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 Dietary Prevention of Obesity-related Disease Research: Grand Forks, ND
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ARS Home Plains Area Grand Forks, North Dakota Grand Forks Human Nutrition Research Center Dietary Prevention of Obesity-related Disease Research Research





- Yan, Lin
- Zeng, Huawei
- Cao, Jay
- 2023
- 2022
- 2021
- 2020
- Publications
- Human Nutrition (107)

Research Project: Modification of Diurnal Patterns to Promote Health in Models for Human Metabolic Dysfunction **Location:
                            Dietary Prevention of Obesity-related Disease Research** 2023 Annual Report **Objectives**
                                

Objective 1 - Define how dietary fatty acids and exercise alter peripheral biological rhythms and metabolic dysfunction.
• Subobjective 1.A. Define whether long-chain n3 polyunsaturated fatty acids correct the obesity-mediated peripheral circadian clock dysfunction. 
• Subobjective 1.B. Define the extent to which exercise overrides peripheral clock dysfunction and metabolic dysfunction. 
Objective 2 - Define the impact of diet timing on colonic bile acid pathways and inflammation. 
Objective 3 - Define the impact of dietary fiber composition on colonic bile acid pathways and inflammation. 
Objective 4 - Define the mechanisms and the influence of daily physical activity timing to improve bone health.
• Subobjective 4.A. Determine the mechanisms through which the timing of exercise alters the diurnal pattern of bone turnover, bone cell physiology, calcium utilization, and bone structure. 
• Subobjective 4.B. Determine the efficacy of morning vs evening exercise to maximize bone anabolic effects. **Approach**
                                

Disruption of biological rhythms in peripheral organs by environmental cues leads to metabolic dysfunction and disorders, including obesity. Food and physical exercise can drive the biological rhythms in peripheral organs. This project will examine the ability of dietary components (dietary fatty acids and fiber), exercise, and the timing of food consumption and exercise to correct the disrupted biological rhythms in peripheral organs and restore metabolic homeostasis. This project will address three questions: (1) Do changes in dietary fatty acid composition and exercise override the disrupted peripheral biological rhythms and restore metabolic homeostasis? (2) Does the timing of food intake and dietary fiber composition regulate bile acid pathways and attenuate colonic inflammation? (3) Does the timing of physical exercise make differences in regulating the diurnal pattern of bone metabolism and improving bone formation? Rodent studies will be performed to address each of these questions. In addition, a human clinical trial will be performed to translate question 3 results to humans. This project takes innovative approaches to addressing these questions in the context of modifying the diurnal patterns to promote health. Results from this research will provide valuable information of how dietary fatty acids and exercise minimize metabolic dysfunction and prevent associated disorders, a greater understanding of food timing and dietary fiber in regulating bile acid pathways and informing guidance for reducing colonic inflammation, and a greater understanding of timing of exercise training in improving bone health, particularly to people with bone loss associated with advancing age. **Progress Report**
                                

