European Journal of Nutrition (v.50, #2)

Naringenin, a flavonoid present in grapefruit, has recently been shown to exert hypolipidemic and hypocholesterolemic effects, which has a particular importance for protecting against chronic diseases. However, the lipid-lowering potential of naringenin at the concentrations in the dietary range and its underlying mechanisms have yet to be fully elucidated.The aim of the present study was (1) to investigate the effects of dietary naringenin on plasma and hepatic triglyceride and cholesterol levels and on adipose deposition in rat and (2) to determine the contribution of hepatic peroxisome proliferators–activated receptor α (PPARα) expression to fatty acid oxidation.Male Long-Evans hooded rats were fed a diet supplemented with naringenin (0.003, 0.006, and 0.012%) for 6 weeks. We analyzed plasma and hepatic lipid contents and determined the protein expression of PPARα, carnitine-palmitoyl transferase 1L (CPT-1), and uncoupling protein 2 (UCP2), all of which are critical genes for fatty acid oxidation.Naringenin supplementation caused a significant reduction in the amount of total triglyceride and cholesterol in plasma and liver. In addition, naringenin supplementation lowered adiposity and triglyceride contents in parametrial adipose tissue. Naringenin-fed animals showed a significant increase in PPARα protein expression in the liver. Furthermore, expression of CPT-1 and UCP2, both of which are known to be regulated by PPARα, was markedly enhanced by naringenin treatment.Our results indicate that the activation of PPARα transcription factor and upregulation of its fatty acid oxidation target genes by dietary naringenin may contribute to the hypolipidemic and anti-adiposity effects in vivo.
Keywords: Naringenin; Hypolipidemic effect; Anti-adiposity; PPAR-α; CPT-1; UCP2; In vivo

The aim of this study is to investigate whether serum n − 3 polyunsaturated fatty acids (PUFAs) or n − 6 to n − 3 ratio is associated with risk of severe depression in middle-aged Finnish men.The association between the serum concentrations of fatty acids and depression was investigated in 2077 men aged 42–60 years at baseline in a prospective follow-up setting. The population-based Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study cohort was recruited between 1984 and 1989 and followed until the end of 2007. The baseline levels of serum total n − 3 PUFAs, n − 6 PUFAs and individual fatty acids were determined. Data on hospital treatments due to major depressive disorder were derived from the national hospital discharge register.During the average follow-up time of 18 years, 46 men received a discharge diagnosis of depression. When the Cox proportional hazards model was adjusted for age, examination year, baseline socioeconomic status, alcohol consumption, smoking, maximal oxygen uptake and body mass index, there was no association between serum total n − 3 PUFAs and the risk of depression [relative risk (RR) in the highest compared to the lowest tertile 0.71, 95% confidence interval (CI): 0.38; 1.43]. Serum concentrations of n − 6 PUFAs, n6/n3 PUFA ratio, or individual fatty acids were not associated with the risk of severe depression, either.We did not find evidence that serum n − 3 PUFA concentration or n − 6/n − 3 ratio would be associated with risk of severe depression in middle-aged Finnish men.
Keywords: Depression; Fatty acids; Polyunsaturated; EPA; DHA

Is a low blood level of vitamin B12 a cardiovascular and diabetes risk factor? A systematic review of cohort studies by Snorri B. Rafnsson; Ponnusamy Saravanan; Raj S. Bhopal; Chittaranjan S. Yajnik (97-106).
To assess the prior hypothesis that low blood vitamin B12, partly through hyperhomocysteinemia and partly through direct effects, increases the risk of cardiovascular diseases and diabetes. As background, we also extracted all-cause mortality from the studies that met our criteria.A systematic review of prospective cohort studies identified through searching six electronic databases, screening of reference lists, and citation search. Included studies reported data on the association between vitamin B12 blood levels, or other appropriate surrogate biological markers e.g. holotranscobalamin or serum/urine methylmalonic acid, and fatal or non-fatal incident diabetes and cardiovascular events.Seven studies were included. Studies differed regarding the population studied, length of follow-up, study outcomes, and data analysis—a narrative synthesis approach was performed to examine the results. Most studies met few of the quality assessment criteria which were adapted from the Scottish Intercollegiate Guidelines Network (SIGN). Only one high-quality study reported that low B12 increased the risk of incident cerebral ischaemia (RR = 1.76; 95% CI = 1.16–2.68). After controlling for homocysteine, the association persisted although weakened (RR = 1.57; 95% CI = 1.02–2.43), suggesting that the effects of low B12 were only partly mediated by homocysteine. In two studies, higher B12 levels were associated with a greater risk of total mortality (RR = 1.00; 95% CI = 1.00–1.00 and HR = 1.15; 95% CI = 1.08–1.22, respectively) and combined fatal and non-fatal coronary events (RR = 1.00; 95% CI = 1.00–1.00). No association between study outcomes and vitamin B12 levels was found in four other studies.Surprisingly, there is only very limited evidence that vitamin B12 deficiency predisposes to the risk of mortality and morbidity from either cardiovascular diseases or diabetes in adults. Current data do not support vitamin B12 supplementation to reduce the risk of cardiovascular diseases or diabetes.
Keywords: Vitamin B12; Cardiovascular diseases; Diabetes mellitus type 2; Cohort studies; Aetiology

