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ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Diet, Genomics and Immunology Laboratory » Research » Research Project #415229

Research Project: Antioxidant Polyphenols in Impaired Brain and Heart Functions Associated with Obesity and Metabolic Diseases

Location: Diet, Genomics and Immunology Laboratory

2014 Annual Report

1a. Objectives (from AD-416):
This project is based on the premise that many chronic diseases, including type 2 diabetes, cardiovascular diseases (CVD), and Alzheimer’s disease (AD), are strongly influenced by insulin resistance. The hypothesis is that diets that lead to improved insulin sensitivity will decrease risk factors to prevent and alleviate these diseases. We propose to evaluate the following objectives: Objective 1: To determine the role of insulin-potentiating, antioxidant polyphenols on improved brain insulin signaling, cognitive function, and antioxidant status in rats fed a high fat, high fructose diet to induce insulin resistance and obesity. Objective 2: To examine the mechanisms by which antioxidant polyphenols (from cinnamon, tea, coffee, and chocolate) protect neural cells from varying levels of glucose and beta-amyloid toxicity. Objective 3: To determine the roles of these polyphenols on the renin-angiotensin system in the heart and related organs via determining their potential effects on potential mediators such as inflammatory cytokines, nitric oxide synthase, NF-kB, ACE, PPARs, serotonin receptors, and adrenoceptors.

1b. Approach (from AD-416):
The epidemic of insulin resistance associated with obesity, metabolic syndrome, type 2 diabetes, and cardiovascular diseases (CVD) is sweeping both developed and emerging countries. Insulin resistance has been implicated in the pathogenesis of Alzheimer’s disease (AD) and the term “type 3 diabetes” has been used to describe AD. Moreover, obesity has been recognized as an important risk factor for AD. Diets high in fat and (or) fructose contribute prominently to insulin resistance. We have recently shown in animal and human studies that cinnamon polyphenols, and related compounds, not only improve insulin function but also act as antioxidant and anti-inflammatory compounds to counteract the negative effects of insulin resistance and obesity. This proposal is designed to test the hypothesis that insulin-potentiating polyphenols from cinnamon, coffee, tea, and chocolate will alleviate insulin resistance and related diseases including CVD and AD. Insulin resistance and related pathologies will be induced by feeding rats diets high in fat and fructose. The effects of insulin potentiating polyphenols on insulin resistance, brain insulin signaling, AD-like neuropathology, cognitive function, antioxidant status, hypertension, and the renin-angiotensin system will be evaluated. Cell culture studies will also be used to elucidate the mechanisms of actions of polyphenols and related compounds derived from natural products. Verification of our hypothesis will support the use of natural products containing insulin-potentiating polyphenols, and related compounds, as important nutritional components for the prevention or decreasing risk of chronic diseases including diabetes, CVD, and AD.

