Dietary Ferulic Acid-Mediated Suppression of Fat Deposits Is Associated with Induction of Beige Adipocyte Formation and Thermogenesis in Inguinal White Adipose Tissue in Mice.

Ferulic acid (FA) is the most abundant phenolic acid in wheat grains. Recent studies have reported that FA intake significantly suppresses body weight gain and accumulation of fat deposits in mice. However, the mechanism by which FA intake affects body fat accumulation remains unclear. We hypothesized that dietary FA induces the formation of beige adipocytes and contributes to the suppression of body fat accumulation. In this study, we investigated whether dietary FA significantly induces beige adipocyte formation and thermogenesis in mice. We found that intake of dietary FA (control diet supplemented with 10 g of FA/kg diet) for 4 wk significantly decreased white adipose tissue (WAT) deposits and body weight gain and significantly induced beige adipocyte formation in inguinal WAT (iWAT) in mice. Furthermore, dietary FA specifically induced thermogenesis in iWAT, dependent upon the significant induction of uncoupling protein 1 expression. These findings suggest that the dietary FA-mediated reduction of WAT accumulation and body weight gain is associated with the induction of beige adipocyte formation and thermogenesis in iWAT, which increases energy expenditure. Our study presents a novel example of dietary FA intake-mediated bioactivity as a functional food-derived factor.

Lactate induces the development of beige adipocytes via an increase in the level of reactive oxygen species.

Recent studies have indicated that lactate acts as a signaling molecule in various tissues. We previously demonstrated that intake of an amino acid mixture combined with exercise synergistically induced beige adipocyte formation in inguinal white adipose tissue (iWAT) in mice. Moreover, plasma lactate levels remained significantly elevated in the amino acid mixture + exercise group even 16 h after exercise, indicating that a lactate-mediated pathway may be involved in the induction of beige adipocyte formation. Against this background, we hypothesized that oral intake of lactate would induce beige adipocyte formation via the lactate signaling pathway without exercise. Furthermore, if oral intake of lactate can produce the same effect as exercise, lactate might be used as a food-derived exercise replacement-factor. Oral intake of lactate (100 mM in drinking water) for 4 weeks significantly induced beige adipocyte formation in iWAT in mice as well as a significant elevation of lactate transporter (monocarboxylic acid transporter 1; MCT1) and lactate dehydrogenase B levels. Administration of lactate to adipocytes significantly increased reactive oxygen species (ROS) and superoxide levels and the NADH/NAD+ ratio. The induction of lactate-mediated uncoupling protein 1 (UCP1) expression and ROS production were significantly suppressed by antioxidant treatment or inhibition of MCT1. However, UCP1 induction was not significantly affected by the inhibition of lactate receptor (hydroxycarboxylic acid receptor 1). These findings suggest that lactate-mediated ROS production induces beige adipocyte formation, and thus oral intake of lactate may confer some benefits of exercise without the need to perform exercise.

Low Dose of Curcumin Combined with Exercise Synergistically Induces Beige Adipocyte Formation in Mice.

Curcumin (Cur) has various biological effects, including anti-obesity and anti-diabetic properties. However, the molecular mechanisms by which Cur exerts these effects remain unclear. In addition, high doses of Cur have been administered in most animal and human trials to date, due mainly to the poor water solubility of native Cur and its low oral bioavailability. In our previous study, we demonstrated that a highly bioavailable Cur formulation (4.5 mg/kg) induces the formation of beige adipocytes in inguinal white adipose tissue (iWAT) in mice. In the present study, to enhance Cur-mediated beige adipocyte formation and reduce the required functional Cur dose, we investigated whether a low dose of Cur combined with exercise synergistically induced beige adipocyte formation. Cur (1.5 mg Cur/kg, daily) combined with exercise for 4 wk significantly induced beige adipocyte formation in iWAT in mice. This effect was associated with the elevation of interleukin-6 level following subsequent Cur administration combined with exercise. These results indicate that exercise combined with Cur synergistically enhances biological activity and reduces the required Cur dose. These findings suggest that Cur could be used as a dietary supplement during exercise to enhance exercise-mediated health benefits.

