Location: Dietary Prevention of Obesity-related Disease Research
2016 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) Supplemental selenium reduces cancer risk. Selenium, an essential mineral to both humans and livestock, is one of a few nutrients that has been extensively studied with demonstrated cancer preventive activities. Completed an extensive, in-depth literature review and wrote a review article that summarized the available evidence of selenium in cancer prevention. This includes evidence from human intervention trials, animal studies of various cancer models and mechanisms behind the selenium anticancer effects. The review concludes that supplemental selenium offers the potential of reducing cancer risk for all selenium-deficient and many non-deficient adults. Status: manuscript in press.
2) Reduction in energy intake reduced high-fat diet-enhanced secondary lung tumorigenesis. Obesity, contributed by an imbalance between energy intake and expenditure, is a risk factor for cancer. Completed an animal study that tested the hypothesis that reduction in energy intake reduces high-fat diet-enhanced lung tumorigenesis. We found that a reduction in food intake by 5% reduced secondary lung tumorigenesis in high-fat diet-fed mice, and the reduction in tumorigenesis was accompanied with reductions in body fat mass and concentrations of proinflammatory cytokines in plasma. Status: manuscript submitted.
3) High-fat diet enhanced mammary tumorigenesis. Obesity contributes to the risk of breast cancer. Completed an animal study that tested the hypothesis that high-fat diet enhances mammary tumorigenesis. Our results supported the hypothesis by demonstrating that high-fat diet enhanced primary and secondary mammary tumorigenesis in mice from a transgenic mammary cancer model, and the enhancement was accompanied with elevation in concentrations of proinflammatory cytokines and angiogenic factors in plasma. Status: data analysis, manuscript preparation.
4) High-sucrose diet did not enhance secondary lung tumorigenesis. Energy imbalance contributes to obesity. Completed an animal study that tested the hypothesis that high-sucrose diet enhances lung tumorigenesis. Our results reject the hypothesis by showing that high-sucrose diet did not enhance secondary lung tumorigenesis compared to a high-fat diet containing an equal amount of energy from dietary fat. These results suggest that energy from different dietary sources may be different in obesogenesis and obesity-related cancer. Status: data collection and analysis.
5) Quantitative running reduces body fat mass in a dose-dependent manner. Sedentary lifestyle contributes to obesity. Completed an animal study that tested the hypothesis that physical exercise reduces body adiposity. We found that regular daily running reduced body fat mass, the reduction was positively correlated with daily running distance and a minimum of four kilometers per day was needed to see the reduction. Status: data collection and analysis.
6) Dietary supplementation with selenium reduced male mammary tumorigenesis. Male breast cancer is a rare but aggressive cancer in men. Successes in prevention and treatment of male breast cancer are far less than that of female breast cancer due to lack of adequate research. Conducting an animal study that tests the hypothesis that dietary supplementation with selenium reduces male breast cancer. Preliminary results from the study showed that selenium reduced primary mammary tumors in male mice. Status: study on-going.
7) Effects of circadian timing of food intake on high-fat diet-enhanced mammary tumorigenesis. All mammals exhibit circadian rhythms in daily functions including eating behavior. Disruption of the circadian rhythm by eating at the “wrong” time may disrupt energy homeostasis and leads to obesity. Initiated an animal study that tests the hypothesis that time-restricted feeding reduces mammary tumorigenesis. Status: study on-going.
8) Irrigation and intercrop treatment improved quinoa seed protein and yield. Quinoa becomes a popular food because of its high nutrition, complete protein, and being gluten free. Its production has gained interest worldwide due to market demand and current limited production. However, there is a lack of information regarding quinoa establishment, production and management. Completed a field study, in collaboration with scientists at Washington State University that investigated effects of different irrigation regimes and intercrop treatments on yield and seed quality of different quinoa varieties. We found that irrigation helped to decrease heat stress in quinoa and allowed higher yields compared with dryland quinoa production in areas with high heat during critical growth stages. Intercrop treatments increased quinoa seed protein without affecting quinoa yield. Status: manuscript in press.
Sub-objective 3A: Determine the roles of dietary fiber and/or in selenium gut bacteria and their metabolite molecules. Gut microbes share a bi-directional relationship with thousands of metabolites in their environment. Completed an animal study that tested the hypothesis that dietary fiber and/or selenium intakes are associated with specific correlation between gut microbial taxa and amino acid metabolites. We found that these specific correlations were clustered prominently among Lactobacilli microbes and metabolites involved in nitrogen metabolism. Status: data collection and analysis, manuscript preparation.
Sub-objective 3B:
1) High-fat diet increases inflammatory molecular signaling and bacteria in the colon. Consumption of an obesogenic, high-fat diet is associated with an increase of inflammation-related colon cancer risk and may alter the gut microbiota. Completed an animal study that tested the hypothesis that the high-fat diet increases inflammatory molecular signaling and bacteria in hindgut. We demonstrated that consumption of a high-fat diet increased colonic inflammation and enhanced beta-catenin signaling accompanied an increase of the Lachnospiraceae/Streptococcaceamodel bacteria. Status: manuscript in press.