Objective 1. Research continued on investigating the effects of the daily timing of eating and dietary fatty acids on metabolic health in rodent models of human adult obesity. Obesity disturbs the daily rhythm of the biological clock that controls metabolic homeostasis. Eating irregularity contributes to obesity. Time-restricted feeding to the active phase of the day may restore biological rhythms in rodent models of obesity. Fish oil (a rich source of long-chain n3-polyunsaturated fatty acids) improves insulin sensitivity and reduces the risk of obesity in laboratory rodents. ARS scientists at Grand Forks, North Dakota, are investigating the benefits of time-restricted feeding and dietary supplementation with long-chain n3-polyunsaturated fatty acid in restoring the daily biological rhythms and reducing the risk of adult obesity. 
As a subordinate project of Objective 1, ARS scientists at Grand Forks, North Dakota, have extended their research to investigate the relationship between circadian disturbance and pubertal breast health. Childhood obesity is associated with adulthood obesity. It is a risk factor for breast cancer in women. In these studies, ARS scientists focused on the effects of (1) tumorigenic initiation and (2) dietary modification on circadian homeostasis in mammary glands of pubertal models of obesity.   
Objective 2. ARS scientists at Grand Forks, North Dakota, completed a study investigating the mechanisms of time-restricted feeding (TRF, without reducing energy intake) against obesity-related diseases (e.g., diabetes and colonic inflammation) in a mouse model. While TRF is an effective approach to reduce obesity related chronic diseases, the underlying TRF mechanistic actions remain to be determined. In this study, ARS scientists demonstrate that (1) anti-obesogenic effects of TRF diets are partly due to an increase in fat excretion in feces in the context high-fat diet induced obesity and (2) fat content of diet and feeding timing differentially affect the fecal microbiota and the relationship between the microbiota and fecal lipids.
Objective 3. Research continued on investigating whether increasing levels of slowly fermentable fiber (SFF) reduce secondary bile acid (BA) signaling in the colon. The consumption of a high-fat, low-fiber diet contributes to obesity, a risk factor for colonic inflammation and ensuing colon cancer. While diets rich in fiber (e.g., sorghum bran containing up to 50% SFF) may reduce the risk of intestinal disorders and cancer, the molecular impact of SFF on obesity-mediated colonic inflammation remains to be determined. ARS scientist at Grand Forks, North Dakota, have initiated a study to determine whether sorghum bran reduces colonic inflammation in a mouse model of obesity.
As subordinate projects of Objective 3, (1) ARS scientists have completed a study identifying the fecal oncogenic signatures (e.g., fecal BA accumulation) related to mechanistic basis of obesogenic diets and colonic inflammation in a mouse model. (2) ARS scientists have completed a study investigating the change of fecal metabolome (e.g., fecal lipid accumulation) related to metabolic basis of obesity-related colon cancer in a mouse model. 
Objective 4. Research continued on determining the mechanisms through which the timing of exercise alters the diurnal pattern of bone turnover, bone cell physiology, calcium utilization, and bone structure and determining the efficacy of morning vs evening exercise to maximize bone anabolic effects. ARS scientists at Grand Forks, North Dakota, completed sample analyses collected from an animal study investigating the impact of the daily timing of exercise on bone in ovariectomized rats – a model of human menopause.  Female ovariectomized or sham-operated Sprague Dawley rats exercised at either rest phase, early active phase, or late active phase five days per week for 12 weeks. Body composition, body weight, serum bone biomarkers, bone structure, and gene expressions were measured to determine the effects of exercise at different times on these parameters. ARS scientists developed and submitted an animal protocol investigating whether exercise prevents bone loss induced by disruption of osteoblast circadian rhythm in mice. In addition, ARS scientists have initiated a human study determining the effects of the time of the day exercise on bone related changes in postmenopausal women. Recruitment of human participants is ongoing. **Accomplishments**
                                

