High-fat Diet-induced Hyperglycemia Research Articles

Green Synthesis of Oxovanadium(IV)/chitosan Nanocomposites and Its Ameliorative Effect on Hyperglycemia, Insulin Resistance, and Oxidative Stress.

In this paper, the preparation, characterization, and ameliorative effect on high-fat high-sucrose diet-induced hyperglycemia, insulin resistance, oxidative stress in mice of novel oxovanadium(IV)/chitosan (OV/CS) nanocomposites were investigated. The nanobiocomposite was produced by chemical reduction by chitosan and L-ascorbic acid using microwave heating, under environment-friendly conditions, using aqueous solutions, and notably, by using both mediators as reducing and stabilizing agents. In addition, OV/CS nanocomposites were characterized by transmission electron microscopy, energy dispersive spectroscopy, particle size, and zeta potential measurements. In vivo experiments were designed to examine whether the OV/CS nanocomposites would provide additional benefits on oxidative stress, hyperglycemia, and insulin resistance in mice with type 2 diabetes. The results rendered insulin resistant by treating with OV/CS nanocomposites alleviate insulin resistance and improve oxidative stress. Such nanocomposite seem to be a valuable therapy to achieve and/or maintain glycemic control and therapeutic agents in the treatment arsenal for insulin resistance and type 2 diabetes.

The H1-receptor antagonist cetirizine ameliorates high-fat diet-induced glucose intolerance in male C57BL/6 mice, but not diabetes outcome in female non-obese diabetic (NOD) mice

Background. It has been proposed that the histamine 1-receptor (H1-receptor) not only promotes allergic reactions, but also modulates innate immunity and autoimmune reactions. In line with this, we have recently reported that the H1-receptor antagonist cetirizine partially counteracts cytokine-induced beta-cell signaling and destruction. Therefore, the aim of this study was to determine whether cetirizine affects diabetes in NOD mice, a model for human type 1 diabetes, and glucose intolerance in high-fat diet C57BL/6 mice, a model for human glucose intolerance.Methods. Female NOD mice were treated with cetirizine in the drinking water (25 mg/kg body weight) from 9 until 30 weeks of age during which precipitation of diabetes was followed. Male C57BL/6 mice were given a high-fat diet from 5 weeks of age. When the mice were 12 weeks of age cetirizine was given for 2 weeks in the drinking water. The effects of cetirizine were analyzed by blood glucose determinations, glucose tolerance tests, and insulin sensitivity tests.Results. Cetirizine did not affect diabetes development in NOD mice. On the other hand, cetirizine treatment for 1 week protected against high-fat diet-induced hyperglycemia. The glucose tolerance after 2 weeks of cetirizine treatment was improved in high-fat diet mice. We observed no effect of cetirizine on the insulin sensitivity of high-fat diet mice.Conclusion. Our results suggest a protective effect of cetirizine against high-fat diet-induced beta-cell dysfunction, but not against autoimmune beta-cell destruction.

Hypolipidemic, hypoglycemic, and antioxidative effects of a new pigmented rice cultivar “Superjami” in high fat-fed mice

Effects of newly-developed pigmented rice Superjami, in comparison with those of its parental cultivars (Heugjinjubyeo and Suweon 425) and ordinary brown rice, on the lipid and glucose metabolisms and antioxidative defense status in high fatfed mice were investigated. The animals were randomly divided and given experimental diets for eight weeks: normal control, high fat, and high fat supplemented with ordinary brown, Heugjinjubyeo, Suweon 425 or Superjami rice powder. Their body weight, plasma lipid profile, blood glucose level, and lipid peroxidation were measured. The enzymes and hormones involved in the lipid and glucose metabolisms were also analyzed. High fat feeding significantly increased the body weight, total cholesterol, triglyceride, blood glucose, and lipid peroxidation in mice. On the other hand, diet supplementation of the rice samples, particularly Superjami, markedly reduced the body weight gain, improved the lipid and glucose profiles, and suppressed oxidative stress through regulation of hepatic lipogenesis and adipokine production, inhibition of glucose-regulating enzymes, and enhancement of antioxidant enzyme activities. Superjami has greater hypolipidemic, hypoglycemic, and antioxidant status-improving effects than its parental cultivars. This study provides the first evidence of the physiological effect of Superjami, which may be useful in the prevention and management of high fat diet-induced hyperlipidemia, hyperglycemia, and oxidative stress.

