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The objective of the studies summarized in the present chapter was to determine if intake of walnuts alone or in combination with two or more other phytochemical-rich foods would ameliorate some of the negative metabolic effects developed from consumption of an obesogenic and diabetogenic, Western-style diet. The two studies summarized in this chapter were designed the same using a C57BL/6 J mouse strain as a model to induce obesity using a high fat, sugar, and cholesterol diet, while supplementing the diet with 1.5 servings/day of various nutrient-dense whole foods. In Part 1, walnut alone and walnut plus green tea supplementation were studied. Based on the results of Part 1, Part 2 studied supplementation with four whole foods (walnut, green tea, cherry, and red raspberry) in combination to determine any synergistic effects. In both studies, the combination of two or more test foods appeared to work synergistically to produce further changes in metabolism than compared to walnuts alone. Key findings included attenuation of weight gain, improved circulating serum insulin and cytokine concentrations, improved hepatic levels of protective omega-3 polyunsaturated fatty acids, as well as decreased levels of hepatic proinflammatory fatty acids.
Department of Food Science and Technology, Oregon State University, Corvallis, Oregon, USA
Neil Shay*
Department of Food Science and Technology, Oregon State University, Corvallis, Oregon, USA
*Address all correspondence to: arbecraft@gmail.com and neil.shay@oregonstate.edu
1. Introduction
Consumption of phytochemical-rich foods has been shown to ameliorate some of the negative metabolic effects resulting from consumption of an obesogenic and diabetogenic, Western-style diet. Specifically, green tea contains a series of polyphenols known as catechins, mainly epigallocatechin gallate (EGCG), epicatechin gallate, and gallocatechin gallate [1]. Many of the demonstrated beneficial effects of green tea are attributed to its most abundant catechin, EGCG. One study demonstrated that EGCG treatment suppressed hyperglycemia, proteinuria, and lipid peroxidation. These results also suggested that EGCG may alleviate renal damage caused by abnormal glucose metabolism-associated oxidative stress [2]. Epigallocatechin gallate may also modulate appetite and reduce food intake [3, 4]. Furthermore, green tea catechin consumption has been shown to stimulate hepatic lipid metabolism, through mechanisms such as increased acyl-CoA oxidase and β-oxidation activity [1], as well as stimulate O2 consumption and energy expenditure [5].
These recent studies demonstrating the therapeutic potential of consuming green tea catechins have led to an interest in consuming green tea and green tea extract to remediate metabolic dysfunction. Green tea extract has been reported to stimulate brown adipose tissue thermogenesis along with fat oxidation. It was suggested that green tea’s thermogenic effect may be stimulated through the interaction of its high catechin and caffeine content with sympathetically released noradrenaline [6]. In addition, a meta-analysis conducted in 2015, demonstrated that green tea drinkers have a reduced risk of liver disease including liver steatosis [7]. Epidemiological studies have also suggested that regular consumption of five to six or more cups of green tea per day has pronounced cardiovascular and metabolic health benefits [8].
It is thought that some phytochemical-rich foods may work synergistically to remediate metabolic syndrome when consumed together. Such foods of interest are fruits like red raspberries and cherries along with polyunsaturated fatty acid-rich nuts like walnuts. Cherries are rich in anthocyanins and have been previously observed to improve glucose tolerance and liver lipid accumulation [9], while bioactive polyphenols present in red raspberries may remediate oxidative stress and inflammation [10]. Walnuts have been shown to improve serum lipid levels as well as other cardiovascular parameters [11].
Part 1 of this chapter summarizes research demonstrating the changes to metabolism when consuming an obesigenic high-fat diet supplemented with walnut alone and walnut plus green tea. Some results from Part 1 were previously published, see [12]. Part 2 adds to the results from Part 1 by including a second study where four whole foods (whole cherry and red raspberry along with walnut and green tea) were consumed together to determine their synergistic effect, if any, on remediating metabolic syndrome, again, in the context of a high-fat diet provided to male mice. Both Part 1 and Part 2 studies were designed the same using a C57BL/6 J mouse strain as a model to induce obesity and study the negative metabolic effects that develop when presented with a high-calorie Western-style diet. The hypotheses of both studies were that consumption of the test foods would work to remediate metabolic complications in C57BL/6 J male mice fed a high-fat, high-sucrose, and high-cholesterol diet modeling an obesigenic and diabetogenic Western-style diet.
