Location: Dietary Prevention of Obesity-related Disease Research
2017 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 male breast cancer. Male breast cancer makes about 1% of all breast cancers, but it is an aggressive disease in men. Successes in prevention of male breast cancer are far less than that of female breast cancer and more research is needed to identify potential nutritional interventions. Selenium is an essential nutrient with demonstrated anticancer activities. We completed an animal study that tested the hypothesis that selenium reduces male breast cancer. We found that dietary supplementation of selenium, in the form of methylseleninic acid, reduced mammary tumor development and growth in male mice. This reduction was accompanied with decreases in cancer-promoting and vascular forming hormones in blood and mammary tumors. Status: manuscript submitted.
2) Physical exercise reduces body fat mass and fat tissue-produced hormones. Sedentary life contributes to obesity. Physical exercise, by increasing energy expenditure, can reduce the risk of obesity. We completed an animal study that tested the hypothesis that running reduces body adiposity. We found, in a mouse voluntary running model, that running reduced body fat mass and fat tissue-produced hormones in a dose-dependent manner and that the reduction correlated positively with daily running distance. Furthermore, we found that running four kilometers per day was the minimal needed to achieve reductions in both body adiposity and fat tissue-produced hormones in this running model. Status: manuscript submitted.
3) 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 the circadian rhythm by eating at the “wrong” time may disrupt energy homeostasis and leads to obesity, a risk factor for breast cancer. We completed an animal study that tested the hypothesis that time-restricted feeding reduces mammary tumorigenesis. We found that time-restricted feeding (12-hours during the active phase of the day) reduced body fat mass and mammary tumor development and growth in mice fed a high-fat diet. Status: data analysis, manuscript preparation.
4) High-sucrose diet does not enhance secondary lung tumorigenesis. Energy imbalance, by excessive caloric intake, contributes to obesity. Feeding mice a high-fat diet enhances secondary tumorigenesis in the lungs. We completed an animal study that tested the hypothesis that high-sucrose diet enhances secondary lung tumorigenesis. We found that the high-sucrose diet, compared to a high-fat diet containing an equal amount of calories from fat, did not increase body fat mass and nor enhanced secondary tumor development and growth in the lungs. Status: data analysis, manuscript preparation.
5) Circadian timing of food intake reduces secondary lung tumorigenesis. All mammals exhibit circadian rhythms in their daily activities including eating behavior. Disruption of the circadian rhythm by eating at the “wrong” time may disrupt energy homeostasis and leads to obesity. For example, eating in both the rest and the active phases of the day may contribute to obesity in humans. We completed an animal study that tested the hypothesis that time-restricted feeding reduces secondary tumorigenesis in the lungs. We found that time-restricted feeding for 12 hours during the active phase of the day reduced secondary cancer formation and growth in the lungs. Status: data collection and analysis.
6) Adipose-specific knockout of monocyte chemotactic protein-1 (MCP1) and secondary tumorigenesis in the lungs. MCP1 is an inflammatory cytokine. Its expression is elevated in chronic inflammatory diseases including cancer. Adipose tissue produces MCP1 in obesity and elevated expression of MCP1 is observed in both obese subjects and cancer patients. Systematic knockout of MCP1 reduces secondary tumor formation and growth in mice fed an obesogenic diet. We initiated an animal study that tests the hypothesis that adipose tissue-produced MCP1 contributes to high-fat diet-enhanced secondary tumorigenesis in the lungs. Status: study on-going.
7) Knockout of adipose-produced monocyte chemotactic protein-1 (MCP1) and breast tumorigenesis. Adipose tissue produces MCP1 and elevated expression of MCP1 is reported in obese breast cancer patients. Concentrations of MCP1 are higher in plasma and mammary tumors in mice fed a high-fat diet than those fed a low-fat diet. We initiated an animal study aimed at testing the hypothesis that adipose-produced MCP1 contributes to high-fat diet-enhanced breast tumorigenesis. Status: study on-going.
Sub-objective 3B: 1) Aberrant crypt formation accompanies an increase of opportunistic pathogenic bacteria in the inflammatory hindgut of C57BL/6 mice fed a high-fat diet. The increasing worldwide incidence of colon cancer is linked to obesity and consumption of a high-fat western diet, but the mechanism underlying this relationship remains to be determined. We completed an animal study that tested the hypothesis that a high-fat diet promotes aberrant crypt (AC) formation associated with a dysbiosis in the hindgut. We demonstrated that a high-fat diet promoted AC formation concurrent with an increase of opportunistic pathogenic bacteria in the inflammatory hindgut. Status: manuscript submitted.
2) Butyrate inhibits the cell growth of bile-acid-resistant colon cancer cells. A subpopulation of colonic epithelial cells resistant to bile acids is reported to be mutated cells, and leads to a high colon cancer risk. In contrast, butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits an anticancer potential against colon tumorigenesis. We initiated a cellular study that tested the hypothesis that butyrate effectively inhibits bile-acid-resistant colon cancer cells. We established a bile-acid-resistant colon cancer cell line, and demonstrated that butyrate effectively inhibited the cell proliferation of bile-acid-resistant colon cancer cells. Status: data collection and analysis, study on-going.