The Murphy Roths Large (MRL) mouse strain is naturally resistant to high fat diet-induced hyperglycemia

ObjectiveDue to their previously identified naturally and chronically increased levels of skeletal muscle pAMPK we hypothesized and now investigated whether the MRL/MpJ (MRL) mice would be resistant to high fat diet (HFD)-induced metabolic changes. Materials/methodsThree-week old male MRL and control C57Bl/6 (B6) mice were randomly assigned to 12weeks of high fat diets (HFD) or control diets (CD). Weekly animal masses and fasting blood glucose measurements were acquired. During the last week of diet intervention, fasted animals were subjected to glucose and insulin tolerance tests. At harvest, tissues were dissected for immunoblots and serum was collected for elisa assays. ResultsThe MRL mouse strain is known for its ability to regenerate ear punch wounds, cardiac cryoinjury, and skeletal muscle disease. Despite gaining weight and increasing their fat deposits the MRL mice were resistant to all other indicators of HFD-induced metabolic alterations assayed. Only the HFD-B6 mice displayed fasting hyperglycemia, hyperinsulinemia and hypersensitivity to glucose challenge. HFD-MRL mice were indistinguishable from their CD-MRL counterparts in these metrics. Skeletal muscles from the HFD-MRL contained heightened levels of pAMPK, even above their CD counterparts. ConclusionsThe MRL mouse strain is the first naturally occurring mouse strain that we are aware of that is resistant to HFD-induced metabolic changes. Furthermore, the increased pAMPK suggests a proximal mechanism for these beneficial metabolic differences. We further hypothesize that these metabolic differences and plasticity provide the basis for the MRL mouse strain's super healing characteristics. This project's ultimate aim is to identify novel therapeutic targets, which specifically increase pAMPK.

Functional rice giant embryo and Aranghyangchal reduce blood glucose level and enhance antioxidative defense status in high fat-fed mice

The effect of functional rice giant embryo and Aranghyangchal on the glucose metabolism and antioxidative defense status in high fat-fed C57BL/6N mice were investigated. The animals were randomly divided into four dietary groups: normal control (NC), high fat (HF), and high fat supplemented with giant embryo rice (HF-GE) or Aranghyangchal rice (HF-AR). After 8 weeks of feeding them with experimental diets, the HF mice exhibited a marked increase in the blood glucose concentration, plasma insulin level, and lipid peroxidation and a significant decrease in the hepatic glycogen level relative to the NC group. On the other hand, diet supplementation of the rice samples suppressed this high fat diet-induced hyperglycemia and oxidative stress through inhibition of the glucose-regulating enzymes and activation of the antioxidant enzymes. These findings demonstrate that the giant embryo and Aranghyangchal rice may be beneficial as biomaterials in the development of functional food with hypoglycemic and antioxidative properties.

Sox17 regulates insulin secretion in the normal and pathologic mouse β cell.

SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1β and FOXA2, which are known to regulate postnatal β cell function. Given this, we investigated the role of SOX17 in the developing and postnatal pancreas and found a novel role for SOX17 in regulating insulin secretion. Deletion of the Sox17 gene in the pancreas (Sox17-paLOF) had no observable impact on pancreas development. However, Sox17-paLOF mice had higher islet proinsulin protein content, abnormal trafficking of proinsulin, and dilated secretory organelles suggesting that Sox17-paLOF adult mice are prediabetic. Consistant with this, Sox17-paLOF mice were more susceptible to aged-related and high fat diet-induced hyperglycemia and diabetes. Overexpression of Sox17 in mature β cells using Ins2-rtTA driver mice resulted in precocious secretion of proinsulin. Transcriptionally, SOX17 appears to broadly regulate secretory networks since a 24-hour pulse of SOX17 expression resulted in global transcriptional changes in factors that regulate hormone transport and secretion. Lastly, transient SOX17 overexpression was able to reverse the insulin secretory defects observed in MODY4 animals and restored euglycemia. Together, these data demonstrate a critical new role for SOX17 in regulating insulin trafficking and secretion and that modulation of Sox17-regulated pathways might be used therapeutically to improve cell function in the context of diabetes.