3. Progress Report:
Disturbances in insulin metabolism are involved in most pathogenic processes that promote the development of chronic diseases including obesity, hypertension, diabetes, and cardiovascular diseases. One of the key components in controlling these diseases is to control the declines in insulin sensitivity associated with eating unhealthy diets. We have demonstrated that increased intake of cinnamon, high in polyphenols, improves whole body glucose, insulin, and fat metabolism in human and animal studies. In addition to improvements in peripheral insulin resistance, cinnamon also has effects on the brain. Changes in behavior, insulin signaling and Alzheimer-associated mRNA expression in the brain were measured in male rats fed a high fat/high fructose diet to induce insulin resistance, with or without cinnamon. There was a decrease in insulin sensitivity associated with the high fat/high fructose diet that was reversed by cinnamon. The cinnamon fed rats were also more active in a Y maze test than rats fed the control and high fat/high fructose diets. The high fat/high fructose diet fed rats showed greater anxiety in an elevated plus maze test that was lessened by feeding cinnamon. The high fat/high fructose diet also led to a down regulation of the mRNA coding for glucose and insulin factors that were reversed by cinnamon suggesting that neuroprotective effects of cinnamon are associated with improved whole body insulin sensitivity and related changes in the brain. We also developed a method that can be used to quantitate five type A proanthocyanidins found in cinnamon plus coumarin, cinnamaldehyde, and cinnamic acid in a single high pressure liquid chromatography profile. We have used this method to evaluate optimal conditions for extraction of Cinnamomum cassia from several regions of the world plus Cinnamomum zeylanicum to determine the cinnamon extracts that contain the highest amounts of type A proanthocyanidins and the mimimum amounts of coumarin. Using the methods that we developed, we purified type A polyphenol components from cinnamon including, cinnamtanin D1, cinnamtannin B1, cassiatannin A, and parameritannin. The most abundant of these is cinnamtannin D1 but all were shown to have significant bioactivity related to insulin potentiation. Cinnamtannin D1 also prevented the aggregation of tau filaments associated with Alzheimers and also the rise in free radicals associated with swelling of brain cells related to stroke. Health benefits of fruits, vegetables, and plants are relatively well documented. However, there is little information regarding the potential beneficial effects of specific phenolic conjugates (e.g., hydroxycinnamic acids, rosmarinic acid, chlorogenic acids, lignan, caffedymine-type, and safflomide-type phenylpropenoic acid amides) on obesity-related inflammation and hypertension. Therefore, in this project, we investigated potential health effects of the phenolic conjugates found in flaxseeds, coffee, cocoa, garlic, green onion, spices, and herbs on inflammation and hypertension. Our data showed that caffedymine-type phenylpropenoic acid amides (e.g., N-caffeoyltyramine, N-caffeoyldopamine, N-coumaroyldopamine, N-feruloyltyramine) and rosmarinic acid suppressed inflammation, as well as platelet activation via inhibiting cyclooxygenase (COX), lipooxygenase (LOX) and related enzymes in vitro and in vivo. Also, we found that safflomide (N-caffeoyltryptamine) with serotonin receptor antagonist and anti-inflammatory activities can up-regulate adiponectin mRNA 1 to 5 fold at concentrations between 1 and 20 uM (P < 0.05). The up-regulation was partially suppressed by treatment with 5-HT2A agonists, suggesting that safflomide may up-regulate adiponectin expression more than by blocking 5-HT2A receptors. Rats supplemented with safflomide (3mg per day) in a high-fat diet were found to have a significant plasma adiponectin increase (more than 30%) with a significant reduction in body weight, visceral fat, and improved insulin resistance compared to non-supplemented rats. These data suggest that safflomide may have beneficial effects on obesity-related conditions such as low adiponectin, visceral obesity, and insulin resistance. The data also suggested a positive relationship between phenolic conjugates and potential health benefits on inflammation and hypertension. We also investigated the potential effects of secoisolariciresinol diglucoside lignan-enriched flaxseed powder (LEFP) on bodyweight, visceral fat, lipid profile, adipokines, and blood pressure using rats divided into four groups (n=8); a normal control diet (NC), a normal control diet with 0.02 % LEFP (NCL), a high-fat and high-fructose diet (HFD), or a high-fat and high-fructose diet with 0.02 % LEFP (HFDL). The average body weight of the HFD group was significantly higher than those of the NC, NCL, and the HFDL groups (P < 0.05). The average weight of kidneys from the HFD and HFDL groups was also higher than those of the NC and NCL groups (P < 0.05), although not significantly different in the weights of livers and hearts. The visceral fat weight was significantly higher in rats in the HFD group, but notably reduced in the HFDL fed rats (P < 0.05). Accordingly, plasma leptin increased significantly in rats fed the HFD diet, higher than rats fed the HFDL diet. Also, the rats in the HFDL group showed improved lipid profile, compared to the rats in the HFD group (P < 0.05). Furthermore, a moderate reduction in blood pressure was observed in the rats of the HFDL group compared to the HFD group (P < 0.05). These data suggest that the LEFP supplementation may provide beneficial effects such as the reduction of bodyweight and fat accumulation, the lipid profile improvement, and blood pressure control. In addition, we investigated potential effects of major chlorogenic acids (CHAs) found in coffee on (ROS)-induced apoptosis. For this study, major CHAs were isolated from three major instant coffee brands, confirmed and quantified using HPLC and NMR spectroscopic methods. In the coffee samples, three major CHAs (3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, 5-O-caffeoylquinic acid) and some minor CHAs (3-O-feruloylquinic acid, 4-O-feruloylquinic acid, 5-O-feruloylquinic acid, 3,5-O-dicaffeoylquinic acid, 3,4-O-dicaffeoylquinic acid, and 4,5-O-dicaffeoylquinic acid) were detected. At the concentration of 10 uM, all three major CHAs inhibited ROS-induced mitochondrial membrane depolarization and caspase-9 activation by 27% (P<0.034) and 50% (P<0.05), respectively. This study suggests that the major CHAs found in coffee are likely to be potent antioxidant compounds able to inhibit ROS-induced apoptosis via suppressing mitochondrial membrane depolarization and caspase-9 activation in the cells. The outcomes of this study suggested that the phenolic conjugates found in flaxseeds, coffee, cocoa, garlic, green onion, spices, and herbs can have positive health effects on obesity-induced inflammation and hypertension. Additionally, safflomide and analogues found in plant sources (e.g., coffee, cocoa, garlic, green onion, spices, and herbs), were investigated in vitro and in vivo and found to lower bodyweight in rats fed a high-fat and high-fructose diet. Rats supplemented with safflomide also showed increased adiponectin with apparent reduction in visceral fat, improved insulin resistance, and blood pressure. Also, three major chlorogenic acids were investigated related to inflammation and RAS, and found to have strong anti-oxidant/anti-inflammatory activities including the inhibition of COX and platelet activation. These results are seen as a basis for the new project plan, Health Promoting Roles of Food Bio-Active Phenolic Compounds on Obesity-Altered Heart, and Kidney Functions and Physiology,1235-51000-057-00D.

