Heterogeneous effect of peroxisome proliferator-activated receptor gamma2 Ala12 variant on type 2 diabetes risk

Conflicting results have been reported regarding whether the PPARgamma2 Pro12Ala polymorphism plays a role in the risk of type 2 diabetes (T2D), suggesting genetic heterogeneity. To investigate this issue, a meta-analysis of 41 published and 2 unpublished studies (a total of 42,910 subjects) was conducted. Ala12 carriers had a 19% T2D risk reduction, but this association was highly heterogeneous (p = 0.005). A great proportion (48%) of heterogeneity was explained by the controls' BMI, with risk reduction being greater when BMI was lower. Risk reduction of Ala12 carriers in Asia (35%) was higher than in Europe (15%, p = 0.02) and tended to be higher than in North America (18%, p = 0.10). Difference between Asians and Europeans was no longer significant (p = 0.15) after adjusting for the controls' BMI. Studies from Europe were still heterogeneous (p = 0.02) with risk reduction in Ala12 carriers being progressively smaller (test for trend in the odds ratios, p = 0.02) from Northern (26% reduction, p < 0.0001) to Central (10%, p = 0.04) and Southern (0%, p = 0.94) Europe. In conclusion, in our meta-analysis, the reduced risk of T2D in Ala12 carriers is not homogeneous. It is greater in Asia than in Europe and, among Europeans, it is higher in Northern Europe, barely significant in Central Europe, and nonexistent in Southern Europe.     

(+)‐Z‐Bisdehydrodoisynolic Acid Ameliorates Obesity and the Metabolic Syndrome in Female ZDF Rats

Objective: The putative selective estrogen receptor modulator (+)‐Z‐bisdehydrodoisynolic acid (Z‐BDDA) has been found to improve cardiovascular risk in rodents. The objective of this study was to investigate the effectiveness of (+)‐Z‐BDDA compared with the antidiabetic drug, rosiglitazone, in treating obesity and risk factors associated with the metabolic syndrome. Research Methods and Procedures: Female Zucker Diabetic Fatty rats were randomly assigned to three treatment groups for 29 weeks: control (C), 1.8 mg (+)‐Z‐BDDA/kg diet [control diet + (+)‐Z‐BDDA (CB)], or 100 mg rosiglitazone/kg diet [control diet + rosiglitazone (CR)]. At sacrifice, physiological, biochemical, and molecular parameters were examined. Results: CB animals gained less weight and exhibited a decrease in total body lipids (p < 0.05) as compared with C or CR rats. Body weight and total body lipids were the highest in CR rats (p < 0.05). Liver weights in CB and CR rats were lower (p < 0.05) than in C rats, whereas kidney weights were lower in CB (p < 0.05) than in C and CR animals. Fasting plasma glucose was lower (p < 0.05) in the CB and CR animals when compared with C animals. C rats exhibited the highest concentration of total plasma cholesterol, and CR‐treated rats exhibited the lowest concentration. Plasma triglycerides followed the same pattern as plasma cholesterol. Histomorphometry of heart vasculature revealed that CB and CR treatments produced a significant shift from small to large venules and arterioles compared with C (p < 0.05). Liver expression profiles of peroxisome proliferator‐activated receptor (PPAR) α, PPARγ, and PPAR‐regulated genes revealed encouraging CB‐induced effects. Discussion: These results suggest that (+)‐Z‐BDDA may have applications in treating obesity and complications associated with the metabolic syndrome.     

Identification of endocannabinoids and related compounds in human fat cells

Objective: Recently, an activation of the endocannabinoid system during obesity has been reported. More particularly, it has been demonstrated that hypothalamic levels of both endocannabinoids, 2‐arachidonoylglycerol and anandamide (N‐arachidonoylethanolamine), are up‐regulated in genetically obese rodents. Circulating levels of both endocannabinoids were also shown to be higher in obese compared with lean women. Yet, the direct production of endocannabinoids by human adipocytes has never been demonstrated. Our aim was to evaluate the ability of human adipocytes to produce endocannabinoids. Research Methods and Procedures: The production of endocannabinoids by human adipocytes was investigated in a model of human white subcutaneous adipocytes in primary culture. The effects of leptin, adiponectin, and peroxisome proliferator‐activated receptor (PPAR)‐γ activation on endocannabinoid production by adipocytes were explored. Endocannabinoid levels were determined by high‐performance liquid chromatography (HPLC)‐atmospheric pressure chemical ionization (APCI)‐mass spectrometry (MS) analysis, leptin and adiponectin secretion measured by enzyme‐linked immunosorbent assay (ELISA), and PPAR‐γ protein expression examined by Western blotting. Results: We show that 2‐arachidonoylglycerol, anandamide, and both anandamide analogs, N‐palmitoylethanolamine and N‐oleylethanolamine, are produced by human white subcutaneous adipocytes in concentrations ranging from 0.042 ± 0.004 to 0.531 ± 0.048 pM/mg lipid extract. N‐palmitoylethanolamine is the most abundant cannabimimetic compound produced by human adipocytes, and its levels are significantly down‐regulated by leptin but not affected by adiponectin and PPAR‐γ agonist ciglitazone. N‐palmitoylethanolamine itself does not affect either leptin or adiponectin secretion or PPAR‐γ protein expression in adipocytes. Discussion: This study has led to the identification of human adipocytes as a new source of endocannabinoids and related compounds. The biological significance of these adipocyte cannabimimetic compounds and their potential implication in obesity should deserve further investigations.     