Aqueous extract of post-fermented tea reverts the hepatic steatosis of hyperlipidemia rat by regulating the lipogenic genes expression and hepatic fatty acid composition.

BackgroundPost-fermented tea has been used for the prevention of metabolic syndrome in Western China. Present study reports the biochemical mechanism of lipid-lowering effects of Jing-wei fu tea (JWFT), a variety of post-fermented tea on high-fat diet-induced hyperglycemia and obesity in rats.MethodsAqueous extract of JWFT was prepared by putting them in boiling water, and then concentrated under reduced pressure. The major compounds of JWFT were determined by high performance liquid chromatography (HPLC). High-fat diet fed rats were orally administered different doses of JWFT aqueous extract (0.5, 1.0 and 2.0 g/kg) for four weeks. At the end of this experiment, hepatic lipids, serum leptin and lipids levels were determined using enzyme-linked immunosorbent assay (ELISA). The hepatic fatty acid composition was analyzed using gas chromatography mass (GC-MS). The relative expression of lipids metabolism genes was analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR).ResultsThe results showed that JWFT inhibited the increase in the body weight, abdominal adipose weight, serum lipids and hepatic lipids, and decreased serum leptin levels of high-fat diet fed rats. JWFT normalized hepatic fatty acid composition of hyperlipidemia rats by up-regulating hepatic acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase 1 (SCD1) and fatty acid synthase (FAS) gene expression, and down-regulating carnitine palmitoyl transferase-1 (CPT1). Furthermore, the results showed that JWFT inhibited the absorption of lipids.ConclusionJWFT could mitigate the obesity-induced hepatic steatosis by regulating hepatic lipogenesis and lipolysis.

Hypoglycemic and Antioxidative Effects of Functional Rice Goami and Nokwon in High Fat-Fed Mice

Effects of newly developed functional rice grains Goami (high-amylose rice) and Nokwon (green-kerneled rice) on the glucose metabolism and antioxidative defense system in C57BL/6N mice under high fat diet condition were investigated. Animals were randomly divided into five groups (n = 8) and given experimental diets for eight weeks: normal control diet (NC), high fat diet (HF), and high fat diet supplemented with white rice (HF-WR), Goami rice (HF-GR), and Nokwon rice (HF-NR). At the end of the experimental period, the HF group exhibited markedly higher blood glucose level, insulin concentration, plasma lipid peroxidation and lower hepatic glycogen concentration than that exhibited by NC group. However, diet supplementation of Goami and Nokwon suppressed the high fat diet-induced hyperglycemia and oxidative stress through inhibition of the glucose-regulating enzymes and enhancement of the antioxidant enzymes activities. The results illustrate that the new functional rice Goami and Nokwon may be useful in the development of functional foods with preventive effect against high fat diet-induced hyperglycemia and oxidative stress.

Validation of the Antidiabetic and Hypolipidemic Effects of Hawthorn by Assessment of Gluconeogenesis and Lipogenesis Related Genes and AMP-Activated Protein Kinase Phosphorylation

Since with the increased use of antidiabetic and antihyperlipidemic effect of phytonutrients for daily supplement has gained considerable attention worldwide, we examine the effect and molecular mechanism of Crataegus pinnatifida Bge. var. major N.E. Br. (hawthorn) by quantifying the expression of hepatic gluconeogenesis and lipogenesis on diabetes and dyslipidemia in high-fat (HF)-fed C57BL/6J mice. Firstly, mice were divided randomly into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed a 45% HF diet for 8 weeks. Afterwards, the CON group was treated with vehicle, whereas the HF group was subdivided into five groups and was given orally hawthorn extract (including 0.2, 0.5, 1.0 g/kg/day extracts) or rosiglitazone (Rosi) or vehicle for 4 weeks afterward. Diabetic mice showed an increase in plasma glucose and insulin. Glucose lowering was comparable with Rosi-treated mice. This study demonstrated that hawthorn was effective in ameliorating the HF diet-induced hyperglycemia, hypertriglyceridemia and hypercholesterolaemia. Hawthorn extract significantly increases the hepatic protein contents of AMP-activated protein kinase (AMPK) phosphorylation and reduces expression of phosphenol pyruvate carboxykinase (PEPCK) and glucose production. Furthermore, hawthorn decreased in hepatic triacylglycerol and cholesterol synthesis (including sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), SREBP2). An increase in expressions of apoA-I gene and high-density lipoprotein cholesterol (HDL-C) was detected in HF-fed mice treated with high dose hawthorn. Our data suggest that hawthorn extract are capable of decreasing glucose production and triacylglycerol synthesis by inducing AMPK-phosphorylation and hawthorn is a candidate source of antidiabetic and antihyperlipidemic phytonutrients factors.

