Location: Dietary Prevention of Obesity-related Disease Research
2019 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
Overweight and obesity have reached epidemic proportions, affecting 2/3 of Americans. These conditions increase the risk of many chronic diseases including cancer. The estimated health care costs of obesity-related illness are $190 billion or 20% of annual medical spending in the U.S. Obesity is a health and economic burden to the American people.
Project 3062-51000-050-00D has three objectives. Objective 1 was to determine whether obesity-related impairment of selenium-antitumorigenesis in appropriate models is due to adiposity, energy imbalance or excessive dietary fat. Using models for prevention of human breast and lung cancer, ARS scientists found that obesity-enhanced tumor growth and obesity-related impairment of selenium-antitumorigenesis occur with elevated blood levels of cancer promoting cytokines (e.g. monocyte chemotactic protein-1; MCP1) in mice fed an obesogenic diet. Using a mouse model in which MCP1 was removed from fat tissue, we found that deficiency of MCP1 in fat tissue under obese conditions reduces obesity-enhanced breast and lung tumorigenesis. This is direct laboratory evidence that adipose-produced cytokines in the obese environment contribute to cancer development and growth.
Disruption of healthy lifestyles contribute to obesity; the most evidenced are erratic dietary practice and sedentariness. Using models for human metabolic dysfunction, ARS scientists investigated the effect of timing of food intake on obesity development. We found that timing of feeding mice to the active phase of the day, compared with the feeding to both rest and active phases, reduces body fat buildup and fat-produced cytokines. Similarly, exercise prevents fat buildup and cytokine productions. Most strikingly, exercise at the level that does not change body fat reduces blood level of cytokine MCP1. These findings demonstrate the benefits of the restoration of a healthy lifestyle (healthy eating pattern and moderate exercise) in obesity prevention. Furthermore, restoration of a healthy eating pattern by feeding restricted to the active phase of the day reduces obesity-enhanced breast and lung cancer development and growth in models for human cancer prevention. These findings demonstrate that lifestyle changes to reduce obesity may reduce cancer development. Further clinical study is needed to explore these possibilities.
Objective 3 was to study the influences of selenium and obesity and their interaction on colonic microbiota and its metabolites that may improve health.
Subobjective 3B was to determine the role of gut microbiota in colonic selenium anti-tumorigenesis. Using models of human colon cancer, ARS scientists investigated gut bacterial composition and selenium anti-tumorigenesis. We first found that selenomethionine, a natural form of selenium from food, does not reduce colonic aberrant crypts (a type of putative precancerous lesion in the colon), even at levels (four-fold) greater than the daily nutritional requirement. Similarly, selenomethionine does not alter the gut bacterial composition. Second, consumption of a Western diet high in dietary fat changes the gut bacterial composition and increases colonic secondary bile acids, which are risk factors for colon cancer. In addition, a high-fat diet increases bacterial-imbalance, pathogenic bacteria (e. g, Anaeroplasm), and inflammation in the colon. In contrast, bean fiber-fermentation products (e.g., short chain fatty acids) inhibit lipid accumulation and key fat accumulation genes while increasing the expression of energy expenditure genes. Furthermore, short chain fatty acids (e.g., butyrate) inhibit cancerous colonic cells but to a lesser extent in noncancerous colonic cells. These findings help to uncover the underlying molecular mechanisms whereby high dietary fiber intake inhibits fat buildup, increases energy utilization in the body, and reduces colon cancer risk.
Accomplishments
1. Timing of food intake reduces obesity-induced breast cancer development and growth. Humans exhibit daily patterns in physiological and biological functions including the eating/fasting pattern. Alterations of the daily eating pattern by eating at a “wrong” time may disrupt the rhythms of energy metabolism and lead to obesity. Obesity is a risk factor for breast cancer; it is positively associated with the increased death rates of breast cancer in women. Using a mouse model for human breast cancer, ARS researchers in Grand Forks, North Dakota, found that restricted feeding to the active phase of the day, compared to unrestricted feeding to both rest and active phases, reduces body fat mass and breast tumor development and growth in mice. These findings indicate the importance of maintaining a healthy eating pattern in health promotion and breast cancer prevention. Scientists, university faculty members and students, health professionals, and the general public are interested in this work for research in nutrition and disease prevention, public health, and policy making.
2. High-sucrose diet does not enhance lung tumor development and growth. Energy imbalance through excessive caloric intake contributes to obesity. It is well known that high-fat consumption leads to obesity and increases cancer risk in humans. However, studies on high-sugar consumption and cancer risk are relatively limited. ARS scientists in Grand Forks, North Dakota, investigated tumorigenic effects of high-sugar consumption in a mouse model for human lung cancer, a leading cause of cancer-related deaths in both men and women in the U.S. We found that mice on a high-sucrose diet develop less body fat and have fewer lung tumors than mice on a high-fat diet when both diets were compared on an equal amount of calorie basis. These findings indicate that body fat buildup, rather than types of food consumed, plays a key role in cancer promotion. Furthermore, it indicates that maintenance of a healthy dietary practice and healthy body weight are beneficial in health promotion and disease prevention, including prevention of lung cancer.