2. Part 1: effect of walnut and synergistic effect of walnut plus green tea consumption
A rodent model using C57BL/6 J mice fed an obesogenic and diabetogenic high fat diet with added sucrose and cholesterol was designed to evaluate changes in metabolism when supplemented with walnut (W) or walnut plus green tea (W + GT). Walnuts were provided in the diets as ground nuts and the green tea was a dried powder derived from an aqueous extract of dried green tea leaves (Triarco Industries). Diets were formulated to mimic a typical 2000 kcal/day diet with whole walnuts added at an equivalence to 1.5 servings per day and green tea added at 1% (wt:wt), which is consistent with normal human intake levels shown in other rodent studies [13].
The final body weight of the HF diet group provided with walnuts alone did not significantly differ from the HF-fed control. However, the group supplemented with additional green tea (W + GT) was significantly lower than the HF-fed control group (p ≤ 0.05), despite consuming a similar amount of energy (Figure 1A and B). This result is consistent with other findings demonstrating that green tea polyphenols, specifically (−)-epigallocatechin-3-gallate, may have protective effects against obesity by increasing thermogenesis [14, 15, 16, 17].
Figure 1.
Final body weight (A) and energy intake (B) of obese male mice fed a LF or HF diet alone or one that included walnuts alone or walnut plus green tea for 9 weeks. Values are means ± SEMs, n = 8 mice. One-way ANOVA indicated significant differences between diet groups (p ≤ 0.05). Values that do not share a letter differ (p ≤ 0.05).
Metabolomic analysis comparing 594 different hepatic biochemicals detected in liver samples from the mice in each of the diet groups showed several metabolomic changes, including changes in metabolites related to energetics, inflammation, and redox homeostasis. The W + GT supplemented group showed significant increases in S-methylmethionine, when compared to both HF (p ≤ 0.05) and LF (p ≤ 0.05) control groups and the W supplemented group (p ≤ 0.05). S-methylmethionine is a plant-derived metabolite that can be used as a carbon source for bacterial growth [18] which may imply beneficial effects on the host microbiome with supplementation of green tea. Additionally, increases in xanthine metabolites (e.g., paraxanthine, theobromine, theophylline) in the W + GT supplemented group compared to both the HF (p ≤ 0.05) and LF (p ≤ 0.05) control groups and the W supplemented group (p ≤ 0.05) were observed. This result likely reflects naturally occurring xanthine metabolites in GT as well as liver metabolism of increased caffeine intake from GT extract using the cytochrome P450 system.
The omega-3 polyunsaturated fatty acid linolenate was also elevated in the walnut-supplemented diets, which may indicate potential relevance to inflammation. Both the W and W + GT groups showed significant increases in omega-3 polyunsaturated fatty acids, eicosapentaenoate (EPA), and docosapentaenoate (DPA), compared to LF and HF control groups (Figure 2) These results suggest that walnut and green tea supplementation may negatively regulate inflammation. However, increases in docosapentaenoate (DHA) were not significantly altered. These results are consistent with previous studies reporting that increased ALA consumption (herein via walnut) results in little to no change in DHA plasma lipid fractions, as large amounts of ALA are required to endogenously convert to significant levels of DHA [19, 20, 21, 22, 23, 24].
Figure 2.
Box plots demonstrating metabolomic analysis of livers of obese male mice fed a LF or HF diet alone or one that included walnuts alone or walnut plus green tea for 9 weeks.