Prevention mechanisms of glucose intolerance and obesity by cacao liquor procyanidin extract in high-fat diet-fed C57BL/6 mice

In this study, we investigated whether cacao liquor procyanidin (CLPr) extract, which consists of 4.3% catechin, 6.1% epicatechin, 39.4% procyanidins and others, ameliorated hyperglycemia and obesity in C57BL/6 mice fed a control or high-fat diet for 13weeks. CLPr suppressed high-fat diet-induced hyperglycemia, glucose intolerance and fat accumulation in white adipose tissue. CLPr also promoted translocation of glucose transporter 4 (GLUT4) and phosphorylation of AMP-activated protein kinase α (AMPKα) in the plasma membrane of skeletal muscle and brown adipose tissue. Phosphorylation of AMPKα was also enhanced in the liver and white adipose tissue. CLPr up-regulated the gene and protein expression levels of uncoupling protein (UCP)-1 in brown adipose tissue and UCP-3 in skeletal muscle. These results indicate that CLPr is a beneficial food material for the prevention of hyperglycemia and obesity. Activation of AMPKα, translocation of GLUT4 and up-regulation of UCP expression in skeletal muscle and adipose tissue are involved in the molecular mechanisms by which CLPr prevents hyperglycemia and obesity.

Antihyperglycemic and antioxidative effects of Hydroxyethyl Methylcellulose (HEMC) and Hydroxypropyl Methylcellulose (HPMC) in mice fed with a high fat diet.

The effect of dietary feeding of hydroxyethyl methylcellulose (HEMC) and hydroxypropyl methylcellulose (HPMC) on the glucose metabolism and antioxidative status in mice under high fat diet conditions was investigated. The mice were randomly divided and given experimental diets for six weeks: normal control (NC group), high fat (HF group), and high fat supplemented with either HEMC (HF+HEMC group) or HPMC (HF+HPMC group). At the end of the experimental period, the HF group exhibited markedly higher blood glucose and insulin levels as well as a higher erythrocyte lipid peroxidation rate relative to the control group. However, diet supplementation of HEMC and HPMC was found to counteract the high fat-induced hyperglycemia and oxidative stress via regulation of antioxidant and hepatic glucose-regulating enzyme activities. These findings illustrate that HEMC and HPMC were similarly effective in improving the glucose metabolism and antioxidant defense system in high fat-fed mice and they may be beneficial as functional biomaterials in the development of therapeutic agents against high fat dietinduced hyperglycemia and oxidative stress.

Hypoglycemic and antioxidative effects of hydroxyethyl methylcellulose in mice fed with high fat diet

The effect of hydroxyethyl methylcellulose (HEMC) with different viscosities on the glucose metabolism and antioxidative defense system in high fat-fed mice was investigated. The mice were randomly divided into five dietary groups: normal control diet (NC), high fat diet (HF), and high fat diet supplemented with high viscosity (HF-HV), moderate viscosity (HF-MV), and low viscosity (HF-LV) HEMC fibers. After 6weeks, the HF group showed a marked increase in body weight gain, body fat, blood glucose concentration, insulin level, and erythrocyte lipid peroxidation rate relative to the NC group. However, supplementation of HEMC in the diet suppressed these high fat-induced hyperglycemia and oxidative stress through enhancement of the activities of hepatic glucokinase and antioxidant enzymes. The hypoglycemic and antioxidative effects increased with increased viscosity of the HEMC consumed. These results illustrate that HEMC with high viscosity may be useful in the management of high fat diet-induced hyperglycemia and oxidative stress.

