Progress 07/01/12 to 06/30/15
Outputs
Target Audience:Target Audience The target audience for the work conducted is primarily food and nutrition scientists working in the area of inflammation and diet. This includes those doing basic research on inflammation from a nutrition perspective. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?Opportunities Brett Healy, a former MS student in my laboratory, performed much of the work described in Experiment 1. The result of this work was translated into a MS degree awarded in 2013. Also, protocols developed from this project were used to help train undergraduates in a laboratory class (NDFS 5240). Sara Kellen, a former student in my laboratory performed much of the work described in Experiment 2. The result of this work was translated into a MS degree awarded in the fall of 2014. How have the results been disseminated to communities of interest?Dissemination The results of these studies have been disseminated as two published MS Theses and as public seminars given as part of Brett Healy's and Sara Kellen's MS defenses. Moreover, results related to these project were presented as posters at Experimental Biology 2013 (2 abstracts) Experimental Biology 2015 and The New York Academy of Sciences Sackler Institute Conference on Probiotics, Prebiotics, the Host Microbiome and the Science of Translation (2014). Both MS dissertations are being converted into manuscripts. What do you plan to do during the next reporting period to accomplish the goals?Plan of Work None, project ended.
Impacts
What was accomplished under these goals?
Accomplishments 1) Major activities completed Animal studies have now been completed to determine connections between obesity, metabolic inflammation, iron metabolism, polyunsaturated fatty acids (PUFA) and colorectal cancer. 2) Specific objectives met The hypothesies that high liver iron stores will increase hepatic hepcidin expression and inflammation-induced increases in hepcidin expression are a primary cause of poor iron status in obesity were tested. Furthermore, an additional animal study was completed to investigate the role of dietary PUFA on inflammation induced colorectal cancer. 3) Significant results achieved Experiment 1) Considering the pathway for the regulation of dietary iron, low iron stores would suggest high hepcidin expression in connection with increased amount of inflammatory cytokines. However, the data shows obesity lowered hepatic hepcidin expression compared to lean mice fed the same amount of dietary iron in spite of increased systemic inflammation. The data was collected after an extended period of time on treatment and may thus show a metabolic adaptation to chronically low iron stores. The data also shows that diet-induced obesity resulted in decreased hepatic iron stores when the mice were fed iron deficient, adequate or excessive diets compared to their lean counterparts fed the same amount of dietary iron, supporting the association shown in many different populations. Taken together, the data suggests inflammatory stress may be less important in long-term iron regulation and liver iron stores may be a more important indicator of hepcidin expression and when obesity decreases liver iron stores, hepcidin expression also decreases. Experiment 2) In our study investigating the role of dietary PUFA concentration and n-6 to n-3 ratio on inflammation induced colorectal cancer, we found that diets with a n-6 to n-3 PUFA ratio of 1:1 promoted significantly larger tumors in animals compared to animals consuming diets with an n-6:n-3 ratio of 20:1. The systemic inflammatory markers IL-10, IL-17, and TNF-α were significantly higher in animals on diets containing 2.5% PUFA compared to the animals on the 10% PUFA diets. In regard to the fatty acid profiles, both the ratio and percent of PUFA influenced distribution of fatty acids in RBC membranes and colon mucosa membranes. The highly unsaturated fatty acids were significantly influenced by the PUFA ratio, while C18:1n-9 and the essential fatty acid, C18:2n-6, were significantly influenced by the percent of PUFA in the diet. Fecal metabolites appeared to be influenced by both the dietary PUFA concentration and n-6:n-3 ratio, as well as the carcinogen treatment. From our results, it suggests both the percent and ratio of PUFA play a role in the etiology of inflammation induced colorectal cancer. Further research is needed to determine how these two factors interact and influence gut inflammation and the subsequent impact on colorectal cancer. 4) Key impacts or other accomplishments realized The results obtained from Experiment 1 have unveiled important questions in regards to obesity, inflammation and iron regulation that further research could help answer. To demonstrate the adaptation to chronic inflammation, further studies could include the same endpoints being measured over the same amount of time but at shorter intervals. This type of study would be a great indicator of any immediate effects and give a broader picture of obesity's influence on iron regulation over time. Further, to examine how inflammation affects iron regulation IL-6 knockout mice could be included in the aforementioned study. Doing so would provide a more mechanistic understanding of obesity-induced inflammation and its effects on iron regulation. Moreover, a human study could be carried out to see if similar results occur. A longitudinal study involving obese and lean participants and measuring amounts of IL-6, circulating hepcidin and iron status, though expensive, would provide excellent insight on how this regulatory process works in humans. In experiment 2, mice were fed diets that differed in PUFA concentration and n-6 to n-3 ratios. Mice fed diets with low concentrations of PUFA at a 1:1 n6 to n3 ratio had the highest number of tumors compared to the other experimental diets. From these results it appears dietary PUFA profile influences the etiology of colorectal cancer, with higher ratios of n-6 to n-3 potentially having a protective effect against colorectal cancer. Although the published research suggests the Western diet, which is characterized by a high PUFA content and high n-6:n-3 ratio would promote colorectal cancer, the results from our study suggest diets with a high n-6:n-3 PUFA ratio have a protective effect against inflammation induced colorectal cancer. It was also interesting to note that mice fed a standard rodent diet, AIN-93G, had elevated serum levels of pro- inflammatory cytokines, higher tumor multiplicity, and tended to have some of the largest tumors.
