Wild Alaskan Vaccinium berries, V. vitis-idaea (lowbush cranberry) and V. uliginosum (bog blueberry), were investigated in parallel to their commercial berry counterparts; V. macrocarpon (cranberry) and V. angustifolium (lowbush blueberry). Lowbush cranberry accumulated about twice the total phenolics (624.4 mg/100 g FW) and proanthocyanidins (278.8 mg/100 g) content as commercial cranberries, but A-type proanthocyanidins were more prevalent in the latter. Bog blueberry anthocyanin and total phenolic contents of 220 and 504.5 mg/100 g, respectively, significantly exceeded those of the lowbush blueberry. Chlorogenic acid, however, was quite high in lowbush blueberry (83.1 mg/100 g), but undetected in bog blueberry, and the proanthocyanidins of lowbush blueberry had significantly higher levels of polymerization. Antioxidant capacity (DPPH, APTS and FRAP) correlated with phenolic content for each berry. A polyphenol-rich fraction from lowbush cranberry exhibited dose-dependent inhibition of LPS-elicited induction of IL-1β in RAW 264.7 cells, indicative of strong anti-inflammatory activity. These results corroborate the historic use of wild Alaskan berries as medicinally-important foods in Alaska Native communities.

Black currant (Ribes nigrum L.) is a rich source of anthocyanins; however, the relationship between their apparently limited bioavailability and significant protection against metabolic pathologies is poorly understood. This study examined the gastrointestinal distribution of black currant anthocyanins and their phenolic acid metabolites in lean and diet-induced obese mice with healthy and antibiotic-disrupted microbiomes. Daily consumption of low- or high-fat diet supplemented with 1% black currant powdered extract (32% anthocyanins) for 8 weeks reduced body weight gain and improved glucose metabolism only in mice with the intact gut microbiome. Administration of antibiotic cocktail resulted in a 16-25-fold increase (P < 0.001) in anthocyanin content of feces, and cyanidin-based anthocyanins showed the largest increase in fecal content upon disruption of gut microbiome (92.3 ± 16.3 vs 4719 ± 158 μg/g feces), indicating their high susceptibility to microbial degradation in the gut. A 3-fold enrichment (P < 0.05) in gallic over protocatechuic acid was observed in the jejunum of both intact and antibiotic-treated animals, suggesting that this effect was likely independent of their gut microbiome status. Taken together, the data clearly demonstrate that gut microbiome and the type of the anthocyanin aglycone moiety can alter the protective effect of anthocyanins against obesity and associated insulin resistance.

Wild lowbush blueberries (Vaccinium angustifolium Ait) are a rich source of anthocyanins and other flavonoids with anti-inflammatory activities; however, their individual effects on cellular signaling remain to be elucidated. This study determined the capacity of blueberry bioactives to protect murine RAW 264.7 macrophages from lipopolysaccharide-induced inflammation. Fractionation of the crude extract (CE) into polyphenol-rich (PPR), anthocyanin-rich (ANC), and proanthocyanidin-rich (PAC) fractions and an ethyl acetate fraction (EA) revealed that PPR, ANC, and PAC components most effectively suppressed mRNA biomarkers of acute inflammation (Cox-2, iNOS, and IL-1β). Among major polyphenols found in the wild blueberries, malvidin-3-glucoside was significantly more effective than epicatechin or chlorogenic acid in reducing the expression of pro-inflammatory genes in vitro.