1. High-fat diet alters metabolic rhythms in liver of pubertal mice. Biological clocks exist in all organs of our bodies. They cycle every 24 hours and controls the daily rhythms of our life. Our dietary practices alter the rhythms of these clocks and affect our health and wellbeing. Childhood obesity is a risk factor for adult obesity and related metabolic disorders. ARS scientists at Grand Forks, North Dakota, investigated whether a high-fat diet, as a change in dietary practice, altered biological clocks and impacted metabolism in pubertal mice. ARS scientists found that the high-fat diet, compared to a normal control diet, alters the diurnal expression of clock genes, genes that regulate lipid metabolism, and metabolic pathways related to lipid, protein, and energy metabolism in livers of pubertal mice. Most importantly, the high-fat diet induced metabolic alterations occur in the active phase of the day in these mice. This research provides insights into the roles of dietary practices in metabolic health at the pubertal age and demonstrates the importance of healthy dietary choices in childhood for development and growth. This research will be of interest to scientists in government, academia, and industry. 2. High-fat diet alters metabolic profile of mammary glands from pubertal mice. Childhood obesity is a risk factor for obesity in adults. In girls, it is associated with an increased risk of breast cancer later in life. Girls with obesity often have early onset of puberty and early breast development with elevation of sex hormones in blood. It has been suggested that consumption of a Western diet (rich in dietary fat) contributes to childhood obesity. ARS scientists at Grand Forks, North Dakota, investigated whether consumption of a high-fat diet altered the metabolic profile of mammary glands from pubertal mice. ARS scientists found that the high-fat diet, compared to a healthy control diet, alters amino acid metabolism considerably. This is evidenced by elevations of both essential and non-essential amino acids and alteration of metabolic pathways related to protein synthesis in mammary glands. Moreover, the high-fat diet alters energy and lipid metabolism in mammary glands. This study demonstrates that consumption of a high-fat diet disturbs metabolism in pubertal mammary glands. This disturbance may affect breast development and growth in puberty. Furthermore, findings from this study indicate the importance of a healthy diet in childhood for breast development and growth. 3. Time-restricted feeding changes fecal lipid and gut bacterial composition. Time-restricted feeding is an effective approach to reduce the risk of obesity-related diseases. However, its underlying molecular basis remains to be determined. ARS scientists at Grand Forks, North Dakota, demonstrated that anti-obesogenic effects of TRF diets are partly due to the increase in fat excretion in feces in the context of high-fat diet induced obesity. Furthermore, fat content of diet and feeding timing differentially affect the fecal microbiota and the relationship between the microbiota and fecal lipids in a mouse model. This work is of interest to health professionals, basic and clinical scientists, and the general public. 4. Identification of oncogenic signatures in obesity-related inflammatory colon. Adoption of a high-fat diet results in obesity and colonic inflammation. However, its underlying molecular basis remains to be determined. ARS scientists at Grand Forks, North Dakota, demonstrated that diet-induced obesity not only accelerates inflammatory process in the colon but also increases concentrations of fecal oncogenic molecules in a mouse model of obesity. This research provides mechanistic and nutritional insights into the diet-related obesity and colon cancer. This work is of interest to health professionals, basic and clinical scientists, and the general public. 5. Obesity-related colonic tumorigenesis accompanies an increase in fecal lipid concentrations. Consumption of a high-fat diet links obesity to colon cancer in humans. However, its underlying metabolic basis remains to be determined. ARS scientists at Grand Forks, North Dakota, demonstrated that chemical-induced colon cancer causes not only a greater fecal biochemical response but also increases concentrations of fecal lipid metabolites in a mouse model of obesity. This research provides mechanistic and nutritional insights into the diet-related obesity and colon cancer. This work is of interest to health professionals, basic and clinical scientists, and the general public. 6. Exercise improves bone structure regardless of the time of day of exercise. Circadian clock genes are expressed in bone and biomarkers of bone resorption and formation exhibit diurnal patterns in animals and humans. Whether the time of day of exercise alters the beneficial effects of exercise on bone is unknown. ARS scientists at Grand Forks, North Dakota, conducted a study with older female rats and investigated changes in bone metabolism in response to exercise at different time of day. The study demonstrated that exercise improved bone structural parameters at tibia and serum insulin-like growth hormone and irisin. However, the time of day of exercise does not alter the beneficial effect of exercise on bone. The findings are of interest to researchers in basic and clinical areas, as well as the general public as the study suggests that exercise benefits bone regardless of the time of day to exercise. 7. High-fat diet is detrimental to bone structure in animals with calcium deficiency. Inadequate dietary calcium intake contributes to the onset of osteoporosis. Whether high-fat induced obesity exacerbates bone structure deterioration during calcium deficiency remains unknown. ARS scientists demonstrated that combined inadequate calcium intake and obesity is detrimental to bone in ovariectomized rats. The findings are of interest to researchers in basic and clinical areas, as well as the general public as the study suggests that adequate calcium can benefit bone in obesity. **Review Publications**
                            *Zeng, H., Safratowich, B.D., Cheng, W., Bukowski, M.R. 2022. Identification of fecal oncogenic signatures in the inflammatory colon of C57BL/6 mice fed a high fat diet. Journal of Nutritional Biochemistry. 111. https://doi.org/10.1016/j.jnutbio.2022.109188.*
                                *Zeng, H., Safratowich, B.D., Cheng, W., Magnuson, A.D., Picklo, M.J. 2022. Changes of the fecal metabolome accompany an increase in aberrant crypt foci in the colon of C57BL/6 mice fed a high-fat diet. Biomedicines. 10(11). Article 2891. https://doi.org/10.3390/biomedicines10112891.*
                                *Yan, L., Sundaram, S., Rust, B., Daniel, P., Luann, J., Zeng, H. 2023. Consumption of a high-fat diet alters transcriptional rhythmicity in liver from pube pubertal mice. Frontiers in Nutrition. 9. Article 1068350. https://doi.org/10.3389/fnut.2022.1068350.*
                                *Yan, L., Rust, B., Sundaram, S., Bukowski, M.R. 2023. Metabolomic alteration in mammary glands of pubertal mice fed a high-fat diet. Nutrition and Metabolic Insights. 16:1-10. https://doi.org/10.1177/11786388221148858.*
                                *Rust, B.M., Picklo, M.J., Yan, L., Mehus, A.A., Zeng, H. 2023. Time-restricted feeding modifies the fecal lipidome and the gut microbiota. Nutrients. 15(7):1-17. https://doi.org/10.3390/nu15071562.*
                                *Huang, Y., Combs, G., Wu, T., Zeng, H., Cheng, W. 2022. Selenium status and type 2 diabetes risk. Archives of Biochemistry and Biophysics. 730. https://doi.org/10.1016/j.abb.2022.109400.*


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