Protein Kinase C Delta (PKCδ) Affects Proliferation of Insulin-Secreting Cells by Promoting Nuclear Extrusion of the Cell Cycle Inhibitor p21Cip1/WAF1

BackgroundHigh fat diet-induced hyperglycemia and palmitate-stimulated apoptosis was prevented by specific inhibition of protein kinase C delta (PKCδ) in β-cells. To understand the role of PKCδ in more detail the impact of changes in PKCδ activity on proliferation and survival of insulin-secreting cells was analyzed under stress-free conditions.Methodology and Principal FindingsUsing genetic and pharmacological approaches, the effect of reduced and increased PKCδ activity on proliferation, apoptosis and cell cycle regulation of insulin secreting cells was examined. Proteins were analyzed by Western blotting and by confocal laser scanning microscopy. Increased expression of wild type PKCδ (PKCδWT) significantly stimulated proliferation of INS-1E cells with concomitant reduced expression and cytosolic retraction of the cell cycle inhibitor p21Cip1/WAF1. This nuclear extrusion was mediated by PKCδ-dependent phosphorylation of p21Cip1/WAF1 at Ser146. In kinase dead PKCδ (PKCδKN) overexpressing cells and after inhibition of endogenous PKCδ activity by rottlerin or RNA interference phosphorylation of p21Cip1/WAF1 was reduced, which favored its nuclear accumulation and apoptotic cell death of INS-1E cells. Human and mouse islet cells express p21Cip1/WAF1 with strong nuclear accumulation, while in islet cells of PKCδWT transgenic mice the inhibitor resides cytosolic.Conclusions and SignificanceThese observations disclose PKCδ as negative regulator of p21Cip1/WAF1, which facilitates proliferation of insulin secreting cells under stress-free conditions and suggest that additional stress-induced changes push PKCδ into its known pro-apoptotic role.

Haploid Insufficiency of Suppressor Enhancer Lin12 1-like (SEL1L) Protein Predisposes Mice to High Fat Diet-induced Hyperglycemia

Increasing evidence suggests that endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of type 2 diabetes mellitus. SEL1L is an ER membrane protein that is highly expressed in the pancreatic islet and acinar cells. We have recently reported that a deficiency of SEL1L causes systemic ER stress and leads to embryonic lethality in mice. Here we show that mice with one functional allele of Sel1l (Sel1l(+/-)) are more susceptible to high fat diet (HFD)-induced hyperglycemia. Sel1l(+/-) mice have a markedly reduced β-cell mass as a result of decreased β-cell proliferation. Consequently, Sel1l(+/-) mice are severely glucose-intolerant and exhibit significantly retarded glucose-stimulated insulin secretion. Pancreatic islets from Sel1l(+/-) mice stimulated with a high concentration of glucose in vitro express significantly higher levels of unfolded protein response genes than those from wild-type control mice. Furthermore, dominant-negative interference of SEL1L function in insulinoma cell lines severely impairs, whereas overexpression of SEL1L efficiently improves protein secretion. Taken together, our results indicate that haploid insufficiency of SEL1L predispose mice to high fat diet-induced hyperglycemia. Our findings highlight a critical and previously unknown function for SEL1L in regulating adult β-cell function and growth.

Vascular calcification and aortic fibrosis: a bifunctional role for osteopontin in diabetic arteriosclerosis.

Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)-/- mice fed a high-fat diet. OPN had no impact on high-fat diet-induced hyperglycemia, dyslipidemia, or body composition. However, OPN-/-;LDLR-/- mice exhibited an altered time-course of aortic calcium accrual-reduced during initiation but increased with progression-versus OPN+/+;LDLR-/- controls. Collagen accumulation, chondroid metaplasia, and mural thickness were increased in aortas of OPN-/-;LDLR-/- mice. Aortic compliance was concomitantly reduced. Vascular reexpression of OPN (SM22-OPN transgene) reduced aortic Col2A1 and medial chondroid metaplasia but did not affect atherosclerotic calcification, Col1A1 expression, collagen accumulation, or arterial stiffness. Dosing with the proinflammatory OPN fragment SVVYGLR upregulated aortic Wnt and osteogenic gene expression, increased aortic β-catenin, and restored early-phase aortic calcification in OPN-/-;LDLR-/- mice. OPN exerts stage-specific roles in arteriosclerosis in LDLR-/- mice. Actions phenocopied by the OPN metabolite SVVYGLR promote osteogenic calcification processes with disease initiation. OPN limits vascular chondroid metaplasia, endochondral mineralization, and collagen accumulation with progression. Complete deficiency yields a net increase in arteriosclerotic disease, reducing aortic compliance and conduit vessel function in LDLR-/- mice.

