Location: Dietary Prevention of Obesity-related Disease Research
2018 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
Subobjective 1.B: Circadian timing of food intake reduces obesity-induced breast cancer development and growth. All mammals exhibit circadian rhythms in daily functions including eating behavior. Disruption of circadian rhythms by eating at a “wrong” time may disrupt energy homeostasis and lead to obesity, a risk factor for breast cancer. We completed an animal study during the year that tested the hypothesis that time-restricted feeding reduces mammary tumorigenesis. We found, in an obese mouse model of breast cancer, that time-restricted feeding to the dark phase (active phase for rodents) of the day, compared to mice with free access to diet for the entire day, reduced diet-induced metabolic disturbance and body fat mass and attenuated mammary tumor development and growth. A manuscript has been submitted.
Subobjective 1.B: High-sucrose diet does not enhance secondary lung tumorigenesis. Energy imbalance through excessive energy intake contributes to obesity. Feeding mice an obesogenic, high-fat diet enhances cancer spread and secondary tumorigenesis in distant organs. We completed an animal study during the year that tested the hypothesis that a high-sucrose diet enhances secondary lung tumorigenesis. We found that a high-sucrose diet, compared to a high-fat diet containing an equal amount of energy from fat, did not increase body fat mass and associated cancer-promoting inflammation nor enhance secondary tumor development and growth in the lungs. A manuscript has been submitted.
Subobjective 1.B: Circadian timing of food intake reduces secondary lung tumorigenesis. All mammals exhibit circadian rhythms in their daily activities including eating behavior. Disruption of circadian rhythms by eating at a “wrong” time may disrupt energy homeostasis and lead to obesity. During the year, we completed an animal study that tested the hypothesis that time-restricted feeding reduces secondary tumorigenesis in the lungs. In an obese mouse model of cancer spread, we found that time-restricted feeding to the dark phase (active phase for rodents) of the day, compared to mice with free access to food for the entire day, reduced body fat mass and secondary cancer formation and growth in the lungs.
Subobjective 1.B: Monocyte chemotactic protein-1 (MCP1) is a pro-inflammatory cytokine. Its expression is elevated in chronic inflammatory diseases including cancer. Adipose tissue produces MCP1 in obesity; elevated expression of MCP1 is observed in both obese subjects and cancer patients. Systematic knockout of MCP1 reduces secondary tumor formation and growth in obese mice. We completed an animal study that tested the hypothesis that adipose tissue-derived MCP1 contributes to obesity-enhanced secondary tumorigenesis. Our preliminary analysis of obtained data showed that knockout of MCP1 from adipose tissue reduced secondary tumor development and growth in the lungs in an adipose-specific MCP1 knockout mouse model.
Subobjective 1.B: Obesity is a risk factor for breast cancer. Adipose tissue produces MCP1. Elevated expression of MCP1 is found in obese breast cancer patients. Concentrations of MCP1 are higher in plasma and mammary tumors in mice fed an obesogenic, high-fat diet than those fed a low-fat control diet. We completed an animal study that tested the hypothesis that adipose-derived MCP1 contributes to high-fat diet-enhanced breast tumorigenesis. Our preliminary analysis of obtained data showed that knockout of MCP1 from adipose tissue reduced mammary tumor growth in an adipose-specific MCP1 knockout mouse model of breast cancer.
Subobjective 3.B: The differential expression of hepatic genes in an advanced-stage hepatic steatosis. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western countries, but the mechanism underlying this relationship remains to be determined. During this year, we completed a study in mice that tested the hypothesis that there is differential expression of hepatic genes in advanced stage hepatic steatosis. We compared differences between diet-induced obesity mice with control mice. We identified highly differentially expressed mRNAs for 79 hepatic genes and their respective signal pathways in this study.
Subobjective 3.B: Butyrate inhibits deoxycholic acid-resistant colonic cell proliferation. Bile acid-resistant colonic cells accumulate DNA mutations and may lead to colon cancer development. Butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits an anticancer potential against colon tumorigenesis. During this year, we established a bile acid-resistant colon cancer cell line and tested the hypothesis that butyrate inhibits the proliferation of bile-acid-resistant colon cancer cells. We found that butyrate inhibited the cell growth of bile-acid-resistant colon cancer cells and also identified its respective molecular pathway.
Subobjective 3.B: A western diet supplemented with calcium and vitamin D regulates gene expression and gut microbiome composition. Adoption of a western diet, low in calcium and vitamin D, may increase the development of obesity, colonic inflammation, and neoplasia. However, the mechanisms underlying this relationship remain to be determined. During this year, we conducted a study in mice that tests the hypothesis that a western diet supplemented with calcium and vitamin D reduces the activation tumor suppressor genes and the abundance of pathogenic bacteria in the colon.
