Sun-Sil Choi

Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice.

Nobiletin is a polymethoxylated flavone found in certain citrus fruits that exhibits various pharmacological effects including anti-inflammatory, antitumor and neuroprotective properties. The present study investigated the effects of nobiletin on insulin sensitivity in obese diabetic ob/ob mice, and the possible mechanisms involved. The ob/ob mice were treated with nobiletin (200mg/kg) for 5 weeks. Nobiletin significantly improved the plasma glucose levels, homeostasis model assessment index, glucose tolerance in an oral glucose tolerance test and plasma adiponectin levels. In white adipose tissue (WAT), nobiletin significantly decreased the mRNA expression levels of inflammatory adipokines such as interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 and increased the mRNA expression levels of adiponectin, peroxisome proliferator-activated receptor (PPAR)-gamma and its target genes. At the same time, nobiletin increased the glucose transporter (Glut) 4 expression levels in the whole plasma membrane, and Glut1 and phospho-Akt expression in the whole cell lysates in WAT and muscle. Nobiletin also increased Glut4 protein expression level in the whole cell lysates of the muscle. Taken together, the present results suggest that nobiletin improved the hyperglycemia and insulin resistance in obese diabetic ob/ob mice by regulating expression of Glut1 and Glut4 in WAT and muscle, and expression of adipokines in WAT.

Magnolol enhances adipocyte differentiation and glucose uptake in 3T3-L1 cells

AIMS The nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma plays an important role in adipocyte differentiation. Its ligands, including thiazolidinediones, improve insulin sensitivity in type 2 diabetes. We investigate the effect of magnolol, an ingredient of Magnolia officinalis on adipogenesis and glucose uptake using 3T3-L1 cells. MAIN METHODS The effect of magnolol on adipocyte differentiation was quantified by measuring Oil Rd O staining using 3T3-L1 cells and C3H10T1/2 cells. And real-time PCR and western blot were used to determine the expression of PPARgamma or PPARgamma target genes, respectively. The effect of magnolol on glucose uptake was performed using 3T3-L1 adipocytes. KEY FINDINGS Magnolol dose-dependently enhanced adipocyte differentiation in 3T3-L1 cells and C3H10T1/2 cells. In the early stage of adipogenesis, magnolol induced gene expression of C/EBPdelta, C/EBPalpha and PPARgamma2 and during adipocyte differentiation, it also induced the expression of PPARgamma target genes such as aP2, LPL and adiponectin. In addition, magnolol it also increase expression of PAPRgamma target gene such as C/EBPalpha and aP2 at mRNA and aP2 protein level in mature adipocytes. In PPARgamma ligand binding assays, magnolol exhibited binding affinity to PPARgamma but its activity was weaker than rosiglitazone. At the same time, magnolol-induced adipogenesis was inhibited by co-treatment of GW9662 both 3T3-L1 cells and C3H10T1/2 cells. In mature 3T3-L1 adipocytes, magnolol increased basal and insulin-stimulated glucose uptake accompanied by the up-regulation of mRNA and protein level of Glut4. SIGNIFICANCE Our results suggest that magnolol could improve insulin sensitivity through the activation of PPARgamma as a ligand.

Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice

Nobiletin (NOB) is a polymethoxylated flavone present in citrus fruits and has been reported to have antitumor and anti-inflammatory effects. However, little is known about the effects of NOB on obesity and insulin resistance. In this study, we examined the effects of NOB on obesity and insulin resistance, and the underlying mechanisms, in high-fat diet (HFD)-induced obese mice. Obese mice were fed a HFD for 8 weeks and then treated without (HFD control group) or with NOB at 10 or 100mg/kg. NOB decreased body weight gain, white adipose tissue (WAT) weight and plasma triglyceride. Plasma glucose levels tended to decrease compared with the HFD group and improved plasma adiponectin levels and glucose tolerance. Furthermore, NOB altered the expression levels of several lipid metabolism-related and adipokine genes. NOB increased the mRNA expression of peroxisome proliferator-activated receptor (PPAR)-γ, sterol regulatory element-binding protein-1c, fatty acid synthase, stearoyl-CoA desaturase-1, PPAR-α, carnitine palmitoyltransferase-1, uncoupling protein-2 and adiponectin, and decreased the mRNA expression of tumor necrosis factor-α and monocyte chemoattractant protein-1 in WAT. NOB also up-regulated glucose transporter-4 protein expression and Akt phosphorylation and suppressed IκBα degradation in WAT. Taken together, these results suggest that NOB improves adiposity, dyslipidemia, hyperglycemia and insulin resistance. These effects may be elicited by regulating the expression of lipid metabolism-related and adipokine genes, and by regulating the expression of inflammatory makers and activity of the insulin signaling pathway.