Publications
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Progress 10/01/13 to 09/30/14
Outputs
Target Audience: Target Audience The target audience for the work conducted is primarily food and nutrition scientists working in the area of inflammation and diet. This includes those doing basic research on inflammation from a nutrition perspective. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? Opportunities Brett Healy, a former MS student in my laboratory, performed much of the work described in Experiment 1. The result of this work was translated into a MS degree awarded in 2013. Also, protocols developed from this project were used to help train undergraduates in a laboratory class (NDFS 5240). Sara Kellen, a former student in my laboratory performed much of the work described in Experiment 2. The result of this work was translated into a MS degree awarded in the fall of 2014. How have the results been disseminated to communities of interest? Dissemination The results of these studies have been disseminated as two published MS Theses and as public seminars given as part of Brett Healy's and Sara Kellen's MS defenses. Moreover, results related to these project were presented as posters at Experimental Biology 2013 (2 abstracts) Experimental Biology 2015 and The New York Academy of Sciences Sackler Institute Conference on Probiotics, Prebiotics, the Host Microbiome and the Science of Translation (2014). Both MS dissertations are being converted into manuscripts that will be submitted in 2015. What do you plan to do during the next reporting period to accomplish the goals? Plan of Work Now that all of the experimental work is complete, the period from January 1st 2015 to June 30th 2015 will be devoted to manuscript preparation and submission.
Impacts
What was accomplished under these goals?
Accomplishments 1) Major activities completed Animal studies have now been completed to determine connections between obesity, metabolic inflammation, iron metabolism, polyunsaturated fatty acids (PUFA) and colorectal cancer. 2) Specific objectives met The hypothesies that high liver iron stores will increase hepatic hepcidin expression and inflammation-induced increases in hepcidin expression are a primary cause of poor iron status in obesity were tested. Furthermore, an additional animal study was completed to investigate the role of dietary PUFA on inflammation induced colorectal cancer. 3) Significant results achieved Experiment 1) Considering the pathway for the regulation of dietary iron, low iron stores would suggest high hepcidin expression in connection with increased amount of inflammatory cytokines. However, the data shows obesity lowered hepatic hepcidin expression compared to lean mice fed the same amount of dietary iron in spite of increased systemic inflammation. The data was collected after an extended period of time on treatment and may thus show a metabolic adaptation to chronically low iron stores. The data also shows that diet-induced obesity resulted in decreased hepatic iron stores when the mice were fed iron deficient, adequate or excessive diets compared to their lean counterparts fed the same amount of dietary iron, supporting the association shown in many different populations. Taken together, the data suggests inflammatory stress may be less important in long-term iron regulation and liver iron stores may be a more important indicator of hepcidin expression and when obesity decreases liver iron stores, hepcidin expression also decreases. Experiment 2) In our study investigating the role of dietary PUFA concentration and n-6 to n-3 ratio on inflammation induced colorectal cancer, we found that diets with a n-6 to n-3 PUFA ratio of 1:1 promoted significantly larger tumors in animals compared to animals consuming diets with an n-6:n-3 ratio of 20:1. The systemic inflammatory markers IL-10, IL-17, and TNF-α were significantly higher in animals on diets containing 2.5% PUFA compared to the animals on the 10% PUFA diets. In regard to the fatty acid profiles, both the ratio and percent of PUFA influenced distribution of fatty acids in RBC membranes and colon mucosa membranes. The highly unsaturated fatty acids were significantly influenced by the PUFA ratio, while C18:1n-9 and the essential fatty acid, C18:2n-6, were significantly influenced by the percent of PUFA in the diet. Fecal metabolites appeared to be influenced by both the dietary PUFA concentration and n-6:n-3 ratio, as well as the carcinogen treatment. From our results, it suggests both the percent and ratio of PUFA play a role in the etiology of inflammation induced colorectal cancer. Further research is needed to determine how these two factors interact and influence gut inflammation and the subsequent impact on colorectal cancer. 