Anthocyanins and Curcumin: Possible Abilities of Prevention of Diabetes and Obesity via Stimulation of Glucagon-Like Peptide-1 Secretion and Induction of Beige Adipocyte Formation.

There is growing interest in the health benefits of natural plant pigments such as anthocyanins and curcumin. In this review, we introduce how these pigments can contribute to the prevention of diabetes and obesity by stimulating glucagon-like peptide-1 (GLP-1) secretion or inducing beige adipocyte formation. Of the anthocyanins, delphinidin 3-rutinoside (D3R) was shown to increase GLP-1 secretion. Pre-administered D3R-rich blackcurrant extract (BCE) significantly ameliorated glucose tolerance after intraperitoneal glucose injection in rats by stimulating the secretion of GLP-1 and subsequently inducing insulin secretion. D3R did not break down significantly in the gastrointestinal tract for at least 45-60 min after BCE administration. An increase in endogenous GLP-1 secretion induced by food-derived factors may help to reduce the dosages of diabetic medicines and prevent diabetes. Curcumin has various biological functions, including anti-obesity and anti-diabetic properties. However, high doses of curcumin have been administered in most animal and human trials to date, due mainly to the poor solubility of native curcumin in water and its low oral bioavailability. We demonstrated that a highly dispersible and bioavailable curcumin formulation (HC), but not native curcumin, induces the formation of beige adipocytes. Furthermore, co-administration of HC and artepillin C (a characteristic constituent of Brazilian propolis) at lower doses significantly induces beige adipocyte formation in mice, but administration of the same dose of HC or artepillin C alone does not. Our studies demonstrate that curcumin formulations or the co-administration of curcumin with other food-derived factors provide effects that native curcumin alone does not.

Propolis: Chemical Constituents, Plant Origin, and Possible Role in the Prevention and Treatment of Obesity and Diabetes.

Honeybee products are not only beneficial to human health but also important to the food industry. One such product is propolis, a resinous substance that honeybees collect from certain trees and plants and store inside their hives. Although various health benefits of propolis have been reported, the chemical composition of propolis varies greatly depending on the growing region and plant origin. These differences have led to many misconceptions and conflicting research results. In this paper, we review research findings on how the growing region and plant origin of propolis affects its composition. We also discuss trends in research on the antiobesity and antidiabetes effects of propolis as well as recent findings that a major component of Brazilian green propolis modulates adipocyte function. Finally, we discuss challenges to be tackled in future research on the health benefits of propolis and share our perspective on the future of this field.

Combination of Exercise and Intake of Amino Acid Mixture Synergistically Induces Beige Adipocyte Formation in Mice.

Exercise combined with dietary factors may have significant effects on the suppression of body fat accumulation. Several trials suggest that amino acid mixtures containing alanine, arginine, and phenylalanine (ARF) combined with exercise can significantly reduce body fat accumulation in overweight adults and high-fat diet-induced obesity in mice. We therefore hypothesized that combining ARF and exercise would significantly induce beige adipocyte formation and that this would contribute to reducing body weight, whereas administration of ARF or exercise alone would not. Administration of ARF (1 g/kg body weight, daily) combined with exercise (5 sessions per week) for 4 wk significantly induced formation of beige adipocytes in inguinal white adipose tissue (iWAT) in mice, although ARF or exercise alone did not. Metabolomic analysis showed that plasma lactate concentration was significantly elevated in the exercise+ARF group relative to the exercise group. Furthermore, lactate dehydrogenase B, which increases redox stress by converting lactate to pyruvate in iWAT and triggers induction of uncoupling protein 1 expression was significantly upregulated in iWAT of the exercise+ARF group. These findings demonstrate the unique effect of ARF combined with exercise for inducing beige adipocyte formation, which may be associated with the suggested lactate-mediated pathway. Appropriate mixtures of amino acids could be used as a dietary supplement before exercise and contributed to increasing energy expenditures.

