Location: Dietary Prevention of Obesity-related Disease Research
2015 Annual Report
Objectives
Objective 1 - Determine whether obesity-related impairment of selenium-antitumori-genesis in appropriate animal models is due to adiposity, energy imbalance or excess dietary fat.
Sub-objective 1.A: Determine whether reduction of Se-antitumorigenesis by a high-fat diet depends on development of adiposity.
Sub-objective 1.B: Determine the metabolic basis for the effect of obesity in reducing the antitumorigenic effects of dietary Se.
Objective 2 - Examine the effect of high selenium status on the diabetogenic effect of obesity, including effects on glucose metabolism. Also examine the influence of obesity and its metabolic consequences on selenium metabolism.
Sub-objective 2.A: Determine whether high Se status is related to increased risk of type 2 diabetes risk.
Sub-objective 2.B. Determine whether obesity affects Se metabolism.
Objective 3 - Study the influences of selenium and obesity and their interaction on colonic microbiota and its metabolites that may improve health.
Sub-objective 3.A: Determine whether Se promotes a hindgut microbiota that produces metabolites beneficial to the host.
Sub-Objective 3.B: Determine the role of gut microbiota in colonic Se-antitumorigenesis.
Approach
This project builds upon the work of our last project by addressing the interaction of the cancer-preventive effects of dietary selenium (Se) and the cancer-promoting effects of obesity. The anticarcinogenic potential of Se has been established in hundreds of studies with animal/cell models; however, clinical trial results have been inconsistent. It is likely that obesity contributed to that inconsistency. Many subjects in the most recent, and largest, relevant clinical trial were overweight/obese, and obesity is a known cancer risk factor, enhancing each stage of carcinogenesis through mechanisms inhibitable by dietary Se. At the same time, high Se status has been associated with increased risk to type 2 diabetes (T2D). These associations involving risk (rather than causality), raises two questions relevant to understanding the health value of Se-containing foods: Who can benefit from increased Se intake? Who may be at risk from increased Se intake?
This project takes innovative approaches in addressing these questions in the context of the effects of obesity. Objective 1 will determine whether obesity-related impairment of Se-antitumorigenesis is due to adiposity, energy imbalance or excess dietary fat. Objective 2 will examine the effect of high Se status on the diabetogenic effect of obesity, and the influence of the metabolic features of obesity on Se metabolism. Objective 3 will determine the effects of Se and obesity on the colonic microbiota, which has relevance to colon cancer, dietary energy extraction, and immunity. This project comprises the first multidisciplinary studies of obesity-Se interactions relevant to cancer prevention and diabetes. Results will show whether obese individuals are likely to benefit from dietary Se.
Progress Report
Sub-objective 1A:
1) Dietary essential n3 fatty acids and adipokine production. Adipose-produced pro-inflammatory cytokines (adipokines) contribute to obesity. We completed an animal study (including data collection and analysis) that tested the hypothesis that differences in dietary n3 fatty acids affect adipokine production. We found that different types of dietary oils with varying amounts of the n3 fatty acid alpha-linolenic acid did not affect adipokine production. Fish oil, enriched in the long chain n3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA), had anti-inflammatory activity. Status: manuscript preparation.
2) Depletion of adipokine monocyte chemoattractant protein-1 (MCP-1) from the body reduced high-fat diet-enhanced tumorigenesis. Adipose-produced inflammatory cytokines may exert pro-tumorigenic activities. We completed an animal study that tested the hypothesis that MCP-1 contributes to high-fat diet-enhanced tumorigenesis. Our results supported our hypothesis by showing that depletion of MCP-1 from the body reduced high-fat diet-enhanced tumorigenesis. Status: data collection and analysis, manuscript preparation.
Sub-objective 3A:
Selenium increased proportion of beneficial microbacteria in hindgut. Obesity may increase colorectal cancer risk through it actions on hindgut microbacteria. Completed three animal feeding studies that tested the hypothesis that dietary fiber and selenium supplementation attenuate obesity-related increases in colon cancer risk by affecting microbacteria in hindgut. We found that dietary supplementation with selenium increased the proportion of beneficial microbacteria in hindgut that may be associated with a reduction in colon cancer risk; this effect is conditional upon the type of fiber and dietary selenium consumed. Status: data collection and analysis, manuscript preparation.
Sub-objective 3B:
1) High-fat diet increased colon cancer risk via changes of microbacteria population in hindgut. The roles of gut microbacteria in obesity-related colorectal cancer risk remain unexplored. We completed an animal study that tested the hypothesis that the high-fat diet increases colorectal cancer risk by affecting microbacteria in hindgut. We demonstrated that consumption of a high-fat diet increased colorectal tumorigenesis and resulted in proportional changes in hindgut microbacteria in a chemically induced colon cancer model. We are currently analyzing the types of bacteria that were affected. Status: data collection and analysis.
2) Selenium increased short-chain fatty acid production in hindgut. Short-chain fatty acids are suggested to be anti-carcenogenic in colorectal cancer prevention. We conducted a fermentation study using human gut microflora in the presence of variable concentrations of selenium to test for effects on short-chain fatty acid production. Preliminary analysis of data showed that selenium increased short-chain fatty acid production in hindgut. Status: study on-going, data collection and analysis
Accomplishments
1. High-fat diet abrogates anticancer effects of selenium. Obesity is a risk factor to cancer; its interference to selenium, an essential nutrient with demonstrated anti-cancer potentials, remains a concern in cancer prevention research. ARS researchers at Grand Forks, North Dakota, demonstrated that consumption of a high-fat diet reduced anti-cancer activities of selenium in laboratory animals and such a reduction was accompanied by significant increases in concentrations of fat-produced pro-inflammatory hormones in blood. These findings indicate that those fat-produced hormones are, at least partly, responsible for blocking the anticancer activities of selenium. It suggests that excessive production of pro-inflammatory hormones in obesity may attenuate approaches aimed at cancer prevention in clinical practice.
