The prenatal and early postnatal environments are increasingly recognized as important determinants of chronic disease risk. Low birth weight (LBW) is associated with increased risk of diabetes and cardiovascular disease. Altered body composition with increased fat mass is a key contributor to these risks, yet accelerated postnatal adipose tissue growth following prenatal undernutrition is not well understood. The mentor has developed a mouse model of prenatal undernutrition. Food restriction during pregnancy of F0 females causes LBW, increased fat mass, and diabetes in F1 offspring. Prenatally undernourished F1 mice have significant reductions in adipose tissue expression of Pref1, an imprinted gene that is a critical negative regulator of adipogenesis. Furthermore, reductions in Pref1 and obesity risk are transmitted intergenerationally, despite no nutritional manipulation in the F2 generation, raising the possibility of epigenetic regulation. The overarching goal of this proposal is to examine how Pref1 expression contributes to obesity risk following prenatal undernutrition, and to determine whether manipulation of adipose tissue Pref1 expression via genetic or pharmacologic approaches modulates this risk.
In Aim 1, we will dissect the relative contribution of changes within F1 germ cells vs. effects of the F1 intrauterine environment in the inter- generational transmission of obesity and Pref1 expression by using embryo transfer techniques. In addition, we will look for similarities between F0 and F1 gestational environments through a metabolomic approach.
In Aim 2, we will test whether Pref1 expression directly contributes to obesity risk following prenatal undernutrition by imposing our F0 prenatal food restriction protocol on transgenic mice with overexpression of Pref1. We hypothesize that Pref1 overexpression will prevent the development of obesity and diabetes in prenatally undernourished F1 offspring. Finally, in Aim 3, we will test whether treatment with a growth hormone releasing analog can (a) modulate Pref1 expression in vivo and (b) improve body composition in prenatally undernourished F1 mice. These experiments are novel in that they combine genetic and physiologic approaches to examine the regulation of excessive adipose tissue growth following LBW. These data will be used toward the development of biomarkers of adverse prenatal environments and targeted preventive strategies.
Prenatal undernutrition can increase risk of diabetes and abdominal obesity. These studies will examine the causes of obesity in our mouse model of prenatal undernutrition. We will determine how a specific gene, Pref1, is altered, and test whether increasing Pref1 expression genetically or pharmacologically can prevent obesity.
|Costa, S M R; Isganaitis, E; Matthews, T J et al. (2016) Maternal obesity programs mitochondrial and lipid metabolism gene expression in infant umbilical vein endothelial cells. Int J Obes (Lond) 40:1627-1634|
|Hivert, M F; Perng, W; Watkins, S M et al. (2015) Metabolomics in the developmental origins of obesity and its cardiometabolic consequences. J Dev Orig Health Dis 6:65-78|
|Isganaitis, E; Rifas-Shiman, S L; Oken, E et al. (2015) Associations of cord blood metabolites with early childhood obesity risk. Int J Obes (Lond) 39:1041-8|
|Radford, Elizabeth J; Ito, Mitsuteru; Shi, Hui et al. (2014) In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345:1255903|
|Perng, Wei; Gillman, Matthew W; Fleisch, Abby F et al. (2014) Metabolomic profiles and childhood obesity. Obesity (Silver Spring) 22:2570-8|
|Huang, Tianyi; Saxena, Aditi R; Isganaitis, Elvira et al. (2014) Gender and racial/ethnic differences in the associations of urinary phthalate metabolites with markers of diabetes risk: National Health and Nutrition Examination Survey 2001-2008. Environ Health 13:6|
|Isganaitis, Elvira; Woo, Melissa; Ma, Huijuan et al. (2014) Developmental programming by maternal insulin resistance: hyperinsulinemia, glucose intolerance, and dysregulated lipid metabolism in male offspring of insulin-resistant mice. Diabetes 63:688-700|
|Colaneri, Alejandro; Wang, Tianyuan; Pagadala, Vijayakanth et al. (2013) A minimal set of tissue-specific hypomethylated CpGs constitute epigenetic signatures of developmental programming. PLoS One 8:e72670|
|Radford, Elizabeth J; Isganaitis, Elvira; Jimenez-Chillaron, Josep et al. (2012) An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming. PLoS Genet 8:e1002605|
|Woo, Melissa; Isganaitis, Elvira; Cerletti, Massimiliano et al. (2011) Early life nutrition modulates muscle stem cell number: implications for muscle mass and repair. Stem Cells Dev 20:1763-9|