3. Timing of food intake reduces lung tumor development and growth. Humans exhibit daily patterns in physiological and biological functions including the eating/fasting pattern. Disruption of the daily pattern by eating at a “wrong” time may alter the rhythms of energy metabolism and lead to obesity. ARS researchers in Grand Forks, North Dakota investigated the effects of timing of food intake on obesity-enhanced cancer growth in a mouse model of lung cancer, which is a leading cause of cancer-related deaths in both men and women in the U.S. We found that feeding mice a high-fat diet during the active phase of the day results in less body fat buildup and fewer and smaller lung tumors than feeding mice the same high-fat diet in both active and rest phases of the day. These findings indicate that restricted feeding to the active phase restores the rhythm of energy metabolism by increasing energy expenditure which is responsible for reducing body fat mass and lung tumorigenesis. Furthermore, it indicates that maintaining a healthy eating pattern is beneficial in health promotion and prevention of lung cancer. Scientists, university faculty members and students, health professionals, and the general public are interested in this work for research in nutrition and disease prevention, public health, and policy making.
4. Adipose-produced chemical promotes lung cancer growth. Fat tissue is biologically active in producing chemicals that contribute to chronic diseases, including obesity and cancer. The production is elevated in obesity. Monocyte chemotactic protein-1 (MCP1) is a fat-produced cytokine. Its expression is elevated in both obese and cancer patients. ARS scientists in Grand Forks, North Dakota studied the role of fat-produced MCP1 in lung cancer growth by using a transgenic mouse model in which MCP1 was removed from the fat tissue. We found that deficiency in adipose MCP1 results in fewer and smaller lung tumors in mice. These findings are laboratory evidence that adipose-produced chemical MCP1 directly contributes to lung cancer growth. It strengthens our knowledge of obesity in cancer promotion and emphasizes the importance of obesity prevention for health maintenance and cancer prevention. Scientists, university faculty members and students, health professionals, and the general public are interested in this work for research in nutrition and disease prevention, public health, and policy making.
5. Common bean-derived fiber inhibits adipogenesis. Dietary fiber intake decreases the risk for obesity, colon cancer, and improves immunity by modulating the gut bacterial composition. Beans are among the best choices for fiber-rich foods. The fermentation of bean-derived dietary fiber by gut bacteria is proposed to modulate obesity; however, the molecular mechanism remains to be determined. ARS researchers in Grand Forks, North Dakota, along with collaborators, established a fecal fermentation model in mice to study the biological activity of bean fiber-derived fermentation products and demonstrated that bean fiber-fermentation products inhibit lipid accumulation and key fat accumulation genes while increasing the expression of energy expenditure genes. These findings provide direct molecular evidence on the inhibitory effect of dietary fiber (e.g., bean) on obesity. Scientists, university faculty members and students, health professionals, and the general public are interested in this work for research in nutrition and disease prevention, public health, and policy making.
Review Publications
Yan, L., Sundaram, S. 2018. A high-sucrose diet does not enhance spontaneous metastasis of Lewis lung carcinoma in mice. Nutrition Research. https://doi.org/10.1016/j.nutres.2018.07.001.
Sundaram, S., Yan, L. 2018. Time-restricted feeding mitigates high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice. Nutrition Research. http://doi.org/10.1016/j.nutres.2018.07.014.
Yan, L., Sundaram, S., Mehus, A.A., Picklo, M.J. 2019. Time-restricted feeding attenuates high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma in mice. Anticancer Research. https://doi.org/10.21873/anticanres.13280.
Zeng, H., Shahid, U., Rust, B., Darina, L., Michael, B. 2019. Secondary bile acids and short chain fatty acids in the colon: a focus on colonic microbiome, cell proliferation, inflammation and cancer. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms20051214.
Lu, H., Zeng, H., Zhang, L., Porres, J.M., Cheng, W. 2018. Fecal fermentation products of common bean-derived fiber inhibit C/EBP alpha and PPAR gamma expression and lipid accumulation but stimulate PPAR delta and UCP2 expression in the adipogenesis of 3T3-L1 cells. Journal of Nutritional Biochemistry. 60:9-15. https://doi.org/10.1016/j.jnutbio.2018.06.004.
Zacek, P., Bukowski, M.R., Mehus, A.A., Johnson, L., Zeng, H., Raatz, S.K., Idso, J.P., Picklo, M.J. 2018. Dietary saturated fatty acid type impacts obesity-induced metabolic dysfunction and plasma lipidomic signatures in mice. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2018.10.005.
Zhang, L., Zeng, H., Cheng, W. 2018. Beneficial and paradoxical roles of selenium at nutritional levels of intake in healthspan and longevity. Free Radical Biology and Medicine. https://doi.org/10.1016/j.freeradbiomed.2018.05.067.
Yan, L., Sundaram, S. 2019. Adipose-specific monocyte chemotactic protein-1 deficiency reduces pulmonary metastasis of Lewis lung carcinoma in mice. Anticancer Research. https://doi.org/10.21873/anticanres.13279.
