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 ... -  《-》

Piperine, an LXRα antagonist, protects against hepatic steatosis and improves insulin signaling in mice fed a high-fat diet.

This study investigated the role of piperine in the transcriptional regulation of liver X receptor α (LXRα) and the effects of dietary piperine on high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in mice. Furthermore, we explored the potential molecular mechanisms through which the protective effects of piperine may work. In the present study, piperine significantly reduced ligand-induced LXRα activity in a dose-dependent manner and gradually disrupted the interaction between ligand-bound LXRα and GST-CBP. In mice, an HFD supplemented with 0.05% piperine (PSD) significantly decreased body and liver weight as well as plasma and hepatic lipid levels. In agreement with our in vitro study, in mice fed an HFD, dietary piperine markedly decreased LXRα mRNA expression and its lipogenic target genes (i.e., SREBP1c, ChREBPα, FAS, and CD36). Piperine also significantly decreased plasma insulin and glucose concentrations, while increasing insulin sensitivity in mice fed an HFD. In addition, piperine downregulated the expression of genes involved in ER stress, including GRP78, activating transcription factor 6, and eukaryotic translation initiation factor 2α, and upregulated GLUT2 translocation from the cytosol to the plasma membrane in the livers of PSD mice. Piperine antagonized LXRα transcriptional activity by abolishing the interaction of ligand-bound LXRα with the co-activator CBP. The effects of piperine on hepatic lipid accumulation were likely regulated via alterations in LXRα-mediated lipogenesis in mice fed an HFD. Dietary piperine also led to reduced ER stress and increased insulin sensitivity and prevented hepatic insulin resistance in mice fed the HFD.

Jwa H ，Choi Y ，Park UH ，Um SJ ，Yoon SK ，Park T ... -  《-》

Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice.

This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR. Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.

Malloy VL ，Perrone CE ，Mattocks DA ，Ables GP ，Caliendo NS ，Orentreich DS ，Orentreich N ... -  《-》

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 ... -  《-》

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 ... -  《-》