AD01, an Antidiabetic Plant of the Eastern James Bay Cree, Attenuates Insulin Resistance in a Diet-Induced Obesity Mouse Model

We investigated the anti-diabetic effect of a medicinal plant used by the Cree nation of northern Quebec, AD01, in a diet-induced obesity (DIO) mouse model. C57BL6 mice were divided into 5 groups and given a standard CHOW diet (˜ 4% of lipids) or a high fat-diet (˜ 35% of lipids) during 8 weeks until they became obese and insulin resistant. Treatment then began by adding the plant extract at 3 different doses (125, 250, 500mg/kg) into the high fat diet for another 8 weeks. At the end of the study, insulin sensitive tissues (liver, skeletal muscle, adipose tissue) were collected to investigate the plant's molecular mechanisms. AD01 prevented weight gain (by 6%), reduced blood glucose (by 13%) and plasma insulin (by 65%) while preventing hepatic steatosis (up to 42% reduction in hepatic triglyceride levels) in DIO mice. Western immunoblot analysis demonstrated that AD01 stimulated the activation of insulin dependent AKT pathway and increased the expression of Glut 4 in skeletal muscle. In the liver, AD01 stimulated two pathways; the insulin dependent Akt and the insulin independent AMPK ones. The improvement of hepatic steatosis observed in DIO treated mice was associated with a reduction of inflammation and with a decrease in the hepatic content of SREBP-1. These data suggest that AD01 exerts potential anti-diabetic action by improving insulin sensitivity and mitigating high-fat diet-induced obesity and hyperglycemia. They also validate the safety and efficacy of this plant. AD01 thus represents a promising candidate for culturally relevant complementary treatment in Cree diabetics.

Ginseng Leaf Extract Prevents High Fat Diet-Induced Hyperglycemia and Hyperlipidemia through AMPK Activation

This study evaluated the protective effects of ginseng leaf extract (GLE) against high fat-diet-induced hyperglycemia and hyperlipidemia, and explored the potential mechanism underlying these effects in C57BL/6J mice. The mice were randomly divided into four groups: normal control, high fat diet control (HFD), GLE-treated at 250 ㎎/㎏, and GLE-treated at 500 ㎎/㎏. To induce hyperglycemic and hyperlipidemic states, mice were fed a high fat diet for 6 weeks and then administered GLE once daily for 8 weeks. At the end of the treatment, we examined the effects of GLE on plasma glucose, lipid levels, and the expression of genes related to lipogenesis, lipolysis, and gluconeogenesis. Both GLE groups lowered levels of plasma glucose, insulin, triglycerides, total cholesterol, and non-esterified fatty acids when compared to those in HFD group. Histological analysis revealed significantly fewer lipid droplets in the livers of GLE-treated mice compared with HFD mice. To elucidate the mechanism, Western blots and RT-PCR were performed using liver tissue. Compared with HFD mice, GLE-treated mice showed higher levels of phosphorylation of AMP-activated protein kinase (AMPK) and its substrate, acetyl-CoA carboxylase, but no differences in the expression of lipogenic genes such as sterol regulatory element-binding protein 1a, fatty acid synthase, sterol-CoA desaturase 1 and glycerol-3-phosphate acyltransferase. However, the expression levels of lipolysis and fatty acid uptake genes such as peroxisome proliferator-activated receptor-α and CD36 were increased. In addition, phospho-α and CD36 were increased. In addition, phosphoenolpyruvate carboxykinase gene expression was decreased. These results suggest that GLE ameliorates hyperglycemia and hyperlipidemia by inhibiting gluconeogenesis and stimulating lipolysis, respectively, via AMPK activation.

