Lemon (Citrus limon) contains various bioactive flavonoids, and prevents obesity and obesity-associated metabolic diseases. We focused on eriocitrin (eriodictyol 7-rutinoside), a powerful antioxidative flavonoid in lemon with lipid-lowering effects in a rat model of high-fat diet. To investigate the mechanism of action of eriocitrin, we conducted feeding experiments on zebrafish with diet-induced obesity. Oral administration of eriocitrin (32 mg/kg/day for 28 days) improved dyslipidaemia and decreased lipid droplets in the liver. DNA microarray analysis revealed that eriocitrin increased mRNA of mitochondrial biogenesis genes, such as mitochondria transcription factor, nuclear respiratory factor 1, cytochrome c oxidase subunit 4, and ATP synthase. In HepG2 cells, eriocitrin also induced the corresponding orthologues, and reduced lipid accumulation under conditions of lipid loading. Eriocitrin increased mitochondrial size and mtDNA content, which resulted in ATP production in HepG2 cells and zebrafish. In summary, dietary eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis.

Summary The aim of this study was to investigate the effect of dietary lemon polyphenols on high-fat diet-induced obesity in mice, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. Mice were divided into three groups and fed either a low fat diet (LF) or a high fat diet (HF) or a high fat diet supplemented with 0.5% w/w lemon polyphenols (LP) extracted from lemon peel for 12 weeks. Body weight gain, fat pad accumulation, the development of hyperlipidemia, hyperglycemia, and insulin resistance were significantly suppressed by lemon polyphenols. Supplementation with lemon polyphenols also significantly up-regulated the mRNA level of the peroxisome proliferator activated receptor-α (PPARα) compared to the LF and HF groups in the liver. Furthermore, the mRNA level of acyl-CoA oxidase (ACO) was up-regulated in the LP group compared to the LF group, but not HF group in the liver, and was also significantly increased in the epididymal white adipose tissue. Thus, feeding with lemon polyphenols suppressed body weight gain and body fat accumulation by increasing peroxisomal β-oxidation through upregulation of the mRNA level of ACO in the liver and white adipose tissue, which was likely mediated via up-regulation of the mRNA levels of PPARα.

SummaryThe concentrations of metabolites in human plasma after ingestion of flavanone glycosides (FG) and their aglycones (FA) in lemon were examined. FG consisting abundantly of eriocitrin were prepared from lemon peel and FA consisting abundantly of eriodictyol were prepared from FG by treatment with ␤-glucosidase. Eriodictyol, homoeriodictyol, and hesperetin in plasma up to 4 h after ingestion of FG with water or FA with water by subjects were not detected in plasma of non-enzyme treatment but in plasma after treatment with ␤-glucronidase and sulfatase. Metabolites in plasma after ingestion of FG and FA in humans were shown to exist as the glucuro-and/or sulfo-conjugates of eriodictyol, homoeriodictyol, and hesperetin. After ingestion of FA, the concentration of metabolites in plasma exhibited a high maximum peak at 1 h. The AUC (area under the blood concentration time curve) level of metabolites of FA was higher than that of FG. FA were suggested to be absorbed faster and in higher amounts than FG. The AUC of metabolites in subject plasma after ingestion of FG with flavonoid-depleted lemon juice was shown to change to a low level in comparison with that of FG with water. The maximum concentration peak of metabolites in plasma was faster at 0.5 h than FA with water but the AUC level was similar to FA with water, when subjects ingested FA with vodka (40% ethanol). The absorption hour of FG and FA was shown to be affected by the co-existing solution. Key Words lemon flavonoid, eriocitrin, plasma, human, ingestion Epidemiological studies indicate a protective relationship between the consumption of citrus fruits or juice and the risk of ischemic stroke and lung cancer (1, 2). Some fundamental studies support a protective effect provided by flavonoid consumption in these diseases (3-6). Citrus fruits contain various kinds of flavonoids such as flavanone glycoside, flavone glycoside, and polymethoxyflavone (3, 4). Flavonoids in lemon fruit (Citrus limon BURM. f.) have been reported to be such flavanone glycosides as eriocitrin (eriodictyol 7-O-␤-rutinoside) and hesperidin (hesperetin 7-O-␤-rutinoside) and such flavone glycosides as diosmin (diosmetin 7-O-␤-rutinoside) and 6,8 C-diglucosyldiosmetin (7-10). Eriocitrin has been reported to be the most abundant flavonoid in lemon fruit and to have the highest antioxidative activity of the flavonoids in citrus fruits in vitro (9,11). It was also shown to have a suppressive effect for oxidative stress in the liver of streptozotocin-induced diabetic rats (12) or exercise-induced rats (13).For the study of functional compounds such as flavonoids in foods, it is important to determine how the compounds in food are metabolized and absorbed in vivo and how the metabolites function in a living system. There have been several human studies that have investigated the metabolism and absorption of flavonoids (14), such as anthocyanin (15, 16), flavonol (17, 18), isoflavone (19), and flavanone (20-22). As for eriocitrin, it was reported for metabolites by human intestinal bacteri...

We have previously demonstrated that coffee and caffeine ameliorated hyperglycemia in spontaneously diabetic KK-A(y) mice. This present study evaluates the antidiabetic effects of coffee and caffeine on high-fat-diet-induced impaired glucose tolerance in C57BL/6J mice. C57BL/6J mice fed a high-fat diet were given regular drinking water (control group), or a 2.5-fold-diluted coffee or caffeine solution (200 mg/L) for 17 weeks. The ingestion of coffee or caffeine improved glucose tolerance, insulin sensitivity, and hyperinsulinemia when compared with mice in the control group. The adipose tissue mRNA levels of inflammatory adipocytokines (MCP-1 and IL-6) and the liver mRNA levels of genes related to fatty acid synthesis were lower in the coffee and caffeine groups than those in the control group. These results suggest that coffee and caffeine exerted an ameliorative effect on high-fat-diet-induced impaired glucose tolerance by improving insulin sensitivity. This effect might be attributable in part to the reduction of inflammatory adipocytokine expression.