Location: Dietary Prevention of Obesity-related Disease Research
2024 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
In the U.S., over 40% of adults are obese and 30% are overweight. The prevalence of obesity and overweight drastically increases the risk of chronic disorders (for example, metabolic dysfunction, colonic inflammation, and osteoporosis) and results in significant economic impact on the U.S. health care system with estimated direct medical costs over $170 billion yearly. Societal changes in modern world (for example, unhealthy dietary practice and sedentary lifestyles) contribute greatly to the prevalence of obesity in the U.S. prevention and treatment of obesity and associated chronic disorders remain a great challenge to both clinical and laboratory research.
Project 3062-51000-056-00D has four objectives.
Objective 1 was to define how dietary fatty acids and exercise alter peripheral biological rhythms and metabolic dysfunction.
Both physiological and metabolic processes in humans exert biological rhythms, that cycle every 24 hours for maintaining diurnal patterns of human life (for example, eating vs. fasting, sleep vs. wakefulness). Disturbance of the biological rhythms (for example, by erratic eating behavior) results in metabolic dysfunction. Objective 1 of the project focused on restoration of metabolic patterns by adapting healthy lifestyles in rodent models for human metabolic dysfunction. ARS researchers in Grand Forks, North Dakota, found that consumption of an obesogenic high-fat diet disturbs biological rhythms of mammary glands and results in metabolomic and transcriptomic alterations in pubertal mice, indicating that dietary malpractice at younger ages may lead to aberrant breast development and growth, which is a risk factor for breast cancer later in adulthood. Time-restricted feeding (a means of having food available to a fixed time of the day) restores daily metabolic pattern, increases insulin sensitivity, and improves metabolic homeostasis in a model for adult obesity. However, dietary intake of long-chain n-3 unsaturated fatty acids does not alter the disturbed diurnal metabolic pattern in adult obese mice. Furthermore, ARS researchers in Grand Forks, North Dakota, found that adipose-derived chemical monocyte chemotactic protein-1 contributes to diet-induced obesity and enhances breast tumorigenesis in a model for obesity-enhanced breast cancer. These findings demonstrate that the way we live matters to our metabolic health and that maintaining a healthy lifestyle restores metabolic homeostasis altered by circadian disruption and promote health in humans. Further clinical studies are needed to explore these possibilities.
Objective 2 was to define the impact of diet timing on colonic bile acid pathways and inflammation.
The “Western” diet that is high in fat and low in fiber combined with a late mealtime promotes obesity-related colonic inflammation and cancer; and high-fat diets increase not only body adiposity but also pro-inflammatory secondary bile acids (for example, deoxycholic acid, a potential cancer promoter) in the colon. An effective approach to reducing adiposity and its associated negative health consequences is to limit food availability (without reducing energy intake) to no more than 10 to 12 hours per day, known as time-restricted feeding (TRF, in animal models) or time-restricted eating (TRE, in human studies).
Objective 2 of the project focused on determining the inhibitory potential of TRF against increased secondary bile acids and inflammation in the colon using high-fat diet induced obese mouse models for simulating human colonic inflammation. ARS researchers in Grand Forks, North Dakota, found that (1) anti-obesogenic effects of TRF diets are partly due to the improvement of lipid metabolism in the gut, and an increase in fat excretion in feces; (2) TRF reduces systemic inflammatory cytokines, and oncogenic beta-catenin signaling in the colon. These mechanistic data indicate that a healthy lifestyle such as diet timing (for example, TRE) plays a crucial role to prevent diet-induced obesity associated diseases. Future human studies are needed for extrapolating these findings to clinical applications.
Objective 3 was to define the impact of dietary fiber composition on colonic bile acid pathways and inflammation.
Dietary fiber can alter human physiology through multiple mechanisms that result in preventing chronic diseases (for example, diabetes and cancer). There is growing evidence that dietary fiber lowers the risk of colonic inflammation and cancer in humans. These beneficial effects may be associated with short-chain fatty acids (SCFAs) such as butyrate production in colon by bacterial fermentation of dietary fiber. However, with the global transition to a westernized lifestyle, the amount of fiber in our diets has decreased dramatically, which leads to various diseases (including inflammation and cancer in the colon).