Effect of Oryzanol and Ferulic Acid on the Glucose Metabolism of Mice Fed with a High‐Fat Diet

The effects of oryzanol and ferulic acid on the glucose metabolism of high-fat-fed mice were investigated. Male C57BL/6N mice were randomly divided into 4 groups: NC group fed with normal control diet; HF group fed with high-fat (17%) diet; HF-O group fed with high-fat diet supplemented with 0.5% oryzanol; and HF-FA group fed with high-fat diet supplemented with 0.5% ferulic acid. All animals were allowed free access to the experimental diets and water for 7 wk. At the end of the experimental period, the HF-O and HF-FA groups exhibited significantly lower blood glucose level and glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities, and higher glycogen and insulin concentrations and glucokinase (GK) activity compared with NC and HF groups. The results of this study illustrate that both oryzanol and ferulic acid could reduce the risk of high-fat diet-induced hyperglycemia via regulation of insulin secretion and hepatic glucose-regulating enzyme activities.

Eriobotrya japonica improves hyperlipidemia and reverses insulin resistance in high‐fat‐fed mice

The effect of Eriobotrya japonica Lindl. (loquat) on insulin resistance was examined in mice fed a high-fat (HF) diet. First, the mice were divided randomly into two groups: the control (CON) group was fed a low-fat diet, whereas the experimental group was fed with a 45% HF diet for 10 weeks. After 6 weeks of induction, the HF group was subdivided into five groups and was given orally loquat or not for 4 weeks afterward. It was demonstrated that loquat was effective in ameliorating the HF diet-induced hyperglycemia, hyperleptinemia, hyperinsulinemia and hypertriglyceridemia, as well as in decreasing the levels of free fatty acid (FFA), but increasing the adipose PPARγ (peroxisomal proliferator-activated receptor γ) and hepatic PPARα mRNA levels. Loquat significantly decreased the body weight gain, weights of white adipose tissue and visceral fat accompanying the suppressed leptin mRNA levels. Loquat not only suppressed the hepatic mRNA levels of enzymes involved in fatty acid and triacylglycerol synthesis and lowered the sterol regulatory element binding protein-1c (SREBP-1c) mRNA level, but also affected fatty acid oxidation enzyme levels. These regulations may contribute to triacylglycerol accumulation in white adipose tissue. The findings provide a nutritional basis for the use of loquat as a functional food factor that may have benefits for the prevention of hyperlipidemia and diabetes.

Involvement of Inducible 6-Phosphofructo-2-kinase in the Anti-diabetic Effect of Peroxisome Proliferator-activated Receptor γ Activation in Mice

PFKFB3 is the gene that codes for the inducible isoform of 6-phosphofructo-2-kinase (iPFK2), a key regulatory enzyme of glycolysis. As one of the targets of peroxisome proliferator-activated receptor gamma (PPARgamma), PFKFB3/iPFK2 is up-regulated by thiazolidinediones. In the present study, using PFKFB3/iPFK2-disrupted mice, the role of PFKFB3/iPFK2 in the anti-diabetic effect of PPARgamma activation was determined. In wild-type littermate mice, PPARgamma activation (i.e. treatment with rosiglitazone) restored euglycemia and reversed high fat diet-induced insulin resistance and glucose intolerance. In contrast, PPARgamma activation did not reduce high fat diet-induced hyperglycemia and failed to reverse insulin resistance and glucose intolerance in PFKFB3(+/-) mice. The lack of anti-diabetic effect in PFKFB3(+/-) mice was associated with the inability of PPARgamma activation to suppress adipose tissue lipolysis and proinflammatory cytokine production, stimulate visceral fat accumulation, enhance adipose tissue insulin signaling, and appropriately regulate adipokine expression. Similarly, in cultured 3T3-L1 adipocytes, knockdown of PFKFB3/iPFK2 lessened the effect of PPARgamma activation on stimulating lipid accumulation. Furthermore, PPARgamma activation did not suppress inflammatory signaling in PFKFB3/iPFK2-knockdown adipocytes as it did in control adipocytes. Upon inhibition of excessive fatty acid oxidation in PFKFB3/iPFK2-knockdown adipocytes, PPARgamma activation was able to significantly reverse inflammatory signaling and proinflammatory cytokine expression and restore insulin signaling. Together, these data demonstrate that PFKFB3/iPFK2 is critically involved in the anti-diabetic effect of PPARgamma activation.