4) Key impacts or other accomplishments realized The results obtained from Experiment 1 have unveiled important questions in regards to obesity, inflammation and iron regulation that further research could help answer. To demonstrate the adaptation to chronic inflammation, further studies could include the same endpoints being measured over the same amount of time but at shorter intervals. This type of study would be a great indicator of any immediate effects and give a broader picture of obesity's influence on iron regulation over time. Further, to examine how inflammation affects iron regulation IL-6 knockout mice could be included in the aforementioned study. Doing so would provide a more mechanistic understanding of obesity-induced inflammation and its effects on iron regulation. Moreover, a human study could be carried out to see if similar results occur. A longitudinal study involving obese and lean participants and measuring amounts of IL-6, circulating hepcidin and iron status, though expensive, would provide excellent insight on how this regulatory process works in humans. In experiment 2, mice were fed diets that differed in PUFA concentration and n-6 to n-3 ratios. Mice fed diets with low concentrations of PUFA at a 1:1 n6 to n3 ratio had the highest number of tumors compared to the other experimental diets. From these results it appears dietary PUFA profile influences the etiology of colorectal cancer, with higher ratios of n-6 to n-3 potentially having a protective effect against colorectal cancer. Although the published research suggests the Western diet, which is characterized by a high PUFA content and high n-6:n-3 ratio would promote colorectal cancer, the results from our study suggest diets with a high n-6:n-3 PUFA ratio have a protective effect against inflammation induced colorectal cancer. It was also interesting to note that mice fed a standard rodent diet, AIN-93G, had elevated serum levels of pro- inflammatory cytokines, higher tumor multiplicity, and tended to have some of the largest tumors.
Publications
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Progress 01/01/13 to 09/30/13
Outputs
Target Audience: The target audience for the work conducted in 2013 is primarily food and nutrition scientists working in the area of inflammation and diet. This includes those doing basic research on inflammation from a nutrition perspective. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? Brett Healy, a MS student in my laboratory, performed much of the work described in the Accomplishment section. The result of this work was translated into a MS degree awarded in 2013. Also, protocols developed from this project were used to help train undergraduates in a laboratory class (NDFS 5240). How have the results been disseminated to communities of interest? These results have been disseminated as a published MS Thesis and as a public seminar given as part of Brett Healy’s MS defense. Moreover, results related to this project were presented as posters at Experimental Biology 2013 (2 abstracts) and The New York Academy of Sciences Sackler Institute Conference on Probiotics, Prebiotics, the Host Microbiome and the Science of Translation. Currently, Brett Healy’s MS dissertation is being converted into manuscript that will be submitted to the British Journal of Nutrition. What do you plan to do during the next reporting period to accomplish the goals? To investigate AIM 2: (Inflammatory inducing diets, polyunsaturated fatty acids, metabolic inflammation/cancer and poor iron status). An animal study is currently underway to test the effects of dietary polyunsaturated fatty acids (PUFA) on metabolic inflammation colon cancer and iron status parameters. A new graduate student (Sara Kellen) is conducting this study, which will provide valuable insights into connections between metabolic inflammation, PUFA colon cancer and iron status.
Impacts
What was accomplished under these goals?