Dihydromyricetin enhances glucose uptake by inhibition of MEK/ERK pathway and consequent down‐regulation of phosphorylation of PPARγ in 3T3‐L1 cells

Accumulating evidence suggests that inhibition of mitogen‐activated protein kinase signalling can reduce phosphorylation of peroxisome proliferator‐activated receptor γ (PPARγ) at serine 273, which mitigates obesity‐associated insulin resistance and might be a promising treatment for type 2 diabetes. Dihydromyricetin (DHM) is a flavonoid that has many beneficial pharmacological properties. In this study, mouse fibroblast 3T3‐L1 cells were used to investigate whether DHM alleviates insulin resistance by inhibiting PPARγ phosphorylation at serine 273 via the MEK/ERK pathway. 3T3‐L1 pre‐adipocytes were differentiated, and the effects of DHM on adipogenesis and glucose uptake in the resulting adipocytes were examined. DHM was found to dose dependently increase glucose uptake and decrease adipogenesis. Insulin resistance was then induced in adipocytes using dexamethasone, and DHM was shown to dose and time dependently promote glucose uptake in the dexamethasone‐treated adipocytes. DHM also inhibited phosphorylation of PPARγ and ERK. Inhibition of PPARγ activity with GW9662 potently blocked DHM‐induced glucose uptake and adiponectin secretion. Interestingly, DHM showed similar effects to PD98059, an inhibitor of the MEK/ERK pathway. DHM acted synergistically with PD98059 to improve glucose uptake and adiponectin secretion in dexamethasone‐treated adipocytes. In conclusion, our findings indicate that DHM improves glucose uptake in adipocytes by inhibiting ERK‐induced phosphorylation of PPARγ at serine 273.     

Hesperidin modulates dextran sulfate sodium‐induced ulcerative colitis in rats: Targeting sphingosine kinase‐1‐ sphingosine 1 phosphate signaling pathway,mitochondrial biogenesis,inflammation, and apoptosis

Ulcerative colitis (UC) is a chronic gastrointestinal disorder interfering with life quality. A total of 60 male Wistar rats were divided into four equal groups: Control (group I), hesperidin only (group II), UC untreated (group III), and UC treated with hesperidin (group IV). Hesperidin had modulatory effects on UC pathogenesis, which might be through alleviating colonic sphingosine phosphate phosphatase 2 messenger RNA expression and sphingosine kinase‐1 levels, thus suppressing the subsequent downstream inflammatory and apoptotic cascades represented by decreased macrophage inflammatory protein‐1α and enhancement of B‐cell lymphoma 2 immunohistochemistry expression. Also, it improved mitochondrial biogenesis by increasing the peroxisome proliferator‐activated receptor‐gamma‐coactivator 1‐α level. It successfully restored redox potential as evidenced by marked alleviations of the nitric oxide and peroxynitrite levels, increasing total antioxidant capacity, and activating the superoxide dismutase enzyme. Also, hesperidin alleviated the UC disease activity index and improved the histopathological picture. These findings may offer a new therapeutic strategy for UC treatment.     

Metabolites related to gut bacterial metabolism,peroxisome proliferator‐activated receptor‐alpha activation,and insulin sensitivity are associated with physical function in functionally‐limited older adults

