Research - Molecular, Cellular, and Regulatory Aspects of Obesity Development In Children
The Circadian Clock in Nutritional Metabolism and Obesity
Obesity and related co-morbidities, including type 2 diabetes mellitus and cardiovascular disease, are some of the most profound public health problems today. Simplistic explanations based on over-consumption and/or poor diet or physical inactivity are inadequate to account for the dramatic and literal growth in our world population. Recent reports indicate that altered circadian patterns of behavior associated with our “24-hour” lifestyle may contribute to excess adiposity. Circadian clocks are defined as a set of proteins that generate self-sustained transcriptional positive and negative feedback loops with a free-running period of 24 hours. These circadian clocks are intrinsic to the cell, and exist even when cells are isolated and cultured in vitro. Circadian rhythms in physiology and behavior may be influenced by both the central clock in the brain and peripheral clocks in other tissues. We hypothesize that alterations in both the central and peripheral circadian clock mechanisms influence eating behavior, metabolism, and energy balance. We propose that this clock mechanism allows central and peripheral tissues to anticipate diurnal variations in the environment, such as circulating levels of glucose, fatty acid, and triglycerides, as well as various hormones, including insulin and epinephrine. In doing so, the circadian clock prepares the organism/tissue for the anticipated stimulus, allowing an appropriately rapid response. Failure to anticipate the onset of these environmental stimuli correctly may impair responsiveness and precipitate metabolic maladaptation. The long-term objective of this project is to determine the role of the circadian clock in food intake, energy balance, nutritional metabolism, and obesity.
Nutrition and Intestinal Development as Regulators of Health
The goal of our research is to determine how macronutrient composition, bioactive ingredients, and pattern of nutrient delivery to neonates affect protein anabolism, glucose tolerance, composition of growth and incidence of disease in early postnatal life. We will establish a caesarean-delivered pig model to investigate the effect of prematurity on the gastrointestinal and metabolic responses to perinatal nutrition. Specifically, we will determine whether alterations in dietary carbohydrates and pretreatment with glucagon-like peptide-2 affect digestive function and influence the onset of necrotizing enterocolitis using the premature piglet model. In piglets delivered preterm and at term, we also will examine the effect of chronic parenteral nutrition during the neonatal period on glucose tolerance, insulin sensitivity, and body composition during late infancy and adolescence. In other studies, we will use our established neonatal pig model to investigate the effect of feeding modality on protein synthesis and growth during the neonatal period. Specifically, we will investigate the effects of intermittent bolus feeding versus continuous feeding, delivered either enterally or parenterally, on protein synthesis in neonatal pigs. We will examine the role of amino acids and insulin in the response as well as identify the intracellular signaling mechanisms involved. We also will determine the long-term impact of these feeding modalities on growth and body composition. Taken together, this project will provide novel information that will be directly useful to optimize the nutritional management of low birth weight infants.
Characterization of Diet-Induced Changes in Adipose Tissue Leukocytes
The role of leukocytes in adipose tissues, only recently recognized as important in the pathogenic effects of obesity and its related diseases, requires considerable additional research. The proposed experiments investigate an established murine model of diet-induced obesity. There are two objectives in this project plan. The first objective deals with high fat diet-induced activation of inflammation-related events in blood and distinct adipose depots, investigating the evolution of proinflammatory mechanisms (e.g., TLR2, TLR4 and CD11c) with progressing adiposity. The second objective deals with the resolution of the inflammatory process when the high fat diet is replaced by a low fat diet, investigating possible active mechanisms (e.g., γδ T cells) of resolution. The experimental approaches include analysis of candidate inflammation-related genes to characterize leukocyte subsets and possible mediators, focused array analysis to reveal additional candidate genes for monitoring the evolution of inflammation or its resolution, and genome array analysis to establish expression patterns reflective of advancing stages of obesity-related pathology.
Metabolic Regulation in Obesity Development
The molecular mechanisms regulating energy homeostasis in response to food intake is not fully understood. The goal of our research is to address how nutrient-responsive neuropeptide GLP-2 communicates between the gut and the brain; how NAD-dependent deacetylase SIRT3 responds to nutrient availability and signals to AMPK, the cellular fuel sensor; and whether the newly discovered gene PICOT, protein kinase C interacting cousin of thioredoxin, contributes to the regulation of cellular redox state and insulin signaling. We hypothesize that intracellular (SIRT3 and PICOT) and neuroendocrine (GLP-2) systems regulate metabolism in response to changes in food intake. We will address the following issues. First, we will characterize the functions of SIRT3 and PICOT in the liver and their influences on the onset of fatty liver disease and glucose homeostasis. Second, we will investigate intracellular signaling pathways of GLP-2 and their metabolic effects on food intake, energy expenditure, and glucose homeostasis. The knowledge gained will facilitate the development of preventive or therapeutic venues to cope with immense health problems associated with the metabolic diseases.
Nutrition and Epigenetic Programming of Obesity during Development
Obesity prevalence in the US and other developed countries has increased dramatically in recent decades. This trend is affecting individuals at every age, including women of child-bearing age. A major concern is that maternal obesity during pregnancy may alter the intrauterine environmental and thereby perpetuate obesity in her offspring. The biologic mechanisms underlying such developmental ‘programming’ of metabolism and body weight regulation have not been characterized. The overall hypothesis of the proposed research is that maternal obesity and fetal nutrition during development affects the establishment of gene-specific DNA methylation patterns in the developing fetus, causing permanent changes in gene expression, metabolism, food intake regulation, and body weight. Various mouse models, and a human model of epigenetic dysregulation compromising placental development, will be used to test this hypothesis. In particular, genome-wide DNA methylation microarrays will enable us to screen the genome for epigenetic alterations that may mediate developmental programming. This research is necessary to elucidate the mechanisms by which the fetal and early postnatal environment affects body weight regulation; this information will enable us to accurately gauge the impact of such phenomena on the etiology of human obesity and potentially design effective interventions.