1) Major activities completed Animal studies have now been completed to determine connections between obesity, metabolic inflammation, iron metabolism and polyunsaturated fatty acids. 2) Specific objectives met The hypothesies that high liver iron stores will increase hepatic hepcidin expression and inflammation-induced increases in hepcidin expression are a primary cause of poor iron status in obesity were tested. 3) Significant results achieved Considering the pathway for the regulation of dietary iron, low iron stores would suggest high hepcidin expression in connection with increased amount of inflammatory cytokines. However, the data shows obesity lowered hepatic hepcidin expression compared to lean mice fed the same amount of dietary iron in spite of increased systemic inflammation. The data was collected after an extended period of time on treatment and may thus show a metabolic adaptation to chronically low iron stores. The data also shows that diet-induced obesity resulted in decreased hepatic iron stores when the mice were fed iron deficient, adequate or excessive diets compared to their lean counterparts fed the same amount of dietary iron, supporting the association shown in many different populations. Taken together, the data suggests inflammatory stress may be less important in long-term iron regulation and liver iron stores may be a more important indicator of hepcidin expression and when obesity decreases liver iron stores, hepcidin expression also decreases. 4) Key impacts or other accomplishments realized This study has unveiled important questions in regards to obesity, inflammation and iron regulation that further research could help answer. To demonstrate the adaptation to chronic inflammation, further studies could include the same endpoints being measured over the same amount of time but at shorter intervals. This type of study would be a great indicator of any immediate effects and give a broader picture of obesity’s influence on iron regulation over time. Further, to examine how inflammation affects iron regulation IL-6 knockout mice could be included in the aforementioned study. Doing so would provide a more mechanistic understanding of obesity-induced inflammation and its effects on iron regulation. Moreover, a human study could be carried out to see if similar results occur. A longitudinal study involving obese and lean participants and measuring amounts of IL-6, circulating hepcidin and iron status, though expensive, would provide excellent insight on how this regulatory process works in humans.
Publications
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Progress 01/01/12 to 12/31/12
Outputs
OUTPUTS: "Since the start of this project, we demonstrated that obesity reduces liver iron stores independent of dietary iron intake. Based on data published thus far and my increasing visibility in the field, I am hopeful to obtain NIH funding for this line of research in the next year. The overall conclusion of these studies is that obesity increases chronic inflammation through adipocyte hypoxia. Inflammation in turn increases hepcidin production and decreases iron absorption and iron levels in the liver. These studies suggest that obese compared to lean people may be at greater risk for iron deficiency anemia." PARTICIPANTS: "Korry Hintze Brett Healy (graduate student) Robert Ward Collaborator" TARGET AUDIENCES: Local, state, international PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
"Iron is an absolute requirement for life; it is involved in several biochemical reactions ranging from cell respiration to DNA synthesis. The biology of iron is fraught with paradoxes; the same chemical properties that make iron essential can also catalyze the production of free radicals that have been implicated in the etiology of most chronic diseases that plague modern society. Diseases associated with iron toxicity such as hemochromatosis, sickle cell anemia and thalassemia are among the most common inherited diseases worldwide. Conversely, dietary iron deficiency is the most common mineral deficiency affecting an estimated 1.5 billion people worldwide. In the United States, 6.6% of reproductive aged women are iron deficient as well as 11% of children and adolescents. The link between slow cognitive development and iron deficiency makes the potential social and economic impact of iron deficiency great and stresses the need for understanding the mechanisms of iron metabolism and absorption from the diet. Exacerbating the iron deficiency epidemic is obesity. It has long been known that obesity is associated with poor iron status. Studies have demonstrated this association in children and adolescents, adult men and women, and postmenopausal women and as an independent factor contributing to iron deficiency. Obesity is becoming one of the most pressing health issues facing society. Obesity rates are increasing worldwide, the World Health Organization (WHO) estimated recently that, 1.6 billion adults were overweight; and at least 400 million adults were obese. The WHO projects that by 2015, approximately 2.3 billion adults will be overweight and more than 700 million will be obese. For the first time in human history, over-nutrition is emerging as larger problem than under-nutrition. Because a significant proportion of the worlds' population is iron deficient, obese or both; it is absolutely critical to understand the mechanisms underlying obesity induced iron deficiency. The overall impact of these studies is that we now have a better understanding of the relationship between iron deficiency and obesity. The knowledge gained from these studies can help guide iron supplementation interventions, for obese at risk populations."
Publications
- No publications reported this period
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