Identification of mechanisms underlying physical function will be important for addressing the growing challenge that health care will face with physical disablement in the expanding aging population. Therefore, the goals of the current study were to use metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6‐month change in serum mass spectrometry‐obtained amino acids, fatty acids, and acylcarnitines with baseline and the 6‐month change in muscle strength (leg press one repetition maximum divided by total lean mass, LP/Lean), lower extremity function [short physical performance battery (SPPB)], and mobility (400 m gait speed, 400‐m), in response to 6 months of a combined resistance exercise and nutritional supplementation (whey protein or placebo) intervention in functionally‐limited older adults (SPPB ≤ 10; 70–85 years, N = 73). Metabolites related to gut bacterial metabolism (cinnamoylglycine, phenol sulfate, p‐cresol sulfate, 3‐indoxyl sulfate, serotonin, N‐methylproline, hydrocinnamate, dimethylglycine, trans‐urocanate, valerate) that are altered in response to peroxisome proliferator‐activated receptor‐alpha (PPAR‐α) activation (α‐hydroxyisocaproate, α‐hydroxyisovalerate, 2‐hydroxy‐3‐methylvalerate, indolelactate, serotonin, 2‐hydroxypalmitate, glutarylcarnitine, isobutyrylcarnitine, cinnamoylglycine) and that are related to insulin sensitivity (monounsaturated fatty acids: 5‐dodecenoate, myristoleate, palmitoleate; γ‐glutamylamino acids: γ‐glutamylglutamine, γ‐glutamylalanine, γ‐glutamylmethionine, γ‐glutamyltyrosine; branched‐chain amino acids: leucine, isoleucine, valine) were associated with function at baseline, with the 6‐month change in function or were identified in backward elimination regression predictive models. Collectively, these data suggest that gut microbial metabolism, PPAR‐α activation, and insulin sensitivity may be involved in mechanisms that underlie physical function in functionally‐limited older adults.     

PPAR-γ/PGC-1α对支气管哮喘豚鼠肺组织Nrf2/γ-GCS-h作用

目的：观察PPAR-γ、PGC-1α、Nrf2和γ-GCS-h在豚鼠支气管哮喘肺组织中表达而探索PPAR-γ/PGC-1α对Nrf2/γ-GCS-h作用。方法：40只健康雄性豚鼠随机化原则分成对照组（A组）、哮喘组（B组）、地塞米松（C组）和罗格列酮治疗组（D组）,每组10只豚鼠,卵蛋白致敏法复制哮喘模型。原位杂交检测PPAR-γ、PGC-1α、Nrf2和γ-GCS-hmRNA表达,免疫组化和Western blot检测四种蛋白表达。结果：PPAR-γ、PGC-1α、Nrf2和γ-GCS-h的mRNA哮喘组表达最低,四组表达差异有统计学意义（P均〈0.01）;免疫组化和Western blot显示PPAR-γ、PGC-1α、Nrf2和γ-GCS-h的蛋白哮喘组表达几乎都呈阴性而且以核内表达为主,四组差异均有统计学意义（P均〈0.01）。PPAR-γ表达与PGC-1α表达呈正相关,γ-GCS-h mRNA表达与PPAR-γ、PGC-1α、Nrf2核内表达均呈正相关,Nrf2表达与PPAR-γ和PGC-1α表达均呈正相关。结论：PPAR-γ、PGC-1α、Nrf2和γ-GCS-h在卵蛋白致敏急性支气管哮喘模型中表达下降;PPAR-γ/PGC-1α可通过上调Nrf2/γ-GCS-h表达提高组织的抗氧化能力,因而PPAR-γ/PGC-1α在哮喘的发病和防治可能起重要的作用。     

Anti-diabetic properties of Daphniphyllum macropodum fruit and its active compound

We evaluated in vitro anti-diabetic activities of 497 native plants of Jeju Island (South Korea) by measuring the induction of adipocyte differentiation. Among the plants, Daphniphyllum macropodum fruit extract (DME) had the highest peroxisome proliferator-activated receptor γ (PPARγ) agonist activity and was therefore selected as a potential source of anti-diabetic agents. To elucidate the active components of DME, constituent compounds were purified and their effects on the adipocyte differentiation were studied. Using activity-guided fractionation, four compounds were isolated from DME and their adipogenic effects were evaluated. Among the compounds isolated, 5,7-dihydroxychromone potently induced the differentiation of mouse 3T3-L1 preadipocytes. DME and 5,7-dihydroxychromone increased PPARγ and liver X receptor α (LXRα) mRNA expression levels. To determine whether the adipogenic effects we observed might affect serum glucose levels, we undertook in vivo experiment using streptozotocin-/high-fat diet-induced type 2 diabetes mouse model. DME supplementation reduced serum glucose, total cholesterol, and triacylglycerol levels in diabetes mice. These results suggest that DME may be useful for the prevention and treatment of type 2 diabetes mellitus. Moreover, it was proposed that 5,7-dihydroxychromone isolated from DME is one of the active compounds that may contribute to regulate blood glucose levels.     

