Rudolph Leibel, M.D.

Research Summary
Current research activities include efforts to identify genes (and relevant allelic variants) related to obesity and/or type 2 diabetes in mice and humans. This laboraratory participated in the cloning of the leptin and leptin receptor genes, and recently cloned the mouse mahoganoid mutation that modifies the obesity of Yellow mice. The lab has particular interest in the molecular physiology of the energy homeostasis and glucose/insulin metabolism and members are expert in the use of naturally occurring and transgenic rodent models to identify candidate molecules and in vetting these candidates in large numbers of human subjects using high throughput methods (DHPLC, pyrosequencing, fluorescence-based SNP detection). The lab shares responsibility with the Columbia Genome Center for the creation and maintenance of the Columbia University microarray facility (CUMAP), and has personnel expert in the relevant molecular and information science. The lab has many graduate and postdoctoral students, and is dedicated to efforts to use clinical, translational, and basic research to understand basis biological questions related to human disease.

1. Rosenbaum M, Vandenborne K, Goldsmith R, Simoneau JA, Heymsfield S, Joanisse DR, Hirsch J, Murphy E, Matthews D, Segal KR, Leibel RL. Effects of experimental weight perturbation on skeletal muscle work efficiency in human subjects. Am J Physiol Regul Integr Comp Physiol. 2003 Jul;285(1):R183-92.

2. Ferrante, A, Jr., Thearle, M., Liao, T., Leibel, R.L. Effects of leptin deficiency and short-term repletion on hepatic gene expression in genetically obese mice. Diabetes. 50:2268-2278, 2001.

3. Zhang, Y., Guo, K-Y., Diaz, P.A., Heo, M., Leibel, R.L. Determinants of leptin gene expression in fat depots of lean mice. Am. J. Physiol. Reg. Integrative Comp. Physiol. 282:R226-R234, 2002.

4. Rosenbaum, M., Murphy, E, Heymsfield, SB, Matthews, DE and Leibel, RL. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab. 87:2391-4. 2002

5. Phan, L.K. Feng, L. LeDuc, C.A., Chung, W.K., and Leibel, R.L. The mouse mahoganoid (md) coat color mutation disrupts a novel C3HC4 Ring domain protein. J. Clin Invest. 110:1449-1460, 2002.

6. Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, RL, and Ferrante, A. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112:1796-1803. 2003.

1. Cloning of a type 2 diabetes modifier in obese mice
We propose to systematically identify and analyze all genes in the DBA congenic interval, using informatics and molecular biological techniques that we have developed. If successful, this project could identify a major gene (and possibly a novel pathway) for diabetes susceptibility in the context of obesity. Such a gene could be used for anticipatory diagnosis and prevention, and the design of therapeutic agents.
National Institute of Diabetes and Digestive and Kidney Diseases
9/30/2003-7/31/2007

2. Leptin in Human Energy and Neuroendocrine Homeostasis
The proposed studies focus on the neuroendocrine, behavioral, autonomic, and metabolic changes that characterize the reduced-obese individual, and the effects on these phenotypes of restoration of circulating concentrations of leptin to levels present prior to weight loss. We predict that leptin administration will reverse the metabolic, autonomic, and neuroendocrine phenotypes characterizing the weight-reduced state. The results of these studies will further delineate the physiology of body weight regulation and of leptin.
National Institute of Diabetes and Digestive and Kidney Diseases
7/01/2003-4/30/2007

3. Molecular Genetic Analysis of Human Obesity
The goal of this project is to identify the genes (and their respective sequence variants) that play a role in conferring susceptibility to obesity in humans. Knowledge of the nature of these genes, and of the biological mechanism(s) of their actions, would contribute enormously to diagnosis, treatment and prevention of obesity and its allied disorders such as diabetes, cardiovascular disease and certain cancers.
National Institute of Diabetes and Digestive and Kidney Diseases
7/15/1996-6/30/2008

4. Molecular Genetic Analysis of Human Obesity & Non-Insulin Dependent Diabetes Mellitus
National Center for Research Resources

5. Energy Homeostasis in Human Obesity
National Center for Research Resources

Pediatric Endocrine Society; American Institute of Nutrition
American Society for Clinical Nutrition, Harvey Society, AAAS, ADA
Scientific Advisory Board, HERITAGE Family Study, Laval University, Quebec, Canada
Scientific Advisory Board, Pennington Center for Biomedical Research
NIH/NIDDK - National Obesity Task force; Planning Group - Genetics, Genomics and Bioinformatics; Oversight committee, Mouse Metabolic Phenotyping Centers
Institute of Medicine of the National Academy of Sciences
Member, National Advisory Council, NIDDK, NIH.

Journal of Clinical Investigation, Associate Editor
Journal of Clinical Endocrinology and Metabolism
Obesity Research (Genetics)
International Journal of Obesity (Genetics)

gene expression, genetic susceptibility, genotype, human population genetics, obesity, diabetes, body composition, caucasian American, gene frequency, DNA footprinting, clinical research, DHPLC, Pyrosequencing, human subject, laboratory mouse, linkage mapping, mass screening, microarray technology, polymerase chain reaction, quantitative trait loci, single nucleotide polymorphism, transgenic animal