The New York Obesity Nutrition Research Center

Co-Director: Dr. Rudolph Leibel of Columbia University Medical Center (effort = 1.8 calendar months) has been Co-Director of the NYONRC since 1999. He shares responsibility for the Center with Dr. Pi-Sunyer. He is particularly involved with supervision of the Center functions at the Columbia University Medical Center and Einstein College of Medicine. He is responsible for supervising the mentoring of trainees at those sites. He is also responsible for administering the finances of the subcontracts at the CUMC. He is on the Pilot and Feasibility Committee and also is responsible for the enrichment program. Please see Molecular Biology Core budget justification for additional details,

Rudolph L. Leibel, MD (Core Director). Columbia. 5.0% effort = 0.60 calendar months. Dr. Leibel is responsible for the overall supervision of the Core and for management of its budgets and resources. He coordinates collaborative arrangements between the Core and interested investigators (NYNORC members as well as non NYNORC members). These projects involves both human and mouse studies related to the genetics and molecular physiology of obesity and diabetes.

Rudolph L. Leibel. MD (Co-Director of the NORC). Columbia. 15% effort = 1.8 calendar months. Dr. Leibel is Co-Director of the NYNORC. He works with Dr. Pi-Sunyer to assure that the scientific cores and the administrative core achieving the programmatic goals of the Center. He has served in this capacity for the past 10 years, and knows the investigators at St. Luke's-Roosevelt, Columbia and Albert Einstein personally and is fully aware of their research efforts. He communicates with Core-Directors regularly and assists in the vetting of Pilot & Feasibility applications. He also serves as Co-Director of the Columbia Diabetes & Endocrinology Research Center- DERC (with Dr. Accilli) and this position enables him to insure full coordination of activities and resources between the NORC and DERC.

Dr. Leibel, as Director of the NYONRC, has five primary responsibilities at the Columbia University Medical Center campus. The first is to take primary responsibility with the investigators of the NYONRC who are at the CUMC site. He orients them on the use of any Core, resolves issues of utilization for the Cores at the CUMC and AECOM sites, encourages application for Pilot and Feasibility grants. The second is to assure the smooth functioning of the Molecular Biology/Molecular Genetics Core. The third is to assure that the trainees of the NYONRC in his Core are appropriately mentored. The fourth is to contribute to the Enrichment aspect of the NYONRC by initiating invitations to outside speakers, organizing and participating in seminars and symposia, encouraging collaborative research with other Users of the NYORC, and providing advice in his area of expertise. The fifth is in being a member of the Pilot and Feasibility Committee.

Dr. Leibel has worked in obesity research for over 30 years. His initial research efforts were focused on adrenergic receptor-mediated effects on lipolysis, and on the control of fatty acid re-esterification in human adipose tissue. He was among the first investigators to describe anatomic site-related differences in alpha 2 and beta 1 adrenoreceptor activity in human adipose tissue, and to assess their roles in determining the sexual dimorphism in human adipose tissue distribution. His studies of the re-esterification pathway in human adipose tissue led to the development of a microassay system for quantifying this process and to insights into the control of circulating free fatty acids in humans.

Dr. Leibel and his associates have conducted studies on the metabolic consequences of experimental weight perturbation in obese and never-obese human subjects. These studies have been done in Clinical Research Center venues, permitting careful control of diet and physical activity. His were the first studies to document and quantify the persistent lowering of energy expenditure-beyond that explicable by altered body mass and composition-that accompanies the maintenance of a reduced body weight. Subsequent studies have shown that altered skeletal muscle metabolism in low work states is an important contributor to the reduction in energy expenditure. Using in-vitro NMR and biochemical/molecular analysis of skeletal muscle biopsy samples, the molecular mechanisms for these changes are being sought.

Recently, Dr. Leibel, with his associate, Michael Rosenbaum, has shown that many of the most important physiological aspects of the formerly-obese state are rectified by the administration of very low (“replacement”) doses of exogenous leptin. These studies suggest that the reduced- obese state is, in some regards, a state of relative leptin deficiency due to reduced body fat. These observations point to potential therapeutic approaches to correcting this phenotype and improving success at long term maintenance of reduced body weight.

