Abstract
Background and Purpose Hinokitiol, a natural monopenoid present in the essential oil of Calocedrus formosana heartwood, exerts potent anticancer, anti-inflammatory, antibacterial, and neuroprotective effects on various cells. However, the antiobesity effect of hinokitiol on adipocytes is unclear. Experimental Approach In this study, we observed that hinokitiol affected the differentiation to adipocytes in mesenchymal stem cells (MSCs). Hinokitiol was treated with 3-isobutyl-1-methylxanthine, insulin, and dexamethasone to induce differentiation and maturing adipocytes in cultured MSCs. Key Results Hinokitiol treatment of MSCs decreased their differentiation to mature adipocytes and increased AMPK phosphorylation in a concentration-dependent manner. Moreover, we confirmed that the antiadipogenic effect of hinokitiol was associated with autophagy. The levels of LC3-II decreased and those of p62 increased in hinokitiol-treated MSCs. The treatment of hinokitiol-treated MSCs with the autophagy activator, rapamycin, restored the hinokitiol-induced decrease in the adipocyte differentiation of MSCs. The inhibition of AMPK phosphorylation also suppressed hinokitiol-mediated inhibition of autophagy and antiadipogenic effects. Conclusions and Implications Taken together, these results indicated that AMPK activation and autophagy flux inhibition mediated by hinokitiol inhibited lipid accumulation and differentiation of MSCs to adipocytes and also suggest that differentiation of mesenchymal stem cells may be regulated by using the modulator of autophagy flux and AMPK signals including hinokitiol.
Highlights
In recent times, the occurrence of obesity has increased worldwide [1]
AMP-activated protein kinase (AMPK) suppresses the expression of C/EBP-α, C/EBP-β, C/EBP-δ, and peroxisome proliferator-activated receptor-γ (PPAR-γ) [29], and AMPK activator AICAR suppresses lipid metabolism by regulating β-oxidation-associated proteins during adipocyte differentiation [30]
Differentiation was induced by incubating 2-day postconfluent mesenchymal stem cells (MSCs) in an MDI induction medium (DMEM supplemented with 10% fetal bovine serum, 0.5 mM IBMX, 1 μm dexamethasone, and 1 μg/mL insulin) for 2 days
Summary
The occurrence of obesity has increased worldwide [1]. Obesity is the key contributor to and a risk factor of various chronic diseases such as hypertension, type 2 diabetes, fatty liver disease, atherosclerosis, degenerative disorders, airway disease, and some cancers [2]. Adipogenesis involves the conversion of free fatty acids in the bloodstream to lipid droplets and their accumulation in adipocytes It is sequentially and cooperatively regulated by various transcription factors and adipocyte-specific genes such as CCAAT enhancer-binding proteins (C/EBP-α and C/EBP-β), peroxisome proliferator-activated receptor-γ (PPAR-γ), and aP2 [3,4,5,6]. AMPK suppresses the expression of C/EBP-α, C/EBP-β, C/EBP-δ, and PPAR-γ [29], and AMPK activator AICAR suppresses lipid metabolism by regulating β-oxidation-associated proteins during adipocyte differentiation [30] These findings have considerably increased the interest in AMPK as a therapeutic target for treating metabolic dysfunction observed in persons with obesity and insulin resistance. We suggested the possibility of hinokitiol as a target against obesity-related disease
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