Submitted by Joe Napoli on
Current worldwide epidemic of metabolic disorders calls for effective strategies for its prevention and treatment. Accumulating evidence from research laboratories and clinical studies show that overweight and obesity in animals and humans develop due to changes in energy and micronutrient metabolism, and cause further irreversible perturbations in energy metabolism leading to diabetes, neurodegenerative disorders and other chronic diseases. My laboratory studies vitamin A metabolism and its relationship to energy metabolism in the context of obesity, diabetes and neurodegenerative diseases. This particular SPUR project focuses on regulation of vitamin A metabolism in brown adipose tissue function and its role in regulating energy metabolism.
In my laboratory we are using modern genetics tools to inactivate or delete critical genes regulating vitamin A metabolism in mice. One of the models we are currently focusing on is a genetic deletion of retinol dehydrogenase 1 (rdh1) gene in the mouse. The Rdh1 protein functions as an enzyme, oxidizing vitamin A (retinol) into its metabolic intermediate retinal. Another class of enzymes called retinaldehyde dehydrogenases further oxidize retinal into all-trans retinoic acid (atRA), the active form of vitamin A. Retinoic acid binds directly to nuclear receptors in cells and regulate expression of more than 600 genes. Results form our laboratory showed that genetic deletion of rdh1 in the mouse initiates long-term metabolic changes in the liver and brown adipose tissue causing increased fat accumulation and weight gain compared to wild type age-matched control mice.
Our lab has previously evaluated phenotypic characteristics of adult mice with genetic deletion of rdh1 (Zhang et al., 2007). We showed that adult mice with genetic deletion of rdh1 experience disrupted vitamin A metabolism and storage in the liver and adipose tissue, which is negatively affecting their energy homeostasis leading to expansion of adipose tissue in adulthood. Current studies are investigating molecular mechanisms of regulation of atRA biosynthesis in brown adipose tissue and transcription factors regulating fatty acids metabolism in brown adipose tissue of rdh1 knock out mice.
During the Fall 2014 semester, a postdoctoral fellow in my laboratory, Dr. Marta Vuckovic will use an in vitro cell culture model system to study molecular mechanisms of vitamin A metabolism regulation during the process of adipocyte differentiation in tissue samples from mice with genetic deletion of rdh1 and wild type control mice. Marta will isolate adipose tissue stem cells from kock-out and age-matched control mice, and induce these cells to differentiate into mature adipocytes. Results of our recent studies indicate that adipose stem cells isolated from rdh1 knockout mice have impaired ability to store large amounts of lipids when cultured in media supplemented with high concentrations of fatty acids. This observation suggests rdh1 involvement in regulating fatty acid transporters on the cellular membrane, or selective fuel switch from glucose to fatty acids in supporting high energy demand of brown adipocytes. We are currently focusing on identifying fatty acid transporters in BAT precursor cells that could be involved in process.
Interested students will have an excellent opportunity for hands-on training in basic techniques in molecular biology and cell culture, as well as mouse colony management. Students will assist a postdoctoral fellow in mouse colony maintenance, adipose tissue collection, stem cells isolation, primary cell culture, differentiation procedures and retinoids assays. Depending on students’ ability to work at the bench, hands-on experience in gene expression techniques will be available. Students will work under close supervision of the senior lab member, and will be expected to keep a detailed lab journal regarding conducted experiments, read relevant research articles and attend weekly lab journal clubs. Students will be involved in data collection and analysis.
Applicant should be familiar with fundamentals of chemistry, molecular biology and genetics, and have interest in metabolism research. Previous experience in biology and chemistry laboratory in class settings is required. Previous experience in guided laboratory research is a plus. Ability to follow detailed instructions, pay close attention to details, and learn quickly is necessary. Critical thinking and independent work is fostered and encouraged in our laboratory. Ability to work with live animals is desirable, and comprehensive training will be provided.