Metabolic Programming Lab
The Metabolic Programming Laboratory conducts research leading to fundamental understanding of the development of obesity, metabolic disease and associated co-morbidities. The laboratory leverages a wide range of experimental approaches including animal models, clinical studies, cell and molecular techniques, and physiological approaches. We widely utilize high-dimensional data driven “-omics” methods to comprehensively understand biological mechanisms of developmental programming.
Our group is specifically interested in the consequences of maternal diet and obesity on child health and development. We extensively collaborate with groups in understanding several aspects of offspring physiology. This cross-disciplinary program integrates mechanistic understanding of changes in early development (conception through pregnancy and postnatally) with offspring health into adulthood. We employ animal models (rats and mice) in conjunction with longitudinal prospective clinical studies in an integrative fashion. In a series of publications, our work has begun to elucidate the nature and mechanisms by which maternal obesity and diet impact the offspring, including new insights regarding epigenetic changes that can occur in offspring in response to maternal obesity, diet and physical activity.
Ongoing Project Descriptions
Maternal Obesity & The Offspring
As the prevalence of obesity increases, so does the incidence of maternal overweight during pregnancy. A major area of investigation in our lab is to understand the developmental origins of childhood and adult obesity, specifically the long-term consequences of maternal obesity. Specifically, we are examining aspects of hepatic, skeletal muscle and adipose tissue metabolism in the offspring of obese mothers. We leverage techniques ranging from global gene expression to whole animal integrative physiology and endocrinology. Ongoing work in the lab includes hypothesis-driven studies geared toward addressing the mechanistic basis of programming of obesity risk. Using genetic manipulations in mouse models of maternal obesity, an important goal is to examine the roles of specific obesity-associated changes (inflammation in utero; maternal and offspring gut microbiome; nutrient transport; and lipotoxicity at the maternal-fetal interface) as causative mechanisms leading to epigenetic changes. The overall objective of these studies is to gain a better mechanistic understanding of the physiological basis of fetal programming. Through translational studies, we aim to provide novel opportunities for effective intervention.
Obesity & The Placenta
The proper development of the placenta is critical to the health of the baby. In addition to serving as the lungs, GI and immune systems in the womb, the placenta also may be central in determining the long-term health of the baby. We are currently studying the effects of maternal obesity on the development and function of the placenta in animal models and in samples from human subjects at the end of pregnancy. This provides a unique “window” into the intrauterine environment, and molecular changes in the placenta may report on similar changes that occur in the tissues of the offspring.
Epigenetic Mechanisms of Placental Development
The development of the hemochorial type of placenta (found in humans and rodents) critically depends on the formation of the syncytiotrophoblast (STB), which serves as the definitive materno-fetal barrier. This polarized interface mediates the exchange of nutrients, gases and waste between mother and developing fetus. Formation and constant renewal of the syncytium occurs via cell-syncytial fusion of the underlying mononuclear cytotrophoblasts (CTB). Hence, the process of syncytialization is critical to the integrity of the STB and in maintaining the essential functions of the placenta. Using a combination of genome-scale methods (RNA-seq, ChIP-seq) and systems biology tools, in conjunction with genetic loss-of-function approaches, we are characterizing novel epigenetic processes required for syncytial fusion.