Location: Children's Nutrition Research Center
Project Number: 3092-51000-064-000-D
Project Type: In-House Appropriated
Start Date: Mar 4, 2019
End Date: Mar 3, 2024
Objective:
Obesity and its associated metabolic disorders represent a serious health problem to our society. To address this researchers aim to: 1) determine if potassium channels (SK3) expressed by serotonin neurons are required to regulate feeding behavior and body weight balance using a Cre-loxP strategy to generate mouse models that either lack SK3 selectively in serotonin neurons and test if these manipulations in mice alter animals' food intake and body weight; 2) identify downstream neural circuits that mediate serotonin neuron actions to regulate feeding behavior and body weight balance and selectively stimulate specific downstream neural circuits that originate from brain serotonin neurons in mice, and measure effects on animals' feeding behavior and body weight; 3) identify upstream and downstream signaling molecules of glycogen synthase kinase 3 beta that controls suppressor of cytokine signaling 3 levels and cellular insulin and leptin actions in the hypothalamus by using an ex vivo brain slice model; 4) determine if each component of the glycogen synthase kinase 3 beta-related pathway determines hypothalamic levels of suppressor of cytokine signaling 3 and hypothalamic leptin and insulin actions in vivo by using genetically engineered mouse models; 5) determine the physiological roles of genetically defined Agouti-related protein/proopiomelanocortin-parabrachial nucleus circuit in differential control of feeding behavior and energy metabolism; 6) determine the physiological roles of key gamma amino butyric acid and N-methyl-D-aspartic acid glutamate receptor subunits expressed in the Agouti-related protein/proopiomelanocortin-parabrachial nucleus circuit for the regulation of appetite, energy balance, and development of obesity; 7) investigate the interaction of various phospholipid species with the LRH-1 nuclear receptor, and determine the potential metabolic benefits to insulin resistance in obesity; 8) use transgenic mice with liver specific knockout of the liver receptor homolog LRH-1 nuclear receptor to critically test its role as the potential mediator of the metabolic benefits of phosphatidylcholine agonist ligands in obesity; 9) removed due to investigator departure; 10) removed due to investigator departure; 11) determine if maternal obesity and high-fat diet during gestation induce adipogenic and metabolic program alterations in Wt1 expressing white adipocyte progenitor cells during development; 12) assess if carbohydrate response element binding protein alters macrophage intracellular metabolism and inflammatory response; 13) assess if macrophage carbohydrate response element binding protein activity affects adipose tissue inflammation and the development of diet-induced obesity and insulin resistance; and 14) use wild type mice to determine organ specific metabolism of fatty acids of varying carbon chain lengths, and study their effects on the progression and/or treatment of diet-induced obesity and its related metabolic disorders.
Approach:
A multi-discipline approach will be undertaken to address these concerns. Rodent models will be utilized to examine the role of small-conductance Ca2+-activated K+ currents in 5-HT neurons in the regulation of hedonic feeding and we will work to identify a previously unrecognized neural signaling pathway that controls leptin and insulin actions in the hypothalamus and mediates whole-body energy balance. Collectively, the studies will demonstrate the potential roles of metabolic cues (hormones/nutrients), central nervous system 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. Researchers will also study the role of endogenous phosphatidylcholines in the prevention and treatment of non-alcoholic fatty liver disease and insulin resistance, and test the hypothesis that beneficial effects of these natural phosphatidylcholines are due to LRH-1 activation. We will also will use mouse models of diet-induced obesity and will focus on three general problems associated with obesity: the developmental effects of maternal obesity on offspring adiposity, adipose tissue inflammation that may lead to medical complications, and the effects of dietary fatty acid composition on obesity.