Differences in bioavailability and tissue accumulation efficiency of (all-E)- and (Z)-carotenoids: A comparative study.

This study investigated the differences in bioavailability and tissue accumulation efficiency between all-E- and Z-isomer-rich carotenoids after oral administration to rats. Three commercially important carotenoids (lycopene, ß-carotene, and lutein) were chosen for the study. For all carotenoids, feeding with Z-isomer-rich diets increased their concentrations in plasma and tissues at least similar to or more than the all-E-isomer-rich diets, e.g., in rats fed a Z-isomer-rich lycopene, the lycopene concentrations in the plasma and liver after the 2-week administration were respectively 6.2 and 11.6 times higher than those fed an all-E-isomer-rich diet. These results strongly indicate that carotenoid Z-isomers have higher bioavailability and tissue accumulation efficiency than the all-E-isomers. Moreover, diets rich in carotenoid Z-isomers significantly improved the total Z-isomer ratio in plasma and several tissues compared to the all-E-isomers. Since carotenoid Z-isomers potentially have higher antioxidant activity than the all-E-isomers, their accumulation in the body might bring remarkable health benefits.

Artepillin C, a Key Component of Brazilian Propolis, Induces Thermogenesis in Inguinal White Adipose Tissue of Mice through a Creatine-Metabolism-Related Thermogenic Pathway.

Induction of beige adipocytes in white adipose tissue (WAT) is a potential therapeutic target for the treatment of obesity because beige adipocytes release excess energy via uncoupling-protein-1-associated thermogenesis. In this study, we investigated how artepillin C (ArtC) promotes thermogenesis in vivo. We demonstrated that 28 day administration of ArtC (10 mg/kg of body weight) to mice significantly induced thermogenesis in beige adipocytes in inguinal WAT (iWAT) and suppressed reductions in core body temperature induced by cold exposure at 4 °C. Moreover, ArtC-induced thermogenesis in iWAT was significantly inhibited by treatment with a creatine metabolism inhibitor, and ArtC significantly upregulated the expression of creatine-metabolism-related enzymes in the thermogenic pathway. These results indicate that ArtC induces thermogenesis in beige adipocytes in iWAT, and the observed ArtC-induced thermogenesis is associated with the creatine-metabolism-related thermogenic pathway, which is characteristically observed in beige adipocytes.

Z-Isomers of lycopene exhibit greater liver accumulation than the all-E-isomer in mice.

The effect of oral administration of all-E-isomer-rich and Z-isomer-rich lycopene on liver accumulation in mice was investigated. When a diet rich in the Z-isomers was administered for 4 weeks, the total lycopene concentration in the liver was more than 3 times higher than that of all-E-isomer administration. This result clearly indicates that lycopene Z-isomers show greater bioavailability and/or liver accumulation than the all-E-isomer in mice.

Co-Administration of Curcumin and Artepillin C Induces Development of Brown-Like Adipocytes in Association with Local Norepinephrine Production by Alternatively Activated Macrophages in Mice.

Classical brown adipocytes, characterized by interscapular depots, have multilocular fat depots and are known to release excess energy. Recent studies have shown that induction of brown-like adipocytes, also referred to as beige or brite cells, in white adipose tissue (WAT) results in the release of excess energy through mitochondrial heat production via uncoupling protein 1. This has potential a therapeutic strategy for obesity and related diseases as well as classical brown adipocytes. In our previous studies, we found that artepillin C (ArtC, 10 mg/kg body weight), a characteristic constituent of Brazilian propolis, significantly induced the development of brown-like adipocytes in inguinal WAT (iWAT) of mice. Furthermore, we recently demonstrated that curcumin (Cur, 4.5 mg/kg) also significantly induced the development of brown-like adipocytes in mice. The combined administration of several food-derived factors can enhance their bioactivity and reduce their required functional doses. In this study, we showed that co-administration of Cur and ArtC at lower doses (Cur, 1.5 mg/kg; ArtC, 5 mg/kg) additively induce brown-like adipocyte development in mouse iWAT. Moreover, this induction is associated with the localized production of norepinephrine following accumulation of alternatively activated macrophages in iWAT. These findings suggest that co-administration of Cur and ArtC is significantly effective to reduce the dose and enhance the formation of brown-like adipocyte via a unique molecular mechanism.