2) Butyrate plays differential roles in cellular signaling in cancerous and noncancerous colon cell. Butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits chemoprevention effects in colon. Completed an animal study that tested the hypothesis that butyrate plays differential roles in cancerous and non-cancerous cells through signaling pathways. We demonstrated that butyrate activated the survival signaling in non-cancerous cells and apoptotic signaling in cancerous cells. Status: data collection and analysis, manuscript preparation.
Accomplishments
1. Dysregulation of adipose-produced hormones is a hallmark of obesity. Types and amounts of essential fatty acids in different oils may affect the dysregulation, thus prevent obesity. ARS researchers at Grand Forks, North Dakota, found from a feeding study that fish oil (rich in omega-3 fatty acids) maintained normal levels of insulin, compared to other oils, increased blood level of anti-inflammatory hormone adiponectin and reduced pro-inflammatory hormone leptin. These findings indicate that consumption of fish oil may be beneficial in improving insulin sensitivity by regulating fat tissue hormone production
2. Obesity is a risk factor for cancer; fat tissue produces proinflammatory hormones (for example, monocyte chemotactic protein-1 (MCP-1)) that contribute to the cancer 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 MCP-1 from the body reduced both in animals fed a high-fat diet. These findings indicate that MCP-1 contributes, at least partly, to the high-fat diet-enhanced lung cancer development and growth. It suggests that reduction in MCP-1 may be an effective approach in cancer prevention, particularly in those who are obese.
3. All mammals exhibit circadian rhythms in daily functions including eating behavior. Disruption of the rhythm by eating at the “wrong” time disrupts energy homeostasis and leads to obesity. ARS researchers in Grand Forks, North Dakota showed that feeding mice a high-fat diet 12 hours per day during the dark cycle did not affect energy intake but reduced body fat mass and related obesity-contributing hormones compared to the unrestricted access to the same high-fat diet. These findings indicate that timing of food intake may prevent obesity and abate obesity-related metabolic disturbance.
4. Consumption of a high-fat diet causes an increase in bile acid deoxycholic acid (DCA) in colon lumen and colon cancer risk, while butyrate is an intestinal microbiota metabolite of dietary fiber. ARS researchers in Grand Forks, North Dakota along with collaborators showed that DCA exhibited cancer-promoting effect, whereas butyrate had anticancer effect. These findings provide new insights into the mechanisms of high fiber diets against colon cancer.
5. Nonalcoholic fatty liver disease, a major cause of abnormal liver function, is often associated with obesity. It has been reported that soybean (Glycine max) consumption may reduce liver steatosis. ARS researchers in Grand Forks, North Dakota along with collaborators showed that soy protein greatly reduces inflammation and liver steatosis in obese rats. These findings indicate that an increasing soy protein intake may prevent obesity-related chronic diseases such as fatty liver.
6. Our gastrointestinal tract hosts a complex community of gut bacteria and their metabolites which is critical for human health. ARS researchers in Grand Forks, North Dakota along with collaborators determined and compared a total of 270 low molecular weight molecules in colonic contents and feces. These data demonstrate that fecal samples can be used as non-invasive markers for assessing the health status of the colon.
7. Minerals affect the nutritional, rheological, and safety features of food products. Soybeans represent a good source of minerals. ARS researchers in Grand Forks, North Dakota along with collaborators, demonstrated that within a given soybean genotype, molybdenum and selenium were significantly increased (over 100%) in soybeans grown at higher soil pH with high available molybdenum. Our results indicate that genotype, environmental and the climatic conditions (e.g., air temperature and solar radiation) during the crop seed filling period play critical roles in soybean mineral content.
Review Publications
Sundaram, S., Bukowski, M.R., Lie, W., Picklo, M.J., Yan, L. 2016. High-fat diets containing different amounts of n-3 polyunsaturated acids modulate adipokine production in mice. Lipids. 51(5):571-582.
Yan, L., Sundaram, S. 2016. Monocyte chemotactic protein-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. Oncotarget. 7(17):24792-24799.
Sundaram, S., Yan, L. 2016. Time-restricted feeding reduces adiposity in mice fed a high-fat diet. Nutrition Research. 36(6):603-611.
Zeng, H., Claycombe, K.J., Reindl, K.M. 2015. Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation. Journal of Nutritional Biochemistry. 26:1022-1028.
Zeng, H., Grapov, D., Fahrmann, J., Fiehn, O., Combs, G.F. 2015. Integrating multiple analytical datasets to compare metabolite profiles of mouse colonic-cecal contents and feces. Metabolites. 5:489-501.
Marioli Nobile, C.G., Balzarini, M., Aguate, F.M., Grosso, N., Soldini, D.O., Zeng, H., Cheng, W., Martinez, M. 2016. Climatic thresholds for concentrations of minerals and heavy metals in Argentinean soybeans. Agronomy Journal. 108(2):532-539.
Hakkak, R., Zeng, H., Korourian, S. 2015. Short and long-term soy diet vs. casein protects liver steatosis independent of the arginine content. British Journal of Nutrition [epub ahead of print]. http://online.liebertpub.com/doi/10.1089/jmf.2015.0002.
Walters, H., Carpenter-Boggs, L., Desta, K., Yan, L., Matanguihan, J., Murphy, K. 2016. Effect of irrigation, intercrop and cultivar on agronomic and nutritional characteristics of quinoa. Agroecology and Sustainable Food Systems. 40(8):783-803.
