Shikonin inhibits fat accumulation in 3T3‐L1 adipocytes

Abstract

Shikonin, 5,6-dihydroxyfl avone-7-glucuronic acid, is the main ingredient of Lithospermum erythrorhizon Sieb. et Zucc, and was reported to have various biological activities including antiinfl ammatory, anticancer, antimicrobial and others. This study aimed to elucidate, for the fi rst time, the antiobesity activity of shikonin and its mechanism of action. Shikonin was found to inhibit fat droplet formation and triglyceride accumulation in 3T3-L1 adipocytes. The half inhibitory concentration, IC 50 , for the inhibition of triglyceride accumulation was found to be 1.1 mM. The expression of genes involved in lipid metabolism, such as FABP4 and LPL, were signifi cantly inhibited following shikonin treatment. Shikonin also inhibited the ability of PPARg and C/EBPa, the major transcription factors of adipogenesis, to bind to their target DNA sequences. The expressions of mRNA and protein of PPARg and C/EBPa were signifi cantly down-regulated following shikonin treatment. Among the upstream regulators of adipogenesis, only SREBP1C was found to be down-regulated by shikonin. The results of this study suggest that shikonin down-regulates the expression of SREBP1C and subsequently the expression of PPARg and C/EBPa. Together, these changes result in the down-regulation of lipid metabolizing enzymes and reduced fat accumulation.

Shikonin protects against obesity through the modulation of adipogenesis, lipogenesis, and β-oxidation in vivo

“…PPAR-γ is considered a master regulator of adipocyte differentiation and, along with C/EBPα, regulates downstream target genes such as aP2 and lipoprotein lipase (LPL) (Rosen et al, 2002;Wu et al, 1999). Previous studies show that shikonin inhibits adipocyte differentiation in 3T3-L1 cells (Gwon et al, 2013;Lee et al, 2010Lee et al, , 2011, and we also found that shikonin downregulated PPAR-γ, C/EBPα, aP2, and FAS mRNA expression and protein content in white adipose tissue. These results suggest that shikonin reduced adipogenesis via decreased expression of adipogenic genes.…”

“…Shikonin has anti-adipogenic roles in vitro (Lee et al, 2010(Lee et al, , 2011, but whether it has an anti-obesity effect in vivo has not been investigated. To our knowledge, the present study is the first to assess the role of shikonin on body weight gain and its related metabolic pathways in vivo in an obese mouse model.…”

“…L. erythrorhizon has also been used in traditional herbal medicine to treat various diseases (Ozaki et al, 1994), and we have shown that the L. erythrorhizon extract has an anti-obesity effect in vivo (Gwon, Ahn, Chung, Moon, & Ha, 2012). Shikonin also inhibits adipocyte differentiation in 3T3-L1 cells (Gwon, Ahn, Jung, Moon, & Ha, 2013;Lee et al, 2011;Lee, Kang, & Yoon, 2010), and it increases glucose uptake in 3T3-L1 cells (Kamei et al, 2002) and L6 skeletal muscle myotubes (Oberg et al, 2011) by enhancing insulin sensitivity. However, the anti-obesity effect of shikonin in vivo and the contributing molecular mechanisms have not yet been reported.…”

Antidiabetic Naphthoquinones and Their Plant Resources in Thailand

“…Shikonin also caused the accumulation of Pt-3,4,5-P3, the activation of protein kinase B, and inhibited several protein phosphatases in different cell systems. 150) Hyperglycemia and hyperlipidemia are prime identifying characteristics in the progression of type-2 DM and chronic cardiovascular disorders. 132) Insulin resistance, the main cause of type-2 DM is linked with the release of free fatty acids and proinflammatory cytokines from adipose tissues in subjects with obesity or excessive adiposity, which stimulates beta cells to over-secrete insulin and leads to a reduction in receptors.…”

“…It has also been reported that shikonin inhibits adipogenesis by both up-(SREBP1C) and downstream regulation (PPARγ and CCAAT/ enhancer binding protein alpha (C/EBPα)). 151) Various synthetic naphthoquinones have also been reported upon due to their antidiabetic potential. For example, 5,8-diacetyloxy-2,3-dichloro-1,4-naphthoquinone (48) was obtained through a screening of numerous chemical libraries, consisting of almost 4500 natural and synthetic molecules.…”