2. Depletion of a fat-produced hormone from the body reduces high-fat diet-enhanced lung cancer development. Obesity is a risk factor to cancer; fat tissue produces pro-inflammatory hormones (for example, plasminogen activator inhibitor-1 (PAI-1)) that may be responsible for such a risk. ARS researchers in Grand Forks, North Dakota, demonstrated that a high-fat diet increased lung cancer development and growth in laboratory animals whereas depletion of PAI-1 from the body reduced both in animals fed a high-fat diet. These findings indicate that pro-inflammatory hormone PAI-1 contributes, at least partly, to the high-fat diet-enhanced cancer development. It suggests that reduction in production of PAI-1 may be an effective approach in cancer prevention, particularly in those who are obese.
3. Reduction of adipose-derived inflammatory proteins blocks cancer-associated bone loss in obese mice. Cancer is accompanied by bone loss, a wasting throughout the course of cancer progression that directly affects quality life of cancer patients; fat tissue produces pro-inflammatory hormones (for example, plasminogen activator inhibitor-1 (PAI-1)) that may contribute to obesity and its related disorders. ARS researchers at Grand Forks, North Dakoda, demonstrated that feeding cancer-bearing mice a high-fat diet resulted in greater bone deterioration whereas depletion of PAI-1 from the body attenuated such bone loss. These findings indicate that fat-produced PAI-1 contributes, at least partly, to cancer-associated bone loss. It suggests that reduction in production of PAI-1 may be an effective approach in prevention of cancer-associated bone wasting and improvement quality life of cancer patients.
4. Soy protein is beneficial but voluntary running is detrimental to bone health. Obesity is associated with bone loss. Healthy dietary practice (for example, consumption of vegetable protein) and physical activity are two approaches that may prevent obesity and its related disorders. ARS researchers in Grand Forks, North Dakota, demonstrated that feeding laboratory animals a high-fat diet resulted in bone loss; consumption of soy protein improved whereas voluntary running deteriorates bone structures in mice fed a high-fat diet. These findings indicate that soy protein is beneficial to bone health. The unexpected unfavorable bone loss by voluntary running suggests that unrestricted exercise may not benefit to bone health. As mouse running models are commonly used in obesity research, determination of an optimal level of running is needed that balances energy intake and expenditure without adversely affect bone health.
5. Selenium inhibits colon cancer growth. Colon cancer is the third leading cancer risk to both men and women in the U.S.; selenium is an essential nutrient with great potential of anti-cancer capabilities. ARS researchers in Grand Forks, North Dakota, and their collaborators identified a key inhibitory pathway (enzyme caspase-3) in laboratory animals and through which selenium exerts it inhibition on colon cancer growth. These findings provide new insights into the mechanisms of selenium against colon cancer and potential of selenium chemoprevention of colorectal cancer.
6. Selenium enhances the inhibitory effects of carboplatin on ovarian cancer. Ovarian cancer is one of the leading causes of cancer-related deaths in women in the U.S. Selenium is an essential nutrient with great anti-cancer potentials; carboplatin is a medicine currently used in clinical practice in treatment of ovarian cancer. ARS researchers in Grand Forks, ND and their collaborators demonstrated that the efficacy of carboplatin in the treatment of high grade ovarian cancer in laboratory animals can be greatly increased by a combination with dietary supplementation of selenium. These findings provide new insights into mechanisms of selenium against ovarian cancer and the potential of selenium as a nutritional adjuvant in ovarian cancer prevention in clinical practice.
Review Publications
Karl, J., Thompson, L.A., Niro, P.J., Margolis, L.M., Mcclung, J.P., Cao, J.J., Whigham Grendell, L.D., Combs, G.F., Young, A.J., Liberman, H.R., Pasiakos, S.M. 2014. Transient decrements in mood during energy deficit are independent of dietary protein-to-carbohydrate ratio. Physiology and Behavior. 139:524–531.
Yan, L., Demars, L.C. 2014. Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice. PLoS One. 9(10):e110869.
Yan, L., Graef, G.L., Nielsen, F.H., Johnson, L.K., Cao, J.J. 2015. Soy protein is beneficial but high-fat diet and voluntary running are detrimental to bone structure in mice. Nutrition Research. 35(6):523-531.
Yan, L., Nielsen, F.H., Sundaram, S., Cao, J.J. 2015. High-fat diet enhances and plasminogen activator inhibitor-1 deficiency attenuates bone loss in mice with Lewis Lung carcinoma. Anticancer Research. 35(7):3839-3847.
Tzeng, T.J., Fu, Y., Zeng, H., Cheng, W. 2014. Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin. PLoS One. 9(7):e101664.
Zeng, H., Wu, M. 2015. The inhibitory efficacy of methylseleninic acid against colon cancer xenografts in C57BL/6 mice. Nutrition and Cancer. 67(5):831-838.
Yan, L., Combs, G.F. 2014. Consumption of a high-fat diet abrogates inhibitory effects of methylseleninic acid on spontaneous metastasis of Lewis lung carcinoma in mice. Carcinogenesis. 35(10):2308-2313.
