Metabolic Effects of Ghrelin and Glucagon-Like Peptide Hormones
Obesity is recognized as a global crisis due to its increasing prevalence and severe co-morbidities (such as insulin resistance and diabetes). Therapeutic approaches for obesity are very limited, largely due to a lack of full understanding of the cellular and molecular mechanisms of obesity. We hypothesize that gut-derived hormones, ghrelin and glucagon-like peptide 2(GLP-2), play key roles in the control of energy- and glucose-homeostasis, and may be potential novel therapeutic targets for obesity. Ghrelin is the only known circulating orexigenic hormone; it enhances appetite, increases obesity and promotes insulin resistance. However, the sites of action and the pertinent molecular mechanisms of ghrelin’s functions are unknown. It is suggested that ghrelin regulates glucose production, primarily through gluconeogenesis. However, ghrelin’s direct effect on gluconeogenesis has not been determined because of methodological limitations. GLP-2 plays a crucial role in the control of energy balance and metabolism. However, little is known about the physiological role of central GLP-2 on peripheral glucose homeostasis and insulin sensitivity. To test our hypothesis, we will address the following specific objectives: 1) Determine the tissue-specific roles of ghrelin receptor in thermogenesis (energy burning), adipose inflammation and insulin resistance; 2) Elucidate the effects of ghrelin and ghrelin receptor on gluconeogenesis using “state-of-art” stable isotope method; 3) Investigate GLP-2-initiated intracellular signaling pathways and its receptor (GLP-2R)-modulated neural circuits to elucidate how GLP-2R in the brain affects peripheral insulin sensitivity and glucose homeostasis. The knowledge gained from this project will facilitate the development of prevention and treatment for obesity and diabetes.
Research Faculty: Shaji K Chacko, Ph.D., M.S.
Metabolic Pathways in Obesity
Obesity is manifested by the expansion and remodeling of adipose tissue. Expansion of adipose tissue results from the increase in size of existing adipocytes and from the formation of new adipocytes (adipocyte differentiation). Obesity also remodels fat tissue, resulting in low-grade inflammation with oxidative stress and massive infiltration of immune cells. It is believed that the inflammatory cytokines produced by the inflamed adipose tissue cause systemic insulin resistance and other obesity-related complications. However, the link between obesity-induced changes to adipocytes and adipose inflammation are not fully understood. The first part of our study (Objectives 1 and 2) focuses on the pro-inflammatory transcription factor PU.1, which we have previously reported to be dramatically up-regulated by obesity in the adipocytes of visceral, but not subcutaneous, adipose tissue. We will investigate if obesity-induced adipose hypoxia is responsible for stimulating adipocyte PU.1 expression. We will also explore if deletion of PU.1 in adipocytes protects mice against high fat diet-induced adipose inflammation and insulin resistance. The second part of our study (Objective 3 and 4) focuses on the anti-adipogenic effect of Hedgehog signaling on the formation of white adipose tissue and as a potential strategy for prevention of diet-induced obesity and metabolic syndrome. We will examine the effect of Hedgehog (Hh) signaling on the differentiation of white preadipocytes derived from human subcutaneous and visceral fat depots. We will also investigate if adipocyte-specific activation of Hh signaling will prevent diet-induced weight gain and improve metabolic abnormalities. Results obtained from these studies will advance our understanding of the involvement of PU.1 and Hh signaling in adiposity and provide new insights into how manipulating the activities of these two pathways may prevent obesity and its related complications.
Epigenetics of Stem Cells, Obesity, and Diabetes
Metabolic programming occurs when nutrition and other environmental exposures affect prenatal or early postnatal development, causing structural or functional changes that persist to influence health throughout life. This project integrates work of three investigators working to understand epigenetic mechanisms of metabolic programming. Epigenetic mechanisms regulate cell-type specific gene expression, are established during development, and persist for life. Importantly, nutrition during prenatal and early postnatal development can induce epigenetic changes that persist to adulthood. We focus on DNA methylation because this is the most stable epigenetic mechanism. The inherent cell-type specificity of epigenetic regulation motivates development of techniques to isolate and study specific cell types of relevance to a certain disease. For this reason these projects 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 metabolic programming of body weight regulation. Mouse models will also be used to investigate epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize their involvement in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which the establishment of DNA methylation is especially sensitive to maternal nutrition before and during pregnancy, and identify epigenetic variation that correlates with adverse neonatal outcomes in infants born to mothers affected with pregestational or gestational diabetes. An improved understanding of the mechanisms of metabolic programming will lead to the development of early-life nutritional interventions to improve human health.
Brain Signaling, Metabolism, and Obesity
Obesity and its associated metabolic disorders (e.g., diabetes) represent a serious health problem to our society. The central nervous system (CNS) senses multiple hormonal/nutritional cues and coordinates homeostatic controls of body weight and glucose balance. However, the mechanisms for CNS control of metabolism remain to be fully understood. Primarily using genetic mouse models, supplemented by neuro-pharmacology approaches, three research scientists (Xu, Sisley, and Cheng) seek to tackle this general problem from different angles. Based on the previous observations that brain serotonin (5-HT) neurons regulate feeding, body weight and glucose balance, the Xu lab will continue to identify the efferent and afferent circuits of 5-HT neurons that are physiologically relevant for the metabolic effects of 5-HT. The Sisley lab will explore the central effects of vitamin D on body weight, glucose, and inflammation. The Cheng lab will examine both the response of hypothalamic redox signaling to various dietary challenges and the physiological relevance of these signals in diet-induced obesity. These studies will demonstrate the potential roles of metabolic cues (hormones/nutrients), CNS circuits, and the intra-neuronal signals in the control of energy and glucose homeostasis. Our research results should identify rational targets for the treatment or prevention of obesity and diabetes. Findings will provide evidence to support new guidelines in hormonal/chemical diet supplementation to prevent these diseases. Finally, numerous novel genetic mouse lines will be generated, which will benefit a broader research community.
Role of GABAergic Neural Circuit in Regulation of Feeding Behavior and Obesity
Strong evidence suggests that the pontine parabrachial nucleus (PBN) mediates feeding behavior by integrating visceral signals from vagal afferents and GABAergic signaling from Agouti-related peptide (AgRP) neurons in the hypothalamus. Considering the complex structure of the PBN, very little is known about how gamma-amino butyric acid-A (GABAA) receptors expressed in the PBN contribute to the adaptive mechanism that governs appetite under normal and malnutrition states. We have obtained compelling preliminary data to support that GABAA receptor a5 subunits are strongly associated with the control of feeding by action within distinct PBN microcircuits. Our central hypothesis is that GABAA receptor subtype a5 signaling in the PBN mediates feeding of palatable foods and hunger-driven feeding response by differential action through melanocortin 4 receptor (MC4R) and leptin receptor (LepR) neurons, respectively. We will characterize food intake and energy metabolism by applying optogenetic and chemogenetic approaches to stimulate or suppress distinct neuronal populations in the PBN of recently established Cre-expressing mouse models. These cutting-edge brain techniques will ensure precise manipulation of a genetically defined neuronal population at various levels so as to reveal critical functions mediated by relevant genes within a specific neural circuit. We will examine whether GABAA a5 subunits expressed in the PBN MC4R neurons mediates hedonic feeding of palatable foods and whether GABAA a5 signaling in the PBN LepR neurons controls hunger-driven feeding response. The expected outcome would illuminate novel therapeutic targets in the brain, a critical step which can accelerate the development of next generation of anti-obesity drugs showing much safer and more efficacious profile.
Research Faculty: Qi Wu, Ph.D.