Objective 3 of the project focused on beneficial effects of dietary fiber on colon health. ARS researchers in Grand Forks, North Dakota, found that dietary fiber (for example, resistant starch), in obese mouse models, (1) increases anti-inflammatory bacterial metabolites SCFAs (for example, butyrate) in the colon; (2) reduces systemic inflammatory cytokines, beta-catenin signaling, bacterial dysbiosis, pro-inflammatory secondary bile acids and potential oncomicrobes (for example, Alistipes) in the colon. These findings provide new underlying molecular evidence to partially explain that fiber-rich diets reduce colonic inflammation and cancer risk in humans.
Objective 4 was to define the mechanisms and the influence of daily physical activity timing to improve bone health.
Bone modeling/remodeling is a tightly regulated process that involves bone resorption by osteoclasts and bone formation by osteoblasts. Disruption of the balance of bone resorption and formation can lead to osteoporosis. Bone metabolism regulating hormones and cytokines, such as bone resorption marker, C-terminal telopeptide of type 1 collagen and bone formation marker, osteocalcin, exhibit distinct diurnal oscillations in humans and animals. The benefit of exercise on bone mass and strength is well-established. However, whether timing of exercise affects the beneficial of exercise on bone is unknown. Objective 4 of the project focused on the mechanisms of and the extent to which timing of exercise affects bone metabolism in animal model and humans. ARS researchers in Grand Forks, North Dakota, conducted two animal studies to determine the mechanisms through which the timing of exercise alters the diurnal pattern of bone turnover, bone cell physiology, calcium utilization, and bone structure. ARS researchers in Grand Forks, North Dakota, demonstrated that exercise improved bone structural parameters at tibia and serum insulin-like growth hormone and irisin regardless of when the exercise takes place. In addition, a human study is ongoing to determine the effects of the time-of-day exercise on bone related changes in postmenopausal women.
ARS scientists successfully achieved objectives of project 3062-51000-056-00D.These achievements were crucial in leading ARS scientists to a new research mission aimed at investigating the impact of the diet and physical exercise in the new project entitled “Diet and physical activity interventions to promote health in models for obesity-related diseases”.
Accomplishments
1. Time-restricted feeding restores daily metabolic rhythm in adult obese mice. Obesity in adults presents a great challenge in clinical practice for improving metabolic health and reducing the mortality of obesity-related diseases. Erratic eating behavior disturbs daily metabolic rhythm and leads to excess body fat. Time-restricted feeding is a dietary practice where food intake is restricted to a fixed time of the day (for example, daytime for humans) that establishes a consistent daily eating pattern and prevents erratic eating behavior. Using a model for adult obesity, ARS scientists in Grand Forks, North Dakota, found that time-restricted feeding does not affect body fat mass but restores daily metabolic rhythm, improves insulin sensitivity, and decreases cholesterol in adult obese mice. Over 40% of U.S. adults are obese (108.5 million). Reduction of body weight in adults with obesity is considered a standard of treatments in clinical practice. However, initial and sustained weight loss remains a great challenge because of the multiple behavior changes required for effective weight control. This research informs clinical practice by demonstrating the benefits of the healthy eating behavior on a regular, fixed-time basis for improving metabolic health. This research is of an interest to health care providers, scientists in government and academia, and the general public.
2. Identification of a pro-inflammatory gene which causes intestinal inflammation in a diet-induced obese mouse model. Consumption of a high-fat diet is associated with obesity and colonic inflammation. However, the causality between diet and obesity-related colonic inflammation/cancer remains to be determined. ARS scientists in Grand Forks, North Dakota, demonstrated that the knockout of tumor necrosis factor (TNF) alpha gene reduces intestinal tumorigenesis in obese mouse models. This research provides novel mechanistic insights into the diet-related obesity and colon cancer at gene levels. These findings would be instrumental in adopting precision nutrition strategies tailored to preventing obesity-related diseases. This work is of interest to health professionals, basic and clinical scientists, and the general public.