α-Monoglucosyl Hesperidin but Not Hesperidin Induces Brown-Like Adipocyte Formation and Suppresses White Adipose Tissue Accumulation in Mice.

Hesperidin (HES) is a flavanone glycoside found in citrus peel that contributes to its bitter taste. It has low water solubility and poor oral bioavailability. To improve its solubility and bioavailability, α-monoglucosyl hesperidin (αGH) has been synthesized from HES by transglucosylation using cyclodextrin glucanotransferase. Several reports indicate that αGH significantly decreases body fat, but the underlying molecular mechanism remains unclear. We hypothesized that the antiobesity effects of αGH occur through the induced formation of brown-like adipocytes. The present study verified that dietary αGH induces brown-like adipocytes to form in mouse inguinal white adipose tissue (iWAT), thereby significantly decreasing the weight of white adipose tissue (WAT). Furthermore, dietary αGH significantly induced thermogenesis in iWAT. Dietary αGH also significantly suppressed high-fat-diet-induced WAT accumulation in mice, which may be mediated by brown-like adipocyte formation. These results indicate that dietary αGH induces increased energy expenditure by stimulating the formation of brown-like adipocytes.

Blackcurrant Extract Ameliorates Hyperglycemia in Type 2 Diabetic Mice in Association with Increased Basal Secretion of Glucagon-Like Peptide-1 and Activation of AMP-Activated Protein Kinase.

Blackcurrants are berries that contain high levels of anthocyanins, particularly delphinidin 3-rutinoside (D3R). Several studies have reported that the consumption of blackcurrant extract (BCE) lowers blood glucose levels and ameliorates glucose tolerance, but the mechanism underlying this effect remains unclear. Glucagon-like peptide-1 (GLP-1) and AMP-activated protein kinase (AMPK) are considered one of the most significant molecular targets for the prevention and treatment of type 2 diabetes. In this study, we showed that dietary BCE significantly reduced blood glucose concentration and improved glucose tolerance in type 2 diabetic mice (KK-Ay). The basal GLP-1 concentration in plasma was significantly increased in the BCE group accompanied by upregulation of prohormone convertase 1/3 (PC1/3), the enzyme that processes intestinal proglucagon. Moreover, the level of phospho-AMPKα protein in skeletal muscle was significantly increased in the BCE group, and this was increase accompanied by significant upregulation of glucose transporter 4 (Glut4) proteins in the plasma membrane of BCE group. In conclusion, dietary BCE significantly reduced blood glucose concentration and improved glucose tolerance in association with increased basal GLP-1 concentration in plasma, upregulation of PC1/3 expression, and translocation of Glut4 to the plasma membrane of skeletal muscle in type 2 diabetic mice; furthermore, these effects were accompanied by activation of AMPK. Our findings demonstrated that D3R-rich BCE may help prevent diabetes and allow the dosages of diabetes drugs to be reduced.

Highly Dispersible and Bioavailable Curcumin but not Native Curcumin Induces Brown-Like Adipocyte Formation in Mice.