3) A western diet supplemented with calcium and vitamin D regulates oncogene / tumor suppressor gene expression and changes gut microbiome composition. Adoption of a western diet, low in calcium and vitamin D, is a global problem leading to increased obesity and colonic inflammation and neoplasia, but the mechanism underlying this relationship remains to be determined. We completed an animal study that tested the hypothesis that a western diet supplemented with calcium and vitamin D reduces tumor suppressor gene activation. Moreover, we are examining the change of gut microbiome composition associated with this process. Status: data collection and analysis, study on-going.
4) Time-restricted feeding alters wingless signaling, farnesoid X receptor signaling and gut microbiome composition. The high-fat and high-sugar Western diet is associated with obesity, which results in chronic inflammation and an unhealthy gut microbiome. Time-restricted feeding is reported to prevent metabolic diseases in mice fed a high-fat diet. We initiated an animal study that tested the hypothesis that in the hind gut, time-restricted feeding increases a healthy fecal bile acid profile, enhances intestinal farnesoid X receptor signaling, and subsequently reduces the activation of wingless signaling when compared with that of the unrestricted Western diet consumption. Moreover, we are examining the extent to which obesity associates with a dysbiosis in the hindgut. Status: data collection and analysis, study on-going.
Accomplishments
1. Obesity enhances breast cancer growth and increases fat tissue-produced hormones. Obesity is a risk factor for breast cancer. Fat tissue functions as an endocrine organ and produces hormones in obesity. ARS researchers at Grand Forks, North Dakota, found that eating a high-fat diet increases body fat mass, breast tumor growth and fat tissue-produced hormones in blood in a mouse model of breast cancer. The outcome of the study indicates that fat tissue-produced hormones contribute, at least partly, to the breast cancer growth. It suggests that a reduction in body fat mass, by changing our dietary practice, may be an effective approach in reducing the obesity-associated breast cancer risk.
2. Restriction in energy intake reduces obesity-enhanced cancer spread to the lungs. Cancer spread (i.e. metastasis) is a direct cause of cancer-related deaths in patients. ARS researchers at Grand Forks, North Dakota, found that obesity enhances cancer spread to the lungs and that a reduction in food intake by 5% reduces body fat mass and cancer spread. These findings indicate the usefulness of maintaining a healthy body weight to reduce the risk of obesity-related cancer.
3. Irrigation and intercrop treatment improve quinoa seed protein and yield. Quinoa is 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. ARS researchers at Grand Forks, North Dakota, in collaboration with scientists at Washington State University found that irrigation helps to decrease heat stress in quinoa and allows higher yields compared to dryland quinoa production. Intercrop treatment increases quinoa seed protein without affecting quinoa yield. These findings provide needed data for increasing quinoa production, particularly in dryland areas, to meet worldwide market demand for quinoa.
4. Knockout of a fat tissue-produced hormone reduces cancer-mediated bone loss. Cancer progression is accompanied with bone loss. ARS researchers at Grand Forks, North Dakota, found that obesity enhances cancer-mediated bone loss. Knockout of a fat tissue-produced hormone [monocyte chemotactic protein-1 (MCP1)] in mice blocks this enhanced bone loss. These findings indicate that MCP1 contributes, at least partly, to cancer-related bone loss. It suggests that a reduction in MCP1, by reducing body fat mass, may be an effective approach in prevention of cancer and cancer-associated bone loss.
5. Colonic inflammation accompanies an increase of unhealthy gut microbiota. Consumption of an obesogenic diet is positively associated with colon cancer risk and an unhealthy gut microbiome. ARS researchers at Grand Forks, North Dakota along with collaborators showed that long-term consumption of an obesogenic diet not only increases inflammatory status but also accompanies an increase of cancer gene expression and pathogenic bacteria in the hind gut of experimental mice. These data demonstrate that fecal samples may be used for assessing the health status of the colon.
6. Trifluoroselenomethionine (TFSeM) inhibits colon cancer cell growth. Chemical forms of selenium play a critical role in inhibiting colon cancer cell growth. ARS researchers at Grand Forks, North Dakota along with collaborators newly synthesized a selenium compound (TFSe) that exhibits a strong potential against colon cancer cell growth. This finding represents the latest research development of the anticancer chemical selenium form, and provides new opportunities for future selenium’s anticancer studies.
7. Loss of selenium-binding protein 1 (SBP1) promotes tumor cell migration and chemoresistance. Loss of the protein SBP1 during carcinogenesis predicts poor prognosis. ARS researchers at Grand Forks, North Dakota along with collaborators demonstrated that the loss of SBP1 decreases intracellular selenium, and promotes migration and chemoresistance of cancer cells. These results suggest a new cancer treatment strategy by sequestering selenium through SBP1.