Insulin resistance is a common symptom of metabolic diseases such as obesity, type 2 diabetes and hyperlipidemia.We investigated whether Gastrodia elata Blume water extract(GEB), containing phenolic compounds, had a beneficial action on insulin resistance in male Sprague–Dawley rats fed a high fat diet(HFD) and determined how this effect was produced. In addition, the bioactive candidates involved were identified.Rats fed HFD were daily administered with 0.3 g GEB(GEB-L), 1 g GEB(GEB-H), or 1 g cellulose(control) per kg body weight for 8 weeks, while rats in the fourth group were fed a low fat diet(LFD). In vitro study, 4 major components of GEB were tested for their impact on fat accumulation.Rats in the control group exhibited a higher weight gain of epididymal and retroperitoneal fat pads than those fed LFD, while GEB prevented such an increment in a dose-dependent manner. GEB-H significantly decreased energy intake partly through potentiating STAT3 phosphorylation and attenuating AMPK phosphorylation in the hypothalamus. GEB-H also increased energy expenditure with the increase in fat oxidation. GEB-H increased whole body glucose disposal rates and decreased hepatic glucose output compared to the control. Among the major components of GEB, 4-hydroxybenzaldehyde and vanillin decreased triglyceride accumulation by modulating the expression of genes involved in fat metabolism in 3T3-L1 adipocytes. They increased insulin-stimulated glucose uptake to reduce insulin resistance.GEB-H, mainly as a result of the action of 4-hydroxybenzaldehyde and vanillin, reduces insulin resistance by decreasing fat accumulation in adipocytes by activating fat oxidation and potentiating leptin signaling in diet-induced obese rats.
Keywords: Gastrodia elata Blume; Energy expenditure; AMP kinase; Glucose tolerance; Insulin resistance; Euglycemic hyperinsulinemic clamp; Hypothalamus

Plasma folate concentrations after a single dose ingestion of whole and skimmed folic acid fortified milks in healthy subjects by María Achón; Ángeles Arrate; Elena Alonso-Aperte; Gregorio Varela-Moreiras (119-125).
Since mandatory folic acid fortification of grains and cereals was introduced in order to prevent neural tube defects, the number of products that are being fortified with folic acid is growing, especially milk and dairy products. However, the effectiveness of this action remains controversial.To investigate the efficiency of skimmed milk as a vehicle for folic acid fortification by the determination of the acute absorption from low-fat fortified milk compared to fortified and unfortified whole milk in healthy subjects.A single-dose bioavailability study was performed using three commercially available milks (whole and skimmed milk fortified with folic acid and unfortified whole milk). Healthy volunteers (3 women, 2 men) were administered a single dose of 430 ml of each milk, at 1-week intervals between test days. Plasma total folate concentrations, at baseline and hourly from 1.5 up to 6.5 h after ingestion, were measured.Plasma folate concentration was significantly increased, when compared to baseline values, 1.5 h after ingestion of skimmed fortified milk, and 2.5 h after whole fortified milk, and remained significantly higher than baseline values for up to 6.5 h after both treatments. The highest plasma folate concentration (20.9 ± 3.1 nmol/l) was obtained 6.5 h postprandial in response to skimmed fortified milk. The acute absorption of folic acid, calculated on the basis of area under the plasma folate concentration curve, was significantly higher from skimmed fortified milk compared to fortified and unfortified whole milk.The absorption of folic acid from fortified skimmed milk is faster than the absorption of folic acid from fortified whole milk, and it renders significantly higher plasma folate concentration when compared to whole milk. These findings indicate that skimmed milk could be considered an efficient food matrix for folic acid fortification.
Keywords: Folic acid; Fortification; Skimmed milk; Plasma folate; Bioavailability