Overconsumption of energy dense foods and sedentary lifestyle are considered as major causes of obesity-associated insulin resistance and abnormal glucose metabolism. Results from both cohort studies and randomized trials suggested that anthocyanins from berries may lower metabolic risks, however these reports are equivocal. The present study was designed to examine effects of six berries with structurally diverse anthocyanin profiles (normalized to 400 µg/g total anthocyanin content) on development of metabolic risk factors in the C57BL/6 mouse model of polygenic obesity. Diets supplemented with blackberry (mono-glycosylated cyanidins), black raspberry (acylated mono-glycosylated cyanidins), blackcurrant (mono- and di-glycosylated cyanidins and delphinidins), maqui berry (di-glycosylated delphinidins), Concord grape (acylated mono-glycosylated delphinidins and petunidins), and blueberry (mono-glycosylated delphinidins, malvidins, and petunidins) showed a prominent discrepancy between biological activities of delphinidin/malvidin-versus cyanidin-type anthocyanins that could be explained by differences in their structure and metabolism in the gut. Consumption of berries also resulted in a strong shift in the gastrointestinal bacterial communities towards obligate anaerobes that correlated with decrease in the gastrointestinal luminal oxygen and oxidative stress. Further work is needed to understand mechanisms that lead to nearly anoxic conditions in the gut lumens, including the relative contributions of host, diet and/or microbial oxidative activity, and their implication to human health.

September 11, 2007; doi:10.1152/ajpendo.00420.2007.-An ethanolic extract of Russian tarragon, Artemisia dracunculus L., with antihyperglycemic activity in animal models was reported to decrease phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression in STZ-induced diabetic rats. A quantitative polymerase chain reaction (qPCR) assay was developed for the bioactivity-guided purification of the compounds within the extract that decrease PEPCK expression. The assay was based on the inhibition of dexamethasone-stimulated PEPCK upregulation in an H4IIE hepatoma cell line. Two polyphenolic compounds that inhibited PEPCK mRNA levels were isolated and identified as 6-demethoxycapillarisin and 2Ј,4Ј-dihydroxy-4-methoxydihydrochalcone with IC50 values of 43 and 61 M, respectively. The phosphoinositide-3 kinase (PI3K) inhibitor LY-294002 showed that 6-demethoxycapillarisin exerts its effect through the activation of the PI3K pathway, similarly to insulin. The effect of 2Ј,4Ј-dihydroxy-4-methoxydihydrochalcone is not regulated by PI3K and dependent on activation of AMPK pathway. These results indicate that the isolated compounds may be responsible for much of the glucose-lowering activity of the Artemisia dracunculus extract. phosphoenolpyruvate carboxykinase; polyphenols; diabetes TYPE 2 DIABETES has reached epidemic proportions not only in the US, but worldwide (15a). The major factors contributing to the hyperglycemia of diabetes are multifactorial but are secondary to the failure of the ␤-cells of the pancreas to adequately compensate for the insulin resistance, characterized by decreased whole body insulin-mediated glucose utilization and elevated hepatic glucose output. With regard to enhanced glucose production by the liver, phosphoenolpyruvate carboxykinase (PEPCK) is the key enzyme catalyzing the first step in hepatic gluconeogenesis (5). Glucagon and stress hormones, such as glucocorticoids, upregulate PEPCK gene expression in hepatocytes via a cyclic AMP (cAMP)-dependent pathway (5). Alternatively, insulin strongly represses PEPCK transcription through the activation of the phosphoinositide-3 kinase (PI3K) pathway (4).Normally, the increase in blood glucose levels after food intake stimulates the secretion of insulin from the pancreas. This increase in blood insulin concentration then leads to the downregulation of PEPCK gene expression and, subsequently, the cessation of gluconeogenesis by the liver (4). Insulinresistant hepatocytes, however, are unable to effectively convey the insulin signal, leading to a decrease in PEPCK mRNA transcription. Thus, the de novo glucose synthesis persists despite a high blood glucose concentration (12). The compounds that are able to repress PEPCK expression and overcome insulin resistance could constitute a new class of glucoselowering agents.Plants have traditionally been a rich source of medicinal compounds for many indications, including diabetes. In fact, metformin is one of the most prescribed glucose-lowering medicines currently used and is derived from a chemical isola...

