Project : USDA ARS

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Research Project: Metabolic and Epigenetic Regulation of Nutritional Metabolism

Location: Children's Nutrition Research Center

2022 Annual Report

Objectives
We will: 1)study the effect of enteral nutrition on the downstream signaling pathways and metabolism;2)study if increased FGF19 availability controls rate of growth, tissue protein synthesis and intestinal development;3)study if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4)identify by which amino acids, regulate protein synthesis, degradation, and accretion and how responses change with age;5)removed due to investigator departure;6)study molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts;7)study the impact of maternal dietary protein level during lactation;8)study if vitamin D receptors in the brain are critical for glucose regulation;9)study if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A/B reduces gluconeogenesis;10)study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway;11)alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and PA;12)find the causes of interindividual epigenetic variation and consequences for human energy balance;13)study the functional impact of folic acid supplementation and in intestinal carcinogenesis;14)study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone and endothelial function; 15)study the effect of vitamin D therapy on change in bone and endothelial function;16)removed due to investigator departure;17)study the CNS circuit architecture and explore circuit complexities that regulate non-homeostatic feeding behaviors via environmental signals transduced by epigenetic mechanisms;18)study the tumorigenic effects of HFCS on a humanized colon tumor mouse model;19)study the effects of HFCS on the gut microbiota of a humanized colon tumor mouse model;20)study the role of HFCS-induced gut microbiota in CRC development; create multi-omic nutritional data share portal to resolve the unmet demand for an efficient access to the large volumes of heterogeneous multi-omic data across various research labs;21)integrate heterogeneous multi-omic datasets such as genetic (SNPs), transcriptomic, epigenetic, proteomic, metabolomic and microbiome to infer molecular network structures illustrating eating disorder dynamics;&22)decode genetic and epigenetic patterns of disordered eating using machine learning methods.

Approach
This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. Studies will be conducted in mice that will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets. Researchers will also conduct a multi-omic integrative study to systematically decipher the molecular interplay of disordered eating and neuron specific brain circuits that control feeding behavior.

Progress Report
To review the progress made during the year, please refer to the following projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2), 3092-51000-065-03S (Project #3) and 3092-51000-065-04S (Project #4).

Accomplishments
1. Vitamin D receptors in the brain are important for blood glucose regulation in males but not females. Vitamin D deficiency is associated with diabetes, but the mechanisms are unclear. We had evidence that vitamin D receptors in the paraventricular hypothalamus were important for regulating blood glucose in male mice however, we had not determined if females behaved similarly. Researchers at the Children's Nutrition Research Center in Houston, Texas, used two different mouse models in which there is a loss of the vitamin D receptor in the paraventricular hypothalamus of the brain to determine the effect in female mice. In both of our mouse models, we found that male mice that had decreased vitamin D receptors in that area of the brain had higher glucose levels than their controls, whereas female mice showed no effect of the loss of the vitamin D receptors. These findings of sex differences in mice are important to human studies investigating the role of vitamin D deficiency and overall treatment and prevention of type 2 diabetes based upon the individual's sex.

2. SIRT3 protects the heart against damaging side effects of anti-cancer drug. The chemotherapy drug Doxorubicin is used to treat breast cancer, bladder cancer, ovarian cancer, lymphoma, and leukemia and despite its benefits it may also cause damage to the heart. In searching for ways to alleviate the toxicity of Doxorubicin, researchers at the Children's Nutrition Research Center in Houston, Texas, have found that a metabolic regulating enzyme, SIRT3, offers protection against the heart impacting side-effects of Doxorubicin. We generated two mouse models with elevated heart expression of two SIRT3 isoforms, treated these mice with doxorubicin and investigated the damage to the heart using ultra-sound and other methods. We found that increased SIRT3 expression in the heart protected mice against doxorubicin-induced damage to the structure and function of the heart. SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced heart-damage. Since we have previously shown that fasting or dietary restriction increased SIRT3 expression in various tissues, fasting or dietary restriction might also mitigate the side effect of doxorubicin.