Rosiglitazone inhibits monocyte/macrophage adhesion through de novo adiponectin production in human monocytes

Rosiglitazone (RSG) has a variety of actions on both insulin sensitization and anti‐atherogenic effects. The molecular effect of RSG on monocyte/macrophage function in terms of de novo synthesis of adiponectin is not fully understood. Here, we examined the regulation of adiponectin expression in human monocytes/macrophages by RSG and its function on monocyte adhesion during initiation of atherosclerosis. Adiponectin expression in monocytes and macrophages was studied by RT‐PCR, quantitative real‐time PCR, Western blot, and immunocytochemistry. Signal transduction and adhesion molecules were studied in order to describe the function of de novo synthesized adiponectin in monocyte adhesion. Adiponectin was expressed and upregulated during monocyte differentiation. The expression of adiponectin was enhanced, albeit at a much lesser degree, by a peroxisome proliferator‐activated receptor gamma (PPARγ) agonist RSG, which was similar to what was found in adipocytes. Monocyte adhesion was remarkably reduced when the cells were treated with RSG for 12 h. This inhibitory effect of RSG was abolished by specific anti‐adiponectin antibodies but not by non‐immune immunoglobulin G in a serum‐free condition. Adiponectin‐induced suppression on monocyte adhesion was inhibited by a selective AMP‐activated protein kinase (AMPK) inhibitor compound C. The reduced expression and/or function of adhesion molecule integrins may underlie the mechanism contributing to reduced monocyte adhesion upon AMPK activation. Our data suggest that the inhibitory effect of RSG on monocyte adhesion might be at least in part through de novo adiponectin expression and activation of an AMPK‐dependent pathway, which might play an important role in atherogenesis. J. Cell. Biochem. 110: 1410–1419, 2010. © 2010 Wiley‐Liss, Inc.     

Resveratrol inhibits lipid accumulation in the intestine of atherosclerotic mice and macrophages

Disordered intestinal metabolism is highly correlated with atherosclerotic diseases. Resveratrol protects against atherosclerotic diseases. Accordingly, this study aims to discover novel intestinal proatherosclerotic metabolites and potential therapeutic targets related to the anti‐atherosclerotic effects of resveratrol. An untargeted metabolomics approach was employed to discover novel intestinal metabolic disturbances during atherosclerosis and resveratrol intervention. We found that multiple intestinal metabolic pathways were significantly disturbed during atherosclerosis and responsive to resveratrol intervention. Notably, resveratrol abolished intestinal fatty acid and monoglyceride accumulation in atherosclerotic mice. Meanwhile, oleate accumulation was one of the most prominent alterations in intestinal metabolism. Moreover, resveratrol attenuated oleate‐triggered accumulation of total cholesterol, esterified cholesterol and neutral lipids in mouse RAW 264.7 macrophages by activating ABC transporter A1/G1‐mediated cholesterol efflux through PPAR (peroxisome proliferator‐activated receptor) α/γ activation. Furthermore, we confirmed that PPARα and PPARγ activation by WY14643 and pioglitazone, respectively, alleviated oleate‐induced accumulation of total cholesterol, esterified cholesterol and neutral lipids by accelerating ABC transporter A1/G1‐mediated cholesterol efflux. This study provides the first evidence that resveratrol abolishes intestinal fatty acid and monoglyceride accumulation in atherosclerotic mice, and that resveratrol suppresses oleate‐induced accumulation of total cholesterol, esterified cholesterol and neutral lipids in macrophages by activating PPARα/γ signalling.     

Shorea roxburghii Leaf Extract Ameliorates Hyperglycemia Induced Abnormalities in High Fat/Fructose and Streptozotocin Induced Diabetic Rats

This study investigated the hypoglycemic effect of the methanol extract of Shorea roxburghii leaves (SRL) in high fat diet/high fructose solution (HFDHF) and streptozotocin (STZ) induced type 2 diabetes mellitus (T2DM) in rats as well as evaluating its ameliorative potentials in altered biochemical and hematological parameters in the treated rats. T2DM was induced in Sprague Dawley (SD) rats by feeding with HFDHF for 4 weeks and administering STZ (35 mg/kg, i. p.). Diabetic rats were given SRL extract at doses of 100 and 400 mg/kg for 30 days. The food and water intake were monitored on a daily basis, while the fasting blood glucose (FBG) levels and body weight were measured weekly. Biochemical and hematological parameters as well as histopathological studies of the pancreas were also evaluated. SRL significantly decreased FBG and improved the body weight, food and water intake of treated diabetic rats. Furthermore, biochemical and hematological parameters including liver and kidney function enzymes, lipid profiles, white blood and red blood cells parameters were markedly ameliorated by SRL. Histopathological analyses of the pancreas indicated reconstitution of β‐cells architecture in SRL treated rats. The results of this study suggest that SRL has antidiabetic potential and can be considered for the treatment of T2DM.