consists of a complex series of events in which both cellular and extracellular factors act together and lead to transformation to a mature, lipid-filled adipocyte from a fibroblast-like pre-adipocyte. Therefore, pre-adipocyte differentiation has been one of the well-known models used to study adipogenesis [4], and underlying mechanisms, due to its implication in metabolic syndrome, such as insulin resistance, type 2 diabetes, hypertension, and atherosclerosis [5].E2 promoter binding factor 1 (E2F1) is a transcriptional factor involved in cell cycle progression, cell differentiation, and apoptosis [6]. Several lines of studies show that E2F1 is a novel regulator of metabolic homeostasis [7][8][9]. Protein level of E2F1 is increased in the visceral white adipose tissue of obese human subjects and is positively correlated with development of insulin resistance, circulating free fatty acids level, and incidence of non-alcoholic fatty liver disease [7,[10][11][12][13]. In contrast, E2F1 −/− mice have a reduced fat accretion, increased insulin sensitivity, and a decreased circulating lev...

Oxysterol-binding protein-like 2 contributes to the developmental progression of preadipocytes by binding to β-catenin

“…Preadipocyte development and adipocyte differentiation are delicate and complicated, biological processes. With the treatment of a classical induction cocktail (MDI: 3-isobutyl-1-methylxanthine, dexamethasone, and insulin), 3T3-L1 preadipocytes were induced and to differentiate into mature adipocytes 27 , 29 . As showed in Supplementary Fig.…”

Orbital manifestations of hypercorticism

“…Далее, в каноническом пути, сигнал передается на ß-катенин [4]. При активации этого пути накапливающийся свободный β-катенин проникает в ядро, где он связывается с LEF/TCF (lymphoid enhancer binding factor/T-cell specific transcription factor) и запускает транскрипцию генов-мишеней Wnt [23,24]. Wnt/β-catenin pathway ингибирует адипогенез (блокируя PPARg и CEBPA).…”

“…Важно отметить, что данные, полученные in vitro с использованием экспериментальных моделей, следует интерпретировать с осторожностью. К примеру, ряд исследований исключают EGR2, KLF4 из списка адипогенных факторов in vivo, объясняя это тем, что их положительное влияние на адипогенез было подтверждено лишь in vitro на 3T3-линии [16,23].…”

A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

“…Although these mechanisms mainly control the progression of the cell cycle (26), recent studies have reported important roles for the E2F1-pRb-CDK4 pathway beyond the sole regulation of cell proliferation (27,28). Indeed, several reports have demonstrated the role of the E2F1 pathway in the control of metabolic functions in non-proliferative cells, including adipocytes (29,30), hepatocytes (31)(32)(33), muscle and brown adipose tissue (34,35) and pancreatic b cells (17)(18)(19)36).…”