Antiobesity effect of polyphenolic compounds from molokheiya (Corchorus olitorius L.) leaves in LDL receptor-deficient mice by Li Wang; Masayuki Yamasaki; Takuya Katsube; Xufeng Sun; Yukikazu Yamasaki; Kuninori Shiwaku (127-133).
Dietary supplementation with polyphenolic compounds is associated with reduced diet-induced obesity and metabolic disorders in humans. The antioxidative properties of polyphenolic compounds contribute to their antiobesity effect in animal experiments and human studies.The aim of the study was to investigate the antiobesity effect of polyphenolic compounds from molokheiya leaves in LDLR-/- mice fed high-fat diet and to elucidate the mechanism of this effect.Three groups of LDLR-/- mice were fed with a high-fat diet, supplemented with 0% (control), 1 or 3% molokheiya leaf powder (MLP). Gene expression in the liver associated with lipid and glucose metabolism was analyzed, and physical parameters and blood biochemistry were determined.Compared to controls, mice body weight gain (P = 0.003), liver weight (P = 0.001) and liver triglyceride levels (P = 0.005) were significantly lower in the two MLP groups. Epididymal adipose tissue weight (P = 0.003) was reduced in the 3% MLP group. Liver tissue gene expression of gp91phox (NOX2), involved in oxidative stress, was significantly down-regulated (P = 0.005), and PPARα and CPT1A, related to the activation of β-oxidation, were significantly up-regulated (P = 0.025 and 0.006, respectively) in the 3% MLP group compared to the control group.Our results demonstrate an antiobesity effect of polyphenolic compounds from molokheiya leaves and that this effect is associated with reduction in oxidative stress and enhancement of β-oxidation in the liver. Consumption of molokheiya leaves may be beneficial for preventing diet-induced obesity.
Keywords: Corchorus olitorius L.; Molokheiya; Obesity; Oxidative stress; β-oxidation; Polyphenolic compounds

Apple juice intervention modulates expression of ARE-dependent genes in rat colon and liver by Bülent Soyalan; Jutta Minn; Hans J. Schmitz; Dieter Schrenk; Frank Will; Helmut Dietrich; Matthias Baum; Gerhard Eisenbrand; Christine Janzowski (135-143).
The risk of cancer and other degenerative diseases is inversely correlated with consumption of fruits and vegetables. This beneficial effect is mainly attributed to secondary plant constituents such as polyphenols, supposed to play a major role in protection against ROS (reactive oxygen species)-associated toxicity.To elucidate the potential of differently manufactured apple juices (clear AJ/cloudy AJ/smoothie, in comparison with a polyphenol-free control juice) to modulate expression of ARE-dependent genes.In male Sprague–Dawley rats (n = 8/group; 10d juice intervention, 4d wash-out; 4 treatment cycles), expression of target genes (superoxide dismutase, SOD1/SOD2; glutathione peroxidase, GPX1/GPX2; γ-glutamylcysteine ligase, GCLC/GCLM; glutathione reductase, GSR; catalase, CAT; NAD(P)H:quinone oxidoreductase-1, NQO1 and transcription factor erythroid-derived 2-like-2, Nrf2) was quantified with duplex RT-PCR, using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as control.In colon and liver of rats consuming polyphenol-free control juice, rather similar basic expressions were observed (relative GAPDH ratios ranging from 2 to 0.7 and 2.5–0.3, respectively). In the distal colon, apple juice intervention slightly but significantly induced most genes (e.g. GPX2, GSR, CAT, Nrf2; p < 0.001), whereas in the liver only GPX1 and NQO1 mRNA were up-regulated; other hepatic target genes were not affected or down-regulated (SOD1, SOD2, GCLC/M, GSR), concomitant with the absence of Nrf2 induction. Induction of antioxidant gene expression differed with juice type (cloudy AJ > clear AJ ~ smoothie).Taken together, the results underline the potential of polyphenol-rich apple juice to increase the expression of ARE-dependent antioxidant genes.
Keywords: Antioxidant gene expression; Antioxidant response element; Apple juice intervention; Polyphenols; Rat colon and liver

Effect of thiamine administration on metabolic profile, cytokines and inflammatory markers in drug-naïve patients with type 2 diabetes by Manuel González-Ortiz; Esperanza Martínez-Abundis; José A. Robles-Cervantes; Viridiana Ramírez-Ramírez; Maria G. Ramos-Zavala (145-149).
To evaluate the effect of thiamine administration on metabolic profile, cytokines and inflammatory markers in drug-naïve patients with type 2 diabetes mellitus (T2DM).A randomized, double-blind, placebo-controlled, pilot-scale clinical trial was carried out in 24 patients with T2DM. Twelve subjects received thiamine orally (150 mg), once daily during a fasting state for 1 month. An additional 12 patients (control group) were given placebo for the same period of time. Before and after the intervention, fasting glucose, A1C, creatinine, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, very low-density lipoprotein, high-sensitive C-reactive protein, interleukin 6, tumor necrosis factor-alpha, leptin and adiponectin levels were estimated. Wilcoxon’s signed-rank and Mann–Whitney U test were used for statistical analyses.There were significant decreases in glucose (6.7 ± 1.0 mmol/l vs. 6.0 ± 1.0 mmol/l, p = 0.024) before and after the intervention, respectively, and leptin concentrations (32.9 ± 13.3 ng/ml vs. 26.9 ± 12.8 ng/ml, p = 0.027) before and after the intervention, respectively, with thiamine administration. There were no changes with the rest of the measurements.Thiamine administration for 1 month decreased glucose and leptin concentrations in drug-naïve patients with T2DM.
Keywords: Thiamine; Metabolic profile; Cytokines; Inflammatory markers; Type 2 diabetes