4. Accomplishments
1. Novel-type phenolic conjugates (safflomide, veskamide, and analogues) found in coffee, cocoa, tea, garlic, green onion, spices, and herbs were demonstrated to affect several human chronic diseases such as obesity, diabetes, and hypertension. We reported that consumption of safflomide and its analogues found in plant sources resulted in lower bodyweight in rats fed a high-fat and high-fructose diet, thereby alleviating hypertension. Also, the rats fed with safflomide demonstrated increased levels of plasma adiponectin, apparent reduction in visceral fat, better lipid profiles, and improved insulin resistance. Since the increased adiponectin is considered beneficial in several chronic diseases such as obesity, diabetes, and hypertension, safflomide is likely to be a potent compound able to attenuate disease conditions of inflammation in diabetes, obesity, and hypertension by inhibiting COX enzymes and up-regulating adiponectin. Also, new plant phenolic conjugates such as veskamide and amkamide were investigated and reported about their potential effects on COX inhibition and platelet activation with those of safflomide. Additionally, the potential effects of three major chlorogenic acids on inflammation and hypertension including COX inhibition and platelet activation were reported.

Review Publications
Park, J.B. 2014. Flaxseed lignan and visceral obesity: a closer look at its chemical properties, absorption, metabolism, bioavailability and effects on visceral fat, lipid profile, systemic inflammation and hypertension. In: Watson, R.R., Academic Press. Nutrition in the Prevention and Treatment of Abdominal Obesity. 1st edition. San Diego, CA: Academic Press. p317-328.

Anderson, R.A., Qin, B., Canini, F., Poulet, L., Roussel, A.M. 2013. Cinnamon counteracts the negative effects of a high fat/high fructose diet on behavior, brain insulin signaling and Alzheimer-associated changes. PLoS One. 8(12):e83243.

Qin, B., Panickar, K., Anderson, R.A. 2013. Cinnamon polyphenols regulate S100ß, sirtuins, and neuroactive proteins in rat C6 glioma cells. Journal of Nutrition. 30(2):210-217.