3. A dietary lipid, palmitoleic acid, suppresses liver glucose production through suppression of SIRT3. The production of glucose by the liver plays a crucial role in maintaining glucose levels during starvation however, uncontrolled glucose production by the liver contributes to elevated blood glucose in individuals with diabetes. Palmitoleic acid is a mono-unsaturated fatty acid that is available from dietary sources and exhibits beneficial effects on diabetes, inflammation, and metabolic diseases. The mechanism by which palmitoleic acid reduces blood glucose is still unclear. Researchers at the Children's Nutrition Research Center in Houston, Texas, conducted a study that revealed that palmitoleic acid reduced liver glucose production and the expression of SIRT3, a key metabolism-regulating enzyme, in high-fat diet fed mice. Overexpression of SIRT3 in the liver or in liver cells enhanced glucose synthesis, and further study revealed that SIRT3 played a role in enhancing the activities of three key enzymes involved in the synthesis of glucose. Our study uncovered the role of SIRT3 in the regulation of liver glucose production and its role in mediating the anti-diabetic effect of palmitoleic acid. These findings may help identify novel treatments of diabetes by palmitoleic acid supplementation or by inhibiting the SIRT3 enzyme.

4. The effect of cardiorespiratory fitness and insulin resistance on bone health in Hispanic children. Obesity appears to have a negative impact on pediatric bone health and insulin resistance may mediate this relationship. It is unclear if cardiorespiratory fitness may have a protective effect on bone health in obese children. Researchers at the Children's Nutrition Research Center in Houston, Texas examined data on a large number of Hispanic youths to evaluate the effect of insulin resistance and cardiorespiratory fitness on bone health. Our results showed that lean body mass is the major determinant of bone mineral content and bone mineral density in Hispanic youth. However, obesity and higher body fat have a negative effect on this relationship, while a higher fitness level was positively related to the measures of bone health. This suggests that greater cardiorespiratory fitness and higher lean mass may reduce the adverse effects of adiposity and insulin resistance on bone health in children. These findings support the importance of promoting an increase in physical activity to prevent the negative impact of obesity on bone health in children.

5. The role of sleep and eating patterns in adiposity gain among preschool-aged children. Short sleep duration (less than 9 hours in preschoolers) is related to risk for obesity in preschool children however, the underlying mechanism(s) are not clear. Researchers at the Children's Nutrition Research Center in Houston, Texas, investigated the relationship between sleep characteristics with body composition and weight-regulating behaviors in preschool-aged children (ages 3 to 5 years old). We examined the relationship between sleep, physical activity and dietary behaviors, and the effect of these behaviors on weight and fat gain a year later and found that children do not consistently meet age-recommended sleep duration. Late sleep timing was related to a delay in morning and evening meals and more caloric intake in the evening, a factor that is related to weight gain in older individuals. Both a decrease in sleep duration and later meal timing were related to fat gain a year later which indicates that insufficient sleep duration influences eating behaviors. This supports the importance of sleep hygiene with appropriate timing and adequate duration in preschool age children.

6. Energy expenditure due to gluconeogenesis in insulin resistance. Insulin resistance is a condition when cells in human muscle, fat, and liver do not respond well to insulin and are unable to easily take up glucose from the circulation of blood. For individuals with insulin resistance, suppression of glucose production from the liver by insulin is impaired, contributing to high blood glucose. Glucose production is energetically costly and may contribute to increased energy expenditure. Researchers at the Children's Nutrition Research Center in Houston, Texas, sought to determine if energy expenditure is attributable to glucose production from the liver in individuals with different types of insulin resistance conditions. We demonstrated that glucose production from the liver is a major contributor to energy expenditure in humans with insulin resistance. The findings from this study are important because they indicate that treatments for diabetes that reduce glucose production from the liver could potentially promote weight gain by decreasing the energy expenditure.

U.S. DEPARTMENT OF AGRICULTURE

Children's Nutrition Research Center: Houston, TX