Accomplishments
1. Selenium reduces male breast cancer growth and metastasis. Male breast cancer is an aggressive disease in men. Successes in preventing male breast cancer are far less than that of female breast cancer and more research is needed to identify potential nutritional interventions. ARS researchers at Grand Forks, North Dakota, found that consumption of a selenium-supplemented diet reduces breast tumor growth and reduces cancer spread to the lungs in a male breast cancer mouse model. This protective effect is accompanied by lower concentrations of cancer promoting hormones in blood. These findings indicate the usefulness of selenium in male breast cancer prevention.
2. Consumption of an obesogenic diet alters fatty acid composition of cancer. Obesity is positively associated with an increased risk of cancer and laboratory rodents fed a high-fat diet exhibit enhanced cancer progression. ARS researchers at Grand Forks, North Dakota, found that feeding mice a high-fat diet alters the fatty acid composition of malignant tumors and that the fatty acid composition of a high-fat diet is reflected in the fatty acid composition of tumors. These findings suggest that changes in lipid composition of cancer cells may contribute to the enhanced cancer progression in mice fed a high-fat diet. These data point to the need to investigate how the intake of specific dietary fats can be leveraged to reduce cancer growth and progression.
3. Exercise reduces body fat mass and hormones related to obesity development. A sedentary lifestyle in our modern society contributes greatly to the epidemic of obesity. ARS scientists in Grand Forks, North Dakota, found that voluntary running improves insulin sensitivity and reduces body fat mass and adipose-derived hormones in an obese mouse model and that these improvements are positively associated with the amount of running. These results demonstrate the effectiveness and benefit of exercise in counteracting the detrimental effects of an increase in body fat mass.
4. Parental exercise protects offspring from diet-induced type 2 diabetes. Parental obesity is a risk factor for obesity in children and a sedentary lifestyle further contributes to this risk. ARS scientists at Grand Forks, North Dakota, using a mouse model of obesity, found increased insulin resistance and type 2 diabetes in offspring from obese parents and that exercise protects against parental obesity-induced insulin resistance. These findings show the benefits of parental exercise in reducing the risk of obesity in offspring. These data build a foundation for further investigations into the benefits of parental exercise and diet upon children.
5. Colonic aberrant crypt formation accompanies an increase of pathogenic bacteria. Colonic inflammation is linked to obesity and consumption of a high-fat, western diet. ARS researchers at Grand Forks, North Dakota, along with collaborators, showed in mice that eating an obesity-causing diet not only increases colonic inflammation and cancer development but also accompanies an increase of pathogenic bacteria in the gut. These results demonstrate diet-induced obesity enhances colon cancer development and increases the abundance of pathogenic gut bacteria.
6. Sex and age change selenotranscriptomes in selenium deficiency. Selenium, an essential nutrient, plays a critical role in human health and longevity, but the mechanism underlying this relationship remains to be determined. ARS researchers at Grand Forks, North Dakota, along with collaborators showed in mice that sex and age are two determinant factors for controlling the content of selenium and selenoproteins in different tissues. These data provide insight into the nutritional impact of selenium during the lifespan.
Review Publications
Cao, L., Zeng, H., Wu, R.T., Wu, T., Cheng, W. 2017. Analyses of selenotranscriptomes and selenium concentrations in response to dietary selenium deficiency and age reveal common and distinct patterns by tissue and sex in telomere-dysfunctional mice. Journal of Nutrition. 147(10):1858-1866.
Sundaram, S., Yan, L. 2017. Dietary supplementation with methylseleninic acid inhibits mammary tumorigenesis and metastasis in male MMTV-PyMT mice. Biological Trace Element Research. https://doi.org/10.1007/s12011-017-1188-7.
Zeng, H., Ishaq, S.L., Liu, Z., Bukowski, M.R. 2017. Colonic aberrant crypt formation accompanies an increase of opportunistic pathogenic bacteria in C57BL/6 mice fed a high-fat diet. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2017.11.001.
Yan, L., Sundaram, S. 2017. Voluntary running of defined distances reduces body adiposity and its associated inflammation in C57BL/6 mice fed a high-fat diet. Applied Physiology, Nutrition & Metabolism. http://dx.doi.org/10.1139/apnm-2017-0285.
Sundaram, S., Zacek, P., Bukowski, M.R., Mehus, A.A., Yan, L., Picklo, M.J. 2018. Lipidomic impacts of an obesogenic diet upon Lewis lung carcinoma in mice. Frontiers in Oncology. 8:134. https://doi.org/10.3389/fonc.2018.00134.
Krout, D.P., Roemmich, J.N., Garcia, R.A., Bundy, A.N., Yan, L., Larson, K.J. 2018. Paternal exercise protects mouse offspring from high-fat-diet-induced type 2 diabetes risk by increasing skeletal muscle insulin signaling. Journal of Nutritional Biochemistry. 57:35-44. https://doi.org/10.1016/j.jnutbio.2018.03.013.