Supplementation with walnuts alone did not result in significant changes to detected eicosanoids when compared to HF control but did show non-significant trends toward decreased prostaglandin F2alpha (p ≤ 0.10) and 12-hydroxyeicosatetraenoic acid (HETE) such that it was statistically indistinguishable from the LF control group (Figure 3). However, W + GT, compared to HF control, showed a significant decrease in 12-HETE, suggestive of declining inflammation. These results are consistent with serum cytokine concentrations measured of MCP-1, giving additional insight into the secretion and recruitment of activated immune cells in supplemented mice. MCP-1 concentrations were elevated with consumption of a HF diet compared to LF diet (p ≤ 0.05); however, the addition of walnut reduced MCP-1 such that it was intermediate to the LF and HF control groups and statistically indistinguishable from the levels measured in the LF group (data not shown). The addition of green tea to the walnut diet resulted in even further lowering of MCP-1 levels, such that they were statistically equivalent to the LF control group (data not shown). Of note, measured concentrations of TNFα and IL-6 were both measured and saw no significant decreases in HF + W group, but significant elevation of IL-6 was observed in W + GT group (p ≤ 0.05) (data not shown).
Figure 3.
Relative concentration of hepatic proinflammatory fatty acids in obese male mice fed a LF or HF diet alone or one that included walnuts alone or walnut plus green tea for 9 weeks. Values are means ± SEMs, n = 8 mice. One-way ANOVA indicated significant differences between diet groups (p ≤ 0.05). Values that do not share a letter differ (p ≤ 0.05). G, walnuts plus green tea; H, high fat, HETE, hydroxyeicosatetraenoic acid; L, low fat; W, walnuts.
3. Part 2: synergistic effects of cherry, red raspberry, walnut, and green tea (CRWG)
The synergistic effects of consuming whole cherry, raspberry, walnut, and green tea in combination were determined in an independent study. The same rodent model as Part 1, C57Bl/6 J mice consuming an obesogenic and diabetogenic high fat diet with added sucrose and cholesterol, was used to evaluate the synergistic impact of these four foods on metabolism and microbiome of the ceca.
Despite consuming similar amounts of energy, the mice supplemented with HF + CRWG had lower final body weight and change in body weight compared to the HF diet alone (Figure 4A and B). This result is consistent with previous studies on cherry, raspberry, and walnut consumption and reduced weight gain [25, 26, 27, 28, 29, 30]. Additionally, walnut and green tea consumption have been demonstrated to increase resting energy expenditure and thermogenesis, which may be a potential mechanism through which decreased weight gain occurred [6, 31]. Elevation of food efficiency in HF-fed mice was also attenuated with the addition of CRWG to the diet (Figure 4D). This observation suggests that, although the CRWG group ate similar amounts of energy as the HF control, the CRWG group was less efficient in converting the diet to energy compared to the HF-fed control. Again, this result may be due to increased thermogenesis initiated by the green tea and walnut consumption.
Figure 4.
Total body weight (A) net change in body weight, (B) average weekly energy intake, (C) energy efficiency, (D) of male C57BL/6 J mice fed either a low fat (LF) diet, a high fat (HF) diet alone, or HF plus cherry, raspberry, walnut, and green tea (CRWG) after 10 weeks. One-way ANOVA indicated significant differences between diet groups (p ≤ 0.05). Values that do not share a letter differ (p ≤ 0.05).
Fasting blood glucose was measured in weeks 9 and 10. Treatment groups fed HF supplemented with CRWG had a slightly reduced fasting blood glucose, but it was not statistically significant from the HF-fed control group (Figure 5A). In addition, results from an insulin sensitivity test performed in week 10 showed the HF + CRWG treatment group was not statistically different from the HF-fed control group (data not shown). However, serum collected from the mice at necropsy was used to perform an ELISA to quantify circulating serum insulin, which was indeed reduced with HF + CRWG supplementation compared to HF diet alone such that it was statistically indistinguishable from the LF control mice (Figure 5B). Insulin secretion by β-cells increases in response to insulin resistance to moderate elevated blood glucose [32]. Therefore, initial upregulation of β-cell function in response to a HF diet may be regulated with CRWG supplementation as evidenced by reduced serum insulin concentrations compared to HF diet alone. The HOMA-IR and HOMA-%β calculations support this conclusion, as the HF-fed control mice were assessed to have greater development of insulin resistance and heightened β-cell function compared to the HF + CRWG treatment group (Figure 5C and D). Tart cherry extracts have been shown to increase nitric oxide (NO) production in cell and animal models [33, 34]. Similarly, (−)-epicatechin, found in green tea, may help maintain healthy blood pressure ranges when consumed with HF diet via restoration of NO bioavailability [35]. Increased NO production may improve insulin sensitivity and decrease glucose concentrations via NO-mediated increases in blood flow, resulting in more efficient uptake of glucose by skeletal muscle [36, 37, 38]. Therefore, insulin sensitivity and β-cell function may have been improved by CRWG supplementation because of increased NO production from the tart cherry and green tea components of the diet.
