Dietary camphene attenuates hepatic steatosis and insulin resistance in mice.

The aim of this study was to investigate the protective effects of camphene on high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in mice and to elucidate its mechanism of action. Male C57BL/6N mice were fed with a normal diet, HFD (20% fat and 1% cholesterol of total diet), or HFD supplemented with 0.2% camphene (CPND) for 10 weeks. Camphene alleviated the HFD-induced increases in liver weight and hepatic lipid levels in mice. Camphene also increased circulating adiponectin levels. To examine the direct effects of camphene on adiponectin secretion, 3T3-L1 adipocytes were incubated with camphene. Consistent with in vivo result, camphene increased adiponectin expression and secretion in 3T3-L1 adipocytes. In HFD-fed mice, camphene increased hepatic adiponectin receptor expression and AMP-activated protein kinase (AMPK) activation. Concordant with the activation of adiponectin-AMPK signaling, camphene increased hepatic expression of fatty acid oxidation-related genes and decreased those of lipogenesis-related genes in HFD-fed mice. Moreover, camphene increased insulin-signaling molecules activation and stimulated glucose transporter-2translocation to the plasma membrane in the liver. These results suggest camphene prevents HFD-induced hepatic steatosis and insulin resistance in mice; furthermore, these protective effects are mediated via the activation of adiponectin-AMPK signaling.

Kim S ，Choi Y ，Choi S ，Choi Y ，Park T ... -  《-》

Piperine reverses high fat diet-induced hepatic steatosis and insulin resistance in mice.

This study examined the effect of piperine on hepatic steatosis and insulin resistance induced in mice by feeding a high-fat diet (HFD) for 13 weeks and elucidated potential underlying molecular mechanisms. Administration of piperine (50 mg/kg body weight) to mice with HFD-induced hepatic steatosis resulted in a significant increase in plasma adiponectin levels. Also, elevated plasma concentrations of insulin and glucose and hepatic lipid levels induced by feeding a HFD were reversed in mice when they were administered piperine. However, piperine did not reduce body weight and other biochemical markers to an extent where they became equal to the levels found in the CD-fed mice. Piperine reversed HFD-induced down-regulation of adiponecitn-AMP-activated protein kinase (AMPK) signalling molecules which play an important role in mediating lipogenesis, fatty acid oxidation and insulin signalling in the livers of mice. The expressions of lipogenic target genes were decreased, whereas the expression of carnitine palmitoyltransferase 1 (CPT1) gene involved in fatty acid oxidation was increased in the livers of the Pin50 group. Piperine significantly decreased the phosphorylation of insulin receptor substrate-1 (IRS-1) compared with the HFD-fed mice. Administration of piperine appeared to reverse preexisting HFD-induced hepatic steatosis and insulin resistance, probably by activation of adiponectin-AMPK signalling in mice.

Choi S ，Choi Y ，Choi Y ，Kim S ，Jang J ，Park T ... -  《-》

Piperonal prevents high-fat diet-induced hepatic steatosis and insulin resistance in mice via activation of adiponectin/AMPK pathway.

Li X ，Choi Y ，Yanakawa Y ，Park T ... -  《-》

Oleuropein attenuates hepatic steatosis induced by high-fat diet in mice.

Oleuropein, a secoiridoid derived from olives and olive oil, has been known to possess antimicrobial, antioxidative, and anticancer activities. The purpose of the present study was to determine whether oleuropein has a protective effect against hepatic steatosis induced by a high fat diet (HFD) and to elucidate its underlying molecular mechanisms in mice. Male C57BL/6N mice were fed a normal diet (ND), HFD, or an oleuropein-supplemented diet (OSD) for 10 weeks. The plasma and hepatic lipid levels were determined, and the hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively. The supplementation of HFD with oleuropein reversed the HFD-induced increases in liver weight along with plasma and hepatic lipid levels in mice. The expression of Wnt10b inhibitor genes, such as secreted firizzed-related sequence protein 5 and dickkopf homolog 2, was downregulated, whereas the β-catenin protein expression was upregulated in the liver of OSD-fed mice compared to HFD-fed mice. Fibroblast growth factor receptor 1 (FGFR1), phosphoextracellular-signal-regulated kinase 1/2, cyclin D, and E2F transcription factor 1, along with several key transcription factors and their target genes involved in adipogenesis, were downregulated by oleuropein. OSD-fed mice exhibited decreased expression of the toll-like-receptor-(TLR)-mediated signaling molecules (TLR2, TLR4, and myeloid differentiation primary-response gene 88) and proinflammatory cytokines, in their livers, as compared to HFD mice. These results suggest that the protective effects of oleuropein against HFD-induced hepatic steatosis in mice appear to be associated with the Wnt10b- and FGFR1-mediated signaling cascades involved in hepatic lipogenesis, along with the TLR2- and TLR4-mediated signaling implicated in hepatic steatosis.

Park S ，Choi Y ，Um SJ ，Yoon SK ，Park T ... -  《-》

Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high-fat diet fed mice.

Mice fed high-fat diet (HFD) demonstrate obesity-related systemic insulin resistance (IR). Aim of this study is to clarify the role of interleukin (IL)-6 in IR in vivo focusing on skeletal muscle, adipose tissue and liver. Plasma markers of IR and hepatic IL-6 signalling were examined in eight-week HFD feeding C57/BL6 mice. Furthermore, IR-related molecules in skeletal muscles, adipose tissues and livers were investigated following a single injection of anti- IL-6 receptor neutralizing antibody (MR16-1) in two-week HFD feeding mice. To investigate the role of IL-6 in hepatic steatosis by prolonged HFD, hepatic triglyceride accumulation was assessed in eight-week HFD feeding mice with continuous MR16-1 treatment. High-fat diet for both 2 and 8 weeks elevated plasma IL-6, insulin and leptin, which were decreased by MR16-1 treatment. A single injection of MR16-1 ameliorated IR as assessed by glucose and insulin tolerance test, which may be attributable to upregulation of glucose transporter type 4 via phosphorylation of AMP-activated protein kinase as well as upregulation of peroxisome proliferator-activated receptor alpha in livers and, particularly, in skeletal muscles. MR16-1 also decreased mRNA expression of leptin and tumour necrosis factor-alpha and increased that of adiponectin in adipose tissue. High-fat diet for 8 weeks, not 2 weeks, induced hepatic steatosis and increased hepatic triglyceride content, all of which were ameliorated by MR16-1 treatment. Blockade of excessive IL-6 stimulus ameliorated HFD-induced IR in a skeletal muscle and modulated the production of adipokines from an early stage of NAFLD, leading to prevention of liver steatosis for a long term.

Yamaguchi K ，Nishimura T ，Ishiba H ，Seko Y ，Okajima A ，Fujii H ，Tochiki N ，Umemura A ，Moriguchi M ，Sumida Y ，Mitsuyoshi H ，Yasui K ，Minami M ，Okanoue T ，Itoh Y ... -  《-》