3. Fermentation products of dietary fiber (in the colon) inhibit colon cancer cell proliferation. Increasing dietary fiber consumption is linked to lower colon cancer incidence, and this anticancer effect is tied to elevated levels of short-chain fatty acids (e.g., butyrate) because of the fermentation of fiber by colonic bacteria. ARS scientists at Grand Forks, North Dakota, demonstrated that butyrate effectively inhibits colon cancer cell proliferation, which is a gene-directed and cell type specific-dependent process. These mechanistic data (in human cultured colon cell models) may help explain clinical variability of butyrate’s benefits. This research is of interest to health care providers, scientists in government and academia, and the general public.
4. Inadequate calcium intake decreases bone mass without affecting fat mass in estrogen-deficient rat model. Obesity induced by a high-fat diet is detrimental to bone structure. Studies show calcium intake affects bone mass and fat mas. Whether calcium deficiency affects bone in obese rats with estrogen deficiency is unknown. ARS scientists at Grand Forks, North Dakota, demonstrated that inadequate calcium intake and a high-fat diet have independent negative effects on bone structure and calcium deficiency does not affect fat mass. 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 intake and/or reducing obesity benefits bone health.
5. Incorporation of dry edible beans to a high-fat diet does not affect body composition and bone structure in obese mice. Studies have demonstrated health benefits of pulse consumption in humans, including reduction in obesity-induced chronic disorders. The 2020 USDA Dietary Guidelines for Americans recommend weekly intake up to 1.5 cups of dry edible beans (pulses) as part of healthy U.S.-style dietary pattern. ARS scientists at Grand Forks, North Dakota, demonstrated that including pulses in a high-fat diet increases certain mineral content in bone but has minimal beneficial effect on lean body mass and bone structure in obese mice. The findings are of interest to researchers in basic and clinical areas, as well as the general public as the study suggests that reducing obesity is important to improve bone mass.
Review Publications
Gregoire, B.R., Cao, J.J. 2023. Time of day of exercise does not affect the beneficial effect of exercise on bone structure in older female rats. Frontiers in Physiology. 14:1-11. https://doi.org/10.3389/fphys.2023.1142057.
Cao, J.J., Gregoire, B.R. 2024. Calcium deficiency decreases bone mass without affecting adiposity in ovariectomized rats fed a high-fat diet. Nutrients. 16(4). Article 478. https://doi.org/10.3390/nu16040478.
Yan, L., Rust, B., Palmer, D. 2024. Time-restricted feeding restores metabolic flexibility in adult mice with excess adiposity. Frontiers in Nutrition. 11:1-14. https://doi.org/10.3389/fnut.2024.1340735.
Oncel, S., Safratowich, B.D., Lindlauf, J., Liu, Z., Palmer, D., Briske Anderson, M.J., Zeng, H. 2024. Efficacy of butyrate to inhibit colonic cancer cell growth is cell type-specific and apoptosis-dependent. Nutrients. 16(4). Article 529. https://doi.org/10.3390/nu16040529.
Li, J., Tang, Y., Lin, T., Zeng, H., Mason, J.B., Lui, Z. 2023. Tumor necrosis factor-a knockout mitigates intestinal inflammation and tumorigenesis in obese Apc1638N mice. Journal of Nutritional Biochemistry. 117. Article 109355. https://doi.org/10.1016/j.jnutbio.2023.109355.
Peng, Y., Langermann, S., Kothari, P., Liu, L., Zhao, W., Hu, Y., Chen, Z., Li, J., Cao, J.J., Guo, X., Chen, L., Bauman, W.A., Qin, W. 2023. Anti-siglec-15 antibody prevents the marked bone loss after acute spinal cord injury-induced immobilization in rats. Journal of Bone and Mineral Research Plus. 7(12). Article e10825.