Figure 5.
Average fasting blood glucose concentration at week 9 and week 10 (A) serum insulin concentration, (B) homeostasis model assessment of insulin resistance (HOMA-IR), (C) and homeostatic model assessment of β-cell function (HOMA-%β), (D) of male C57BL/6 J mice fed either a low fat (LF) diet, a high fat (HF) diet alone, or HF plus cherry, raspberry, walnut, and green tea (CRWG) after 10 weeks. One-way ANOVA indicated significant differences between diet groups (p ≤ 0.05). Values that do not share a letter differ (p ≤ 0.05).
Liver weight to body weight ratios were measured postmortem (Table 1). Liver weight and liver weight to body weight ratio of HF-fed control group was significantly higher than the LF-fed mice, while liver weight and liver weight to body weight ratio of HF + CRWG treatment group was reduced such that it was statistically indistinguishable from the LF-fed control group. Additionally, stained cross sections of the liver tissue were used to identify liver lipid accumulation in each group. A representative image for each group is shown in Figure 6. White globules are indicative of lipid accumulation, red staining indicates cytosol, and dark red circles are the nuclei. Analysis of lipid percentage within the hepatocytes of each group is shown in Figure 7. Although not significant, HF + CRWG diet did appear to reduce liver lipid accumulation by approximately 30% compared to HF diet alone. Typically, liver weight increases proportionally to body weight gain, thus these results may suggest potential improvement in liver lipid accumulation in the CRWG supplemented mice.
Tissue weights
Diet groups2
LF
HF
HF + CRWG
Liver (g)
1.1 ± 0.08a
2.24 ± 0.25b
1.55 ± 0.16ab
Liver/body weight (g/g, %)
3.37 ± 0.17a
4.89 ± 0.35b
4.17 ± 0.23ab
Table 1.
Organ tissue weights and weights as percentage of final body weight of male C57BL/6 J mice1.
Values are expressed as means ± SEM of each group, values that do not share a letter differ (p ≤ 0.05).
Low fat diet (LF), high fat diet (HF), or HF plus cherry, raspberry, walnut, and green tea (HF + CRWG).
Figure 6.
Hematoxylin–eosin stained liver cross sections of male C57BL/6 J mice fed either a low fat (LF) diet, a high fat (HF) diet alone, or HF plus cherry, raspberry, walnut, and green tea (CRWG) after 10 weeks. Slides were observed under 400x magnification (40x objective) using Nikon Eclipse 50i microscope (Nikon Corporation, Tokyo, Japan) equipped with an Infinity 1-3C camera (Lumenera Corporation, Ottawa, ON, Canada).
Figure 7.
Liver lipid percentage of hematoxylin–eosin-stained liver cross sections of male C57BL/6 J mice fed either a low fat (LF) diet, a high fat (HF) diet alone, or HF plus cherry, raspberry, walnut, and green tea (CRWG) after 10 weeks. One-way ANOVA indicated significant differences between diet groups (p ≤ 0.05). Values that do not share a letter differ (p ≤ 0.05).
