Jeffrey M.
Friedman, M.D., Ph.D.
Leptin and the Regulation of Body Weight.
Abstract: Leptin, the hormone encoded by the ob gene, plays an important role in regulating the size of the adipose tissue mass. Injections of recombinant leptin reduce body weight and food intake of normal and obese (ob) mice in a dose dependent manner but have no effect on diabetic (db) mice, another recessive obesity gene. These data identify leptin as an important signaling molecule that acts to maintain constant stores of body fat. The complete insensitivity of db mice to leptin and the identical phenotype of ob and db mice suggested that the db locus encodes the leptin receptor. The db gene was found to be identical to a leptin receptor (Ob-R) which was functionally cloned from choroid plexus. However, because this receptor was normal in C57BL/Ks db/db mice, the possibility was raised that this db mutation affected an alternatively spliced form. The Ob-R gene was found to encode at lest five different splice variants. One of the splice variants is expressed at a high level in the hypothalamus and at a lower level in other tissues. This transcript is mutant in C57BL/Ks db/db mice. The mutant protein is missing the cytoplasmic region and is defective in signal transduction. Further studies have revealed that the Stat3 transcription factor is activated specifically in hypothalamus within 15 minutes of a single injection of leptin in ob and wild type but not in db mice. In vitro studies indicate that SHP-2, a phosphoprotein phosphatase, is also a component of the leptin signal transduction pathway. Consistent with a CNS site of action, low dose infusions of leptin (5 ng/hr) intracerbroventicularly reproduce the effects of much larger doses given peripherally. In order to elucidate the components of the neural circuit activated by leptin, novel methods for neural tracing are being developed and will be discussed. The nature of the efferent signals form integratory centers in the hypothalamus are also under study. Infusions of leptin ICV result in changes in fat and glucose metabolism that are qualitatively different from those that result from food restriction. Studies of the metabolic response to leptin and the mechanisms by which CNS signals affect glucose and fat metabolism are also underway.
Biographical sketch: Dr. Friedman is a leading researcher on the molecular mechanisms regulating food intake and body weight. His work received national attention when his group isolated the mouse ob gene and its human homologue in 1994. Dr. Friedman's team subsequently discovered that injections of the encoded protein, leptin, decreased body weight of mice by reducing food intake and increasing energy expenditure. Dr. Friedman's current research is aimed at understanding the mechanisms by which leptin transmits its weight-reducing signal.
The leptin gene is detective in ob mice, a massively obese strain that exhibits a syndrome similar to morbid obesity seen in humans. Dr. Friedman's data suggest that leptin functions as an afferent signal in a negative feedback loop regulating body weight in mammals, including humans. Currently, in an attempt to establish the genetic basis of obesity in humans, Dr. Friedman is studying the Kosraen population in Micronesia, which has a high incidence of obesity and diabetes.
Dr. Friedman's pioneering research has been recognized internationally with invited lectures and awards, including the TOPS Award from the North American Association for the Study of Obesity. He also was awarded Grand Prize, Best of What's New-Science and Technology, by Popular Science and was profiled in Time Magazine's Best of Science feature. Other awards include the Alumnus of the Year, 1996, from Albany Medical College, the Shelton Lecture, Harvard University, 1996, Peter's Lecture, Yale University, 1996, Heinrich Wieland Prize, 1996, the Jacobaeus Prize, University of Goteborg, 1997, the Allan D. Bass Lecture, Vanderbilt University, 1997, the Carl Vernon Moore Lecture, Washington University, 1997, the Priscilla White Lecture, Joslin Diabetes Center, 1998, the Chilton Foundation Lecture, University of Texas, 1998, the Jack Gross Memorial Lecture, Israel, 1998, the Steven C. Beering Award, Indiana University School of Medicine, 1999, the Van Wyk Lecture, Baylor College of Medicine, 1999.
Dr. Friedman graduated from Albany Medical College in New York, completed a medical residency at Albany Medical Center Hospital, and earned a Ph.D. from The Rockefeller University. He currently is Director of the Starr Center for Human Genetics, Marilyn M. Simpson Professor at The Rockefeller University, and Investigator, Howard Hughes Medical Institute.
Jeffrey Friedman's homepages at: The Rockefeller University & HHMI