Developmental Determinants of Obesity in Infants and Children
Children's Nutrition Research Center
Project Number: 6250-51000-059-00
Start Date: Mar 23, 2014
End Date: Mar 22, 2019
1) Using mouse model with GHS-R knockout in macrophages, characterize body composition, metabolic and functional characteristics, inflammatory profile, thermogenic phenotype, to establish if GHS-R in macrophages has role in regulation of diet-induced obesity, inflammation, insulin resistance; 2) study macrophage phenotypic switch, inflammation, insulin sensitivity in insulin target tissues; 3) define GHS-R regulated signaling cascades that mediate inflammatory signaling in macrophages, and affected signaling pathways in adipose tissues; 4) determine if ghrelin is involved in regulation of gluconeogenesis, if gluconeogenesis regulation operates via ghrelin receptors; 5) address hypothesis that glucagon-like peptide (GLP)-2 promotes glucose homeostasis and insulin sensitivity through central autonomic pathways by determining effects on hepatic glucose production and feeding behavior; 6) investigate if obesity-induced adipose hypoxia up-regulates PU.1 expression in cultured adipocytes or in mouse adipose tissue; 7) investigate if adipocyte-specific knockout of PU.1 protects mice against high-fat diet induced adipose inflammation and systemic insulin resistance; 8) characterize role of Hedgehog (Hh) pathway in development of white adipose tissues by examining effect of Hh pathway activation on differentiation of preadipocyte cells derived from subcutaneous and visceral white adipose depots from humans; 9) characterize effect of adipocyte-specific activation of Hh pathway on diet-induced obesity and metabolic syndrome using mice carrying elevated Hh pathway activity in white adipocytes to examine if Hh pathway activation can prevent development of obesity and metabolic syndrome; 10) determine if nutritional programming of body weight regulation occurs by inducing specific alterations in hypothalamic DNA methylation; 11) establish if DNA methylation controls selective gene activation and silencing at distinct stages of intestinal epithelial stem cell development; 12) study diet during critical developmental period to assess if it affects epigenetic mechanisms in intestinal epithelial stem cells to modulate their lifelong role in self-renewal and differentiation; 13) identify epigenetic marks on specific genes in children of mothers with pregestational diagnosis of type 1 or 2 diabetes; 14) determine if serotonin 5-HT2C receptors expressed by dopamine neurons are required and/or sufficient to prevent binge eating, obesity and glucose intolerance; 15) identify estrogen receptor alpha sites in the brain that provide redundant mechanisms to regulate glucose balance and body weight; 16) determine if acute or chronic administration of vitamin D3 into the central nervous system affects glucose homeostasis and weight gain; 17) develop a transgenic mouse to investigate effects of acute and chronic administration of vitamin D3 into central nervous system on glucose metabolism and weight gain; 18) define redox signaling in hypothalamic neurons in relation to reactive oxygen species (ROS)-mediated neural activity and eating behavior; 19) investigate function of glutaredoxin (Grx) 3 in the brain and determine its role in food intake and energy expenditure.
These research studies will use various techniques to accomplish the research to be undertaken. Research scientists will conduct phenotypic characterization of LysM-Cre; Ghsr mice to assess the overall metabolic profile and thermogenic phenotype. Using mouse models, we will determine if acyl ghrelin is a primary regulator of hepatic gluconeogenesis and if growth hormone secretagogue receptor (GHS-R1a) is a requirement for ghrelin action; as well as determine the effects on hepatic glucose production and feeding behavior of: a) the GLP-2 receptor (GLP-2R)-PI3K pathway in the hypothalamic arcuate nucleus, b) melanocortin receptor 4 activation in the brainstem dorsal vagal complex (DVC), and c) the influence of GLP-2 in the brainstem DVC. Additional studies will have our researchers investigate if obesity-induced adipose hypoxia is responsible for stimulating adipocyte PU.1 expression and explore if deletion of PU.1 in adipocytes protects mice against high fat diet-induced adipose inflammation and insulin resistance. Scientists will examine the effect of Hedgehog (Hh) signaling on the differentiation of white preadipocytes derived from human subcutaneous and visceral fat depots and also investigate if adipocyte-specific activation of Hh signaling will prevent diet-induced weight gain and improve metabolic abnormalities. Epigeneticists will determine if the persistent effects of postnatal overnutrition on body weight regulation are mediated by induced cell-type specific epigenetic changes in the hypothalamus. They will use intestinal epithelial stem cells isolated at distinct developmental time-points to identify genomic loci that undergo developmentally programmed changes in DNA methylation and investigate the feasibility of epigenomic biomarker discovery in human infants of diabetic mothers and diabetic embryopathy. The resulting data will be used to assess the distribution of class correlations, classifier sensitivity and specificity, positive and negative predictive value, and specific gene content for pathway analysis. Researchers will generate mouse models that either lack 5-HT2CRs selectively in dopamine neurons or express 5- HT2CRs only in dopamine neurons. Examine if these manipulations in mice alter susceptibility to develop eating disorders, obesity and glucose intolerance. Pediatricians will test if central vitamin D3 administration can prevent diet-induced obesity. And finally researchers will analyze the expression and subcellular location of Grx3 in the brain under different dietary conditions, in Grx3-knockout mice, and relate effects of Grx3 to reactive oxygen species signals and NF-B activation and signaling in the hypothalamus.