The microbiome was quantified from the cecum of each mouse, and variation in the top seven most prolific gut bacteria of each group can be seen in Table 2. Among these bacteria, one group was from the phylum Bacteroidetes and family S24–7. This group of bacteria has previously been demonstrated to triple in number in HF diet fed mice that developed diabetes versus HF diet fed mice that were resistant to diabetes development [39]. Our findings showed that LF-fed animals had significantly higher number of S24–7 bacteria than any of the HF-fed groups, suggesting that these bacteria may be beneficial for maintaining a healthy metabolism. Another study found increased abundance of S24–7 bacteria following remission of colitis, again inferring a positive relationship within the host [40]. This variability between studies may be due to differences in diet formulation, animal model, and microbiome composition analysis and demonstrates the difficulty in reaching a scientific consensus on the beneficial and harmful effects of certain intestinal bacterial on metabolism. The second group of bacteria were from the genus Bacteroides, which have been reported to act commensally in the gut [41]. We observed a marked increase in Bacteroides in the HF + CRWG group such that it was significantly higher than both the LF and HF controls. Added fiber, especially from the raspberry component of the diet, may be a contributing factor to the increased frequency.
Relative frequency of the top seven bacteria in the ceca1.
Values are expressed as means ± SEM of each group, values that do not share a letter differ (p ≤ 0.05).
Some populations sequenced were not complete down to the lowest taxonomic level due to incomplete sequences for these bacteria within the Greengenes database in QIIME2, and thus cannot be differentiated.
Low fat diet (LF), high fat diet (HF), or HF plus cherry, raspberry, walnut, and green tea (HF + CRWG).
One of the bacteria analyzed was from the phylum Verrucomicrobia, specifically Akkermansia muciniphila (A. muciniphila). In the current study, we observed the highest degree of A. muciniphila proliferation in the HF control group, which is inconsistent with previous publications demonstrating its beneficial effect on weight maintenance and metabolism [42, 43]. Furthermore, other reports have showed that polyphenol intake promotes A. muciniphila growth; [44, 45] whereas, in the present study, CRWG fed mice had lower relative abundance than the HF-fed controls. The variability of our result with other literature could have been due to differences in diet administration and/or microbiome analysis.
Four of the analyzed bacteria belonged to the order Clostridiales from the phylum, Firmicutes. Members of this order have been previously associated with obesity; however, there is still vast variability within the lower taxonomic levels [43, 46, 47]. In our findings, we observed an increased shift in the frequency of two of the four Clostridiales bacteria in HF-fed mice. These two bacterial populations belonged to the family Ruminococcaceae. Supplementation with HF + CRWG resulted in reduced frequency of both Ruminococcaceae populations identified when compared to the HF diet alone. Alternatively, we observed a decrease in Clostridiales bacteria belonging to the family Lachnospiraceae in HF-fed mice. Supplementation with HF + CRWG resulted in increased frequency of this population. Increased proliferation of Lachnospiraceae with LF diet as well as polyphenol intake has been previously demonstrated [48]. Thus, our findings may suggest a positive intestinal shift in bacterial strains associated with both lean and obese phenotypes of Clostridiales bacteria with supplementation of CRWG.
Part 1: These data suggest that supplementation with walnut and walnut plus green tea provided at typical dietary levels may influence metabolism when consumed with a high-fat obesogenic Western-style diet. Specifically, supplementation with walnuts plus green tea may act synergistically to further decrease energy efficiency, improve levels of protective omega-3 polyunsaturated fatty acids, as well as decrease levels of hepatic proinflammatory fatty acids and cytokine markers of inflammation than walnuts alone.
Part 2: In obese male mice, modest level of dietary supplementation with cherry, raspberry, walnut, and green tea significantly improved circulating serum insulin concentrations and may protect against insulin resistance and heightened β-cell function. Our data suggests these foods may act synergistically to prevent the onset of metabolic syndrome. There was also profound attenuation of weight gain and food efficiency, suggesting that these four foods may act synergistically to help with weight maintenance. Future research investigating the synergistic effect of these four foods in a human trial would help further elucidate how these metabolic benefits translate to human consumption.
We thank the many laboratory colleagues who helped with animal husbandry and other technical tasks related to this project. Additionally, we are grateful to our colleague Jason Kinchen at University of Virginia for assistance in analysis of metabolomic data. Funding was provided in part by the California Walnut Commission. Green Tea powder was generously provided by Triarco Industries.
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Written By
Alexandra Becraft and Neil Shay
Submitted: 11 August 2022Reviewed: 24 August 2022Published: 28 October 2022
Open access peer-reviewed chapter