SCOPE: The induction of brown-like adipocytes in white adipose tissue (WAT) is a potential therapeutic target for the treatment of obesity and metabolic disorders via the ability of these cells to release excess energy as heat in association with uncoupling protein 1. Some experimental trials suggest that curcumin (a yellow pigment from turmeric) has a suppressive effect on the accumulation of body fat. However, there is little evidence to show that curcumin induces the formation of brown-like adipocytes and the molecular mechanisms involved remain elusive. In addition, in most experimental trials, high doses of curcumin are administered. METHODS AND RESULTS: Highly dispersible and bioavailable curcumin (HC, i.e., 4.5 mg native curcumin kg-1 ) but not the same dose of native curcumin induces the formation of brown-like adipocytes in mouse inguinal WAT. Moreover, the formation of brown-like adipocytes induced by HC in inguinal WAT may be mediated by the production of local norepinephrine from accumulated alternatively activated macrophages. CONCLUSION: These novel findings suggest that curcumin increases energy expenditure by inducing the formation of brown-like adipocytes via a unique molecular mechanism. Importantly, they show that HC has significant bioactive effects in vivo at lower doses of curcumin.

Curcumin as a functional food-derived factor: degradation products, metabolites, bioactivity, and future perspectives.

Curcumin is a polyphenol found in turmeric (Curcuma longa), used as a spice, in food coloring, and as a traditional herbal medicine. It has been shown that curcumin has health benefits such as antioxidant, anti-inflammatory, and anticancer properties, improvement of brain function, and control of obesity and diabetes. However, native curcumin easily degrades and has low oral bioavailability, and a recent report has expressed doubt about curcumin's various effects. To overcome its low bioavailability, various curcumin formulations with enhanced bioavailability are currently being developed. This review discusses the chemistry, metabolism, and absorption of curcumin, to which various reported health benefits have been ascribed, as well as curcumin's degradation products and metabolites and their possible functions. Moreover, the research trend towards the obesity- and diabetes-preventing/suppressing aspects of curcumin and the latest case studies on highly water-dispersible and bioavailable curcumin formulations will be discussed. We summarize the challenges concerning research on curcumin's health benefits as follows: clarifying the relationship between curcumin's health benefits and the formation of curcumin-derived oxidation and degradation products and metabolites, determining whether curcumin itself or other components in turmeric are responsible for its effects, and conducting further human trials in which multiple research groups employ the same samples and conditions. High-bioavailability formulations would be useful in such future studies.

Curcumin ß-D-Glucuronide Plays an Important Role to Keep High Levels of Free-Form Curcumin in the Blood.

Curcumin, a polyphenol derived from the rhizome of the naturally occurring plant Curcuma longa, has various pharmacological actions such as antioxidant and anti-inflammatory effects. In this paper, we evaluated the role of its internal metabolite, curcumin ß-D-glucuronide (curcumin monoglucuronide, CMG), by investigating curcumin kinetics and metabolism in the blood. Firstly, we orally administered highly bioavailable curcumin to rats to elucidate its kinetics, and observed not only the free-form of curcumin, but also, curcumin in a conjugated form, within the portal vein. We confirmed that curcumin is conjugated when it passes through the intestinal wall. CMG, one of the metabolites, was then orally administered to rats. Despite its high aqueous solubility compared to free-form curcumin, it was not well absorbed. In addition, CMG was injected intravenously into rats in order to assess its metabolic behavior in the blood. Interestingly, high levels of free-form curcumin, thought to be sufficiently high to be pharmacologically active, were observed. The in vivo antitumor effects of CMG following intravenous injection were then evaluated in tumor-bearing mice with the HCT116 human colon cancer cell line. The tumor volume within the CMG group was significantly less than that of the control group. Moreover, there was no significant loss of body weight in the CMG group compared to the control group. These results suggest that CMG could be used as an anticancer agent without the serious side effects that most anticancer agents have.

Delphinidin 3-rutinoside-rich blackcurrant extract ameliorates glucose tolerance by increasing the release of glucagon-like peptide-1 secretion.