In 1985 Dr.Leibel and his associates (then at Rockefeller University) began a series of experiments to produce molecular maps of mouse single gene obesity mutations: ob, db, fat and tub. These efforts, in collaboration with the Friedman laboratory at Rockefeller, led to the cloning of the ob (leptin) gene in 1994. This discovery, by identifying a major signal of adipose tissue mass to the brain, has had an important impact on obesity research in animals and humans. Among other effects of this discovery has been the elaboration of detailed molecular pathways within the hypothalamus for the control of energy homeostasis in mammals. As part of a comparative mapping project, Dr. Leibel’s group showed that the fatty mutation in the Zucker (fa) study rat was in the same gene as the mouse db mutation. In 1995, working with collaborators at Millennium, Leibel and his associate Dr. Streamson Chua (co-director of the Molecular Biology Core, NYONRC) showed that an apparent leptin receptor cloned from a choroid plexus library using leptin as ligand, mapped to a physical map that included db and fa. This experiment confirmed cloning of the leptin receptor.

Dr.Leibel’s group went on to find the Lepr mutations that account for the obesity of the Zucker and Koletsky (corpulent) rats, and to describe the mechanism by which the fa mutation (a single amino acid transversion) interferes with function of LEPR. The group has subsequently worked out the fine structure of many of the genes in the leptin response pathway, and in collaboration with investigators around the world, have studied the contribution of allelic variation in these genes to aspects of body composition, obesity and type 2 diabetes in humans. In addition, his group has performed studies relating to sexual dimorphism in circulating leptin concentrations to energy expenditure in humans. Many of these studies have been conducted in collaboration with other scientists at the NYORC.

Dr.Leibel’s group has also been instrumental in describing the molecular bases for other mutations of the leptin receptor in mice and rats, and has established small colonies of mice and rats segregating for these mutations on various inbred backgrounds. In 2002 his group reported the cloning of the mouse mahogonoid mutation (named mahogunin = Mgrn1). This gene is an E3 ligase that when inactivated by null mutation is epistatic to the coat color and obesity of the yellow (Ay) mouse. His group is now actively investigating the molecular physiology of this protein, and has screened human subjects for sequence variants in the ortholog.

Among other areas of active research in Leibel’s Division of Molecular Genetics at Columbia are: characterization of the molecular physiology of genes related to energy homeostasis in humans; transgenic analysis of the effects of organ-specific expression of leptin receptor isoforms in the mouse; autocrine and other control mechanisms for anatomic depot-specific regulation of leptin expression; molecular regulation of insulin release from islet beta cells; molecular genetic analysis of derangements in the growth hormone axis in humans.

Most recently, Leibel and his collaborators have been endeavoring to clone genes that mediate susceptibility to type 2 diabetes in the context of obesity. This project has resulted in the creation of a large number of mouse congenic lines in which short segments of DNA conveying susceptibility are segregated on non-susceptible genetic backgrounds. Using a variety of strategies, efforts are underway to clone the responsible genes. This project has led to the development of new computational tools for comparing and displaying DNA sequence analysis among mouse strains, and to novel uses of microarrays for gene and pathway identification.

For the past few years Leibel has worked with his associate, Anthony Ferrante, and MD/PhD graduate student, Stuart Weisberg, to identify the molecular bases for the inflammatory state associated with obesity. They discovered that adipose tissue macrophages and monocyte/macrophages elsewhere in the body are among the major sources of the cytokines implicated in the inflammatory process. They are now using genetic approaches in mice to identify the molecules that mediate the accession of monocytes (hence macrophages) to specific organs such as adipose tissue, liver, muscle and islets.

Dr. Leibel is internationally recognized for this work and has received a number of prizes and honorary lectureships. He is a member of the Institute of Medicine of the National Academy of Sciences, and was a member of the Advisory Council for NIDDK. His laboratory has trained many students at all levels in research related to obesity and diabetes. Within the past 7 months, three of Dr. Leibel’s students have received PhD’s from Columbia University. All these projects were related to the molecular physiology of obesity and/or diabetes in mice.

Dr. Leibel serves on the editorial boards of the Journal of Clinical Investigation, International Journal of Obesity and Obesity Research.

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