8. Low dietary selenium exhibits opposing impacts on healthspan and longevity. Selenium is a trace mineral essential for life, but its nutritional and physiological roles during the aging process remain elusive. ARS researchers at Grand Forks, North Dakota along with collaborators showed that dietary selenium deprivation delays wound healing and accelerates incidence of osteoporosis, gray hair, and cataract, but surprisingly promotes longevity. These findings indicate that there are opposing impacts on healthspan and longevity by limiting dietary selenium intake.
9. Butyrate selectively inhibits colon cancer cell growth. Butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits chemoprevention effects on colon cancer development. However, the mechanistic action of butyrate remains to be determined. ARS researchers at Grand Forks, North Dakota along with collaborators showed that butyrate inhibits cancerous cell growth but to a lesser extent in noncancerous cells through regulating cellular-signaling pathways. These findings demonstrated that butyrate selectively inhibits colon cancer cell growth is the key cellular anticancer action.
10. High daidzein intake does not protect against fatty liver. A high-isoflavone soy protein isolate (HISPI) diet is associated with significantly heavier body weight and reduced fatty liver in obese rat models. However, little is known the role of daidzein (a key soy isoflavone) in the aforementioned observation. ARS researchers at Grand Forks, North Dakota along with collaborators showed that daidzein may not be the main component of HISPI responsible for increasing body weight and reducing fatty liver. These findings indicate that high daidzein intake does not prevent obesity-related fatty liver.
11. High fat diet alters gut microbiota before changing circulating inflammatory cytokines. It is known that diet-induced obesity exacerbates the intestinal inflammatory status by cytokines produced in adipose tissue and the change of gut bacterial composition. However, the time sequence of the cytokine production versus the change of gut bacterial composition needs to be determined during the aforementioned observation. ARS researchers at Grand Forks, North Dakota along with collaborators showed that obesity may stimulate intestinal inflammation via altering the gut microbiome, and it occurs prior to the potential influence by circulating inflammatory cytokines. These findings indicate the importance of gut bacteria, in addition to adipose tissue per se, in driving intestinal inflammation.
Review Publications
Combs, Jr., G.F., Yan, L. 2016. Status of selenium in cancer prevention. In: Hatfield, D.L., Berry, M.J., Gladyshev, V.N., editors. Selenium: Its Molecular Biology and Role in Human Health. Edition 4. New York, New York. Springer-Verlag. p. 321-332. doi:10.1007/978-3-319-41283-2.
Sundaram, S., Yan, L. 2016. High-fat diet enhances mammary tumorigenesis and pulmonary metastasis and alters inflammatory and angiogenic profiles in MMTV-PyMT mice. Anticancer Research. 36(12):6279-6288.
Zeng, H., Taussig, D., Cheng, W., Johnson, L., Hakkak, R. 2017. Butyrate inhibits cancerous HCT116 cell proliferation but to a lesser extent in noncancerous NCM460 colon cells. Nutrients. 9(1):25-38.
Yan, L., Nielsen, F.H., Sundaram, S., Cao, J.J. 2017. Monocyte chemotactic protein-1 attenuates and high-fat diet exacerbates bone loss in mice with pulmonary metastasis of Lewis lung carcinoma. Oncotarget. doi:10.18632/oncotarget.15055.
Sundaram, S., Yan, L. 2016. Dietary energy restriction reduces high-fat diet-enhanced metastasis of Lewis lung carcinoma in mice. Oncotarget. 7:65669-65675. doi:10.18632/oncotarget.11598.
Zhai, C., Wu, R., Zeng, H., Cheng, W. 2016. Loss of selenium-binding protein 1 decreases sensitivity to clastogens and intracellular selenium content in HeLa cells. PLoS One. 11(7):e0158650. doi:10.1371/journal.pone.01586.
Guo, Z., Li, J., Tang, T., Zeng, H., Wood, R., Liu, Z. 2017. High fat diet alters gut microbiota and the expression of Paneth cell-antimicrobial peptides preceding changes of circulating inflammatory cytokines. Mediators of Inflammation. doi:10.1155/2017/9474896.
Wu, R.T., Cao, L., Mattson, E., Witwer, K.W., Cao, J.J., Zeng, H., He, X., Combs, G.F., Cheng, W. 2017. Opposing impacts on healthspan and longevity by limiting dietary selenium in Telomere Dysfunctional mice. Aging Cell. 16(1):125-135.
Bell, A., Korourian, S., Zeng, H., Phelps, J., Hakkak, R. 2017. A diet containing a high- versus low-daidzein level does not protect against liver steatosis in the obese Zucker rat model. Food & Function. 8(3):1293-1298.
Block, E., Booker, S., Flores-Penalba, S., George, G., Landgraf, B., Li, F., Lodge, S.N., Pushie, J., Rozovsky, S., Vattekkatte, A., Yaghi, R., Zeng, H. 2016. Trifluoroselenomethionine: A new unnatural amino acid. ChemBioChem. 17(18):1738-1751.
Zeng, H., Ishaq, S.L., Zhao, F., Wright, A.G. 2016. Colonic inflammation and enhanced-beta-catenin signaling accompany an increase of the Lachnospiraceae/Streptococcaceae in the hind gut of high-fat diet-fed mice. Journal of Nutritional Biochemistry. (35)30-36.
