Abstract
Differentiation of preadipocyte, also called adipogenesis, leads to the phenotype of mature adipocyte. Excessive adipogenesis, however, is largely linked to the development of obesity. Herein we investigated a library of 53 novel chemicals, generated from a number of polyphenolic natural compounds, on adipogenesis. Strikingly, among the chemicals tested, KMU-3, a derivative of gallic acid, strongly suppressed lipid accumulation during the differentiation of 3T3-L1 preadipocytes into adipocytes. On mechanistic levels, KMU-3 inhibited expressions of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), and fatty acid synthase (FAS) during adipocyte differentiation. Moreover, KMU-3 reduced expressions of adipokines, including retinol binding protein-4 (RBP-4), leptin, and regulated on activation, normal T cell expressed and secreted (RANTES) during adipocyte differentiation. Of further note, KMU-3 rapidly blocked the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) during the early stage of adipogenesis. Importantly, pharmacological inhibition studies revealed that AG490, a JAK-2/STAT-3 inhibitor suppressed adipogenesis and STAT-3 phosphorylation, implying that early blockage of STAT-3 activity is crucial for the KMU-3-mediated anti-adipogenesis. These findings demonstrate firstly that KMU-3 inhibits adipogenesis by down-regulating STAT-3, PPAR-γ, C/EBP-α, and FAS. This work shows that KMU-3 is an inhibitor of adipogenesis and thus may have therapeutic potential against obesity.
Highlights
Obesity is a high risk factor for the development of many human pathologies, including insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, cardiovascular disease, and cancer [1,2]
Excessive adipocyte differentiation confers abnormal expansion/accumulation of adipose tissue leading to high secretion of pathological adipokines, which are implicated in inflammation, insulin resistance, and metabolic disorders
We further demonstrated that this effect is mediated through modulation of the expression of CCAAT/enhancer-binding protein-a (C/EBP-a) and peroxisome proliferator-activated receptor-c (PPAR-c) and the phosphorylation of signal transducer and activator of transcription-3 (STAT-3)
Summary
Obesity is a high risk factor for the development of many human pathologies, including insulin resistance, type 2 diabetes, hyperlipidemia, hypertension, cardiovascular disease, and cancer [1,2]. There is strong evidence suggesting that abnormal expansion/accumulation of adipose tissue, which is largely associated with excessive adipocyte differentiation, increased numbers (hyperplasia) and lipid contents (hypertrophy) of fat cells, are closely linked to the development of obesity [3,7,8]. Research has accumulated to indicate that the differentiation of preadipocyte into adipocyte is controlled by a complex network of a variety of cellular proteins, including transcription factors, cell cycle-related proteins, adipocyte-specific genes, lipogenic enzymes, and signaling proteins. A number of signaling proteins and factors, including adenosine 39,59-cyclic monophosphate (cAMP), protein kinase Cs (PKCs), and extracellular-signal regulated protein kinase-1/2 (ERK-1/2), have shown to have a role in controlling adipocyte differentiation [13,14,15,16]
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