Pattern recognition receptors (PRR), Toll-like receptors (TLR), and nucleotide-oligomerization domain-containing proteins (NOD) play critical roles in mediating inflammation and modulating functions in white adipocytes in obesity. However, the role of PRR activation in brown adipocytes, which are recently found to be present in adult humans, has not been studied. Here we report that mRNA of TLR4, TLR2, NOD1, and NOD2 is upregulated, paralleled with upregulated mRNA of inflammatory cytokines and chemokines in the brown adipose tissue (BAT) of the obese mice. During brown adipocyte differentiation, mRNA and protein expression of NOD1 and TLR4, but not TLR2 and NOD2, is also increased. Activation of TLR4, TLR2, or NOD1 in brown adipocytes induces activation of NF-κB and MAPK signaling pathways, leading to inflammatory cytokine/chemokine mRNA expression and/or protein secretion. Moreover, activation of TLR4, TLR2, or NOD1 attenuates both basal and isoproterenol-induced uncoupling protein 1 (UCP-1) expression without affecting mitochondrial biogenesis and lipid accumulation in brown adipocytes. Cellular bioenergetics measurements confirm that attenuation of UCP-1 expression by PRR activation is accompanied by suppression of both basal and isoproterenol-stimulated oxygen consumption rates and isoproterenol-induced uncoupled respiration from proton leak; however, maximal respiration and ATP-coupled respiration are not changed. Further, the attenuation of UCP-1 by PRR activation appears to be mediated through downregulation of the UCP-1 promoter activities. Taken together, our results demonstrate the role of selected PRR activation in inducing inflammation and downregulation of UCP-1 expression and mitochondrial respiration in brown adipocytes. Our results uncover novel targets in BAT for obesity treatment and prevention.

Objectives and methodsUsing a randomized, crossover, counterbalanced approach, cyclists (N = 20, overnight fasted state) engaged in the four 75-km time trials (2-week washout) while ingesting two types of bananas with similar carbohydrate (CHO) but different phenolic content (Cavendish, CAV; mini-yellow, MIY, 63% higher polyphenols), a 6% sugar beverage (SUG), and water only (WAT). CHO intake was set at 0.2 g/kg every 15 minutes. Blood samples were collected pre-exercise and 0 h-, 0.75 h-,1.5 h-, 3 h-, 4.5 h-, 21 h-, 45 h-post-exercise.ResultsEach of the CHO trials (CAV, MIY, SUG) compared to water was associated with higher post-exercise plasma glucose and fructose, and lower leukocyte counts, plasma 9+13 HODES, and IL-6, IL-10, and IL-1ra. OPLS-DA analysis showed that metabolic perturbation (N = 1,605 metabolites) for WAT (86.8±4.0 arbitrary units) was significantly greater and sustained than for CAV (70.4±3.9, P = 0.006), MIY (68.3±4.0, P = 0.002), and SUG (68.1±4.2, P = 0.002). VIP ranking (<3.0, N = 25 metabolites) showed that both CAV and MIY were associated with significant fold changes in metabolites including those from amino acid and xenobiotics pathways. OPLS-DA analysis of immediate post-exercise metabolite shifts showed a significant separation of CAV and MIY from both WAT and SUG (R2Y = 0.848, Q2Y = 0.409). COX-2 mRNA expression was lower in both CAV and MIY, but not SUG, versus WAT at 21-h post-exercise in THP-1 monocytes cultured in plasma samples. Analysis of immediate post-exercise samples showed a decrease in LPS-stimulated THP-1 monocyte extracellular acidification rate (ECAR) in CAV and MIY, but not SUG, compared to WAT.ConclusionsCHO ingestion from bananas or a sugar beverage had a comparable influence in attenuating metabolic perturbation and inflammation following 75-km cycling. Ex-vivo analysis with THP-1 monocytes supported a decrease in COX-2 mRNA expression and reduced reliance on glycolysis for ATP production following ingestion of bananas but not sugar water when compared to water alone.Trial registrationClinicalTrials.gov, U.S. National Institutes of Health, identifier: NCT02994628

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