Artepillin C, as a PPARγ ligand, enhances adipocyte differentiation and glucose uptake in 3T3-L1 cells

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ plays an important role in adipocyte differentiation. Its ligands, including thiazolidinediones, improve insulin sensitivity in type 2 diabetes. We investigated the effects of artepillin C, an ingredient of Baccharis dracunculifolia, on adipogenesis and glucose uptake using 3T3-L1 cells. In PPARγ ligand-binding assays, artepillin C exhibited binding affinity toward PPARγ. Artepillin C dose-dependently enhanced adipocyte differentiation of 3T3-L1 cells. As a result of the artepillin C-induced adipocyte differentiation, the gene expression of PPARγ and its target genes, such as aP2, adiponectin and glucose transporter (GLUT) 4, was increased. These increases were abolished by cotreatment with GW9662, a PPARγ antagonist. In mature 3T3-L1 adipocytes, artepillin C significantly enhanced the basal and insulin-stimulated glucose uptake. These effects were decreased by cotreatment with a PI3K inhibitor. Although artepillin C had no effects on the insulin signaling cascade, artepillin C enhanced the expression and plasma membrane translocation of GLUT1 and GLUT4 in mature adipocytes. In conclusion, these findings suggest that artepillin C promotes adipocyte differentiation and glucose uptake in part by direct binding to PPARγ, which could be the basis of the pharmacological benefits of green propolis intake in reducing the risk of type 2 diabetes.

Effects of a Citrus depressa Hayata (shiikuwasa) extract on obesity in high-fat diet-induced obese mice.

Citrus depressa Hayata (commonly known as shiikuwasa) is cultivated in the northern areas of Okinawa, Japan, and used as a juice. In this study, we examined the anti-obesity effects and mechanism of action of shiikuwasa peel extract (SE) using high-fat diet (HFD)-induced obese mice. Mice were fed a low-fat diet (LFD), HFD or HFD containing 1% or 1.5% (w/w) SE (HFD+1 SE and HFD+1.5 SE, respectively) for 5 weeks. The body weight gain and white adipose tissue weight were significantly decreased in the HFD+1.5 SE group compared with the HFD group. The plasma triglyceride and leptin levels were also significantly reduced in the HFD+1.5 SE group compared with the HFD group. Histological examinations showed that the sizes of the adipocytes were significantly smaller in the HFD+1.5 SE group than in the HFD group. The HFD+1.5 SE group also showed significantly lower mRNA levels of lipogenesis-related genes, such as activating protein 2, stearoyl-CoA desaturase 1, acetyl-CoA-carboxylase 1, fatty acid transport protein and diacylglycerol acyltransferase 1, than the HFD group. These results suggest that the anti-obesity effects of SE may be elicited by regulating the expressions of lipogenesis-related genes in white adipose tissue.

Honokiol and magnolol stimulate glucose uptake by activating PI3K-dependent Akt in L6 myotubes.

Honokiol and magnolol, ingredients of Magnolia officinalis, which is used in traditional Chinese and Japanese medicines, have been reported to have antioxidant, anticancer, and antiangiogenic effects. Effects of these compounds on glucose metabolism in adipocytes have also been reported. However, their effects on skeletal muscle glucose uptake and the underlying molecular mechanisms are still unknown. Here, we investigated the direct effects and signaling pathways activated by honokiol and magnolol in skeletal muscle cells using L6 myotubes. We found that honokiol and magnolol dose-dependently acutely stimulated glucose uptake without synergistic effects of combined administration in L6 myotubes. Treatment with honokiol and magnolol also stimulated glucose transporter-4 translocation to the cell surface. Honokiol- and magnolol-stimulated glucose uptake was blocked by the phosphatidylinositol-3 kinase inhibitor, wortmannin. Both honokiol and magnolol stimulated Akt phosphorylation, a key element in the insulin signaling pathway, which was completely inhibited by wortmannin. These results suggest that honokiol and magnolol might have beneficial effects on glucose metabolism by activating the insulin signaling pathway.

Fargesin improves lipid and glucose metabolism in 3T3‐L1 adipocytes and high‐fat diet‐induced obese mice

This study examined the effects of fargesin, a neolignan isolated from Magnolia plants, on obesity and insulin resistance and the possible mechanisms involved in these effects in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice. Fargesin promoted the glucose uptake in 3T3-L1 adipocytes. In HFD-induced obese mice, fargesin decreased the body weight gain, white adipose tissue (WAT), and plasma triglyceride, non-esterified fatty acid and glucose levels, and improved the glucose tolerance. Fargesin increased glucose transporter 4 (GLUT4) protein expression and phosphorylation of Akt, AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC) in both 3T3-L1 adipocytes and WAT of HFD-induced obese mice. Fargesin also decreased the mRNA expression levels of fatty acid oxidation-related genes, such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase-1 (CPT-1), uncoupling protein-2 (UCP-2) and leptin in WAT. Taken together, the present findings suggest that fargesin improves dyslipidemia and hyperglycemia by activating Akt and AMPK in WAT.

Honokiol, magnolol, and a combination of both compounds improve glucose metabolism in high-fat diet-induced obese mice

Honokiol and magnolol are neolignans contained in the Chinese medicinal herb Magnolia officinalis that exert anti-tumor and anti-inflammatory effects. Both compounds have been reported to enhance glucose uptake. Little is known about effects when used in combination. The effects of honokiol, magnolol, and a combination of both compounds on lipid and glucose metabolism in highfat diet-induced obese mice were investigated, and underlying mechanisms were examined. All 3 treatments significantly (p<0.05) reduced plasma total cholesterol and glucose levels, and improved glucose tolerance, compared with controls. In addition, treatments increased mRNA expression of the peroxisome proliferator-activated receptor (PPAR)-γ, glucose transporter (GLUT)-4, and adiponectin genes in white adipose tissue (WAT). Both compounds individually and in combination significantly (p<0.05) increased Akt phosphorylation and GLUT4 protein expression in WAT compared to the control group. Honokiol and magnolol improve dyslipidemia and hyperglycemia and act synergistically when used in combination.