Glucagon-like peptide-1 (GLP-1) is an incretin that is secreted from enteroendocrine L-cells. Dietary factor-stimulation of endogenous GLP-1 is a promising strategy for increasing the action of GLP-1. Recent studies have shown that berries rich in anthocyanins improve insulin sensitivity and reduce the risk of type 2 diabetes. Our previous study found that the anthocyanin delphinidin 3-rutinoside (D3R) significantly increases GLP-1 secretion in GLUTag cells (enteroendocrine L cell line). Blackcurrants are berries that contain high levels of anthocyanins, particularly D3R. Pre-administered blackcurrant extract (BCE) 5 mg/kg body weight (1 mg D3R/kg) significantly ameliorated glucose tolerance after intraperitoneal glucose injection in rats by stimulating the secretion of GLP-1 and subsequently inducing insulin secretion. D3R did not break down significantly in the gastrointestinal tract for at least 45-60 min after BCE was administered, suggesting that BCE-induced GLP-1 secretion is mainly mediated by D3R and not its degradation products. These findings demonstrate the novel biological function of D3R-rich BCE as a GLP-1 secretagogue. An increase in endogenous GLP-1 secretion induced by BCE may help to reduce the dosages of diabetic medicines and prevent diabetes.

Low-molecular fraction of wheat protein hydrolysate stimulates glucagon-like peptide-1 secretion in an enteroendocrine L cell line and improves glucose tolerance in rats.

The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted by enteroendocrine L cells. Stimulating endogenous GLP-1 secretion by dietary factors is a promising strategy to increase GLP-1 action. Several studies have examined the specific physiological function of wheat protein hydrolysate. Some reports suggested that intake of wheat protein ameliorates hyperglycemia. We hypothesized that wheat protein hydrolysate reduces blood glucose concentration via stimulation of GLP-1 secretion. In this study, we investigated whether wheat protein hydrolysate stimulates GLP-1 secretion and its molecular mechanism in an enteroendocrine L cell line (GLUTag cells), and we examined the effect on glucose tolerance via stimulation of GLP-1 secretion followed by induction of insulin secretion in rats. The low-molecular fraction of wheat protein hydrolysate (LWP) significantly increased GLP-1 secretion, whereas the high-molecular fraction did not. This increase was found to involve activation of the Ca2+/calmodulin-dependent kinase II pathway mediated by G protein-coupled receptor family C group 6 subtype A. Moreover, preadministration of LWP ameliorated hyperglycemia via the stimulation of GLP-1 secretion followed by induction of insulin secretion in rats. Furthermore, this LWP-induced glucose-lowering effect was significantly attenuated by the administration of a GLP-1 receptor antagonist. These results demonstrate that LWP significantly increased GLP-1 secretion through activation of the Ca2+/calmodulin-dependent kinase II pathway mediated by G protein-coupled receptor family C group 6 subtype A in GLUTag cells. Moreover, preadministration of LWP ameliorated hyperglycemia via the stimulation of GLP-1 secretion followed by induction of insulin secretion in rats.

Curcumin improves glucose tolerance via stimulation of glucagon-like peptide-1 secretion.

SCOPE: Glucagon-like peptide-1 (GLP-1) is a type of incretin secreted from enteroendocrine L-cells. Our previous studies demonstrated that curcumin (a yellow pigment of turmeric) significantly increases the secretion of GLP-1 in enteroendocrine L cell line (GLUTag cells). However, it is not clear whether its action in vivo directly enhances GLP-1 secretion, which then leads to a reduction in blood glucose levels via the stimulation of insulin secretion. In addition, the molecular target of curcumin-induced GLP-1 secretion has not been clarified. METHODS AND RESULTS: Glucose tolerance was significantly improved in rats after pre-administered curcumin (1.5 mg/kg) followed by intraperitoneal glucose injections via the stimulation of GLP-1 secretion and the induction of insulin secretion. In GLUTag cells, curcumin-induced GLP-1 secretion was associated with G protein-coupled receptor (GPR) 40/120. Furthermore, the glucose-lowering effect induced by curcumin was significantly reduced after the administration of a GPR40/120 antagonist in rats. CONCLUSION: These findings demonstrate the biological function of curcumin as a GLP-1 secretagogue and the possible molecular target that mediates GLP-1 secretion. Increases in the secretion of endogenous GLP-1 induced by curcumin may allow the dosages of other diabetic medicines to be reduced and aid in the prevention of diabetes.