Heads of Laboratories
Dr. Friedman studies the molecular mechanisms that regulate food intake and body weight. Genetic studies in mice led to the identification of leptin, a hormone made by fat tissue, that plays a key role in regulating weight. With the identification of leptin and its receptors, two of the molecular components of a system that maintains constant weight have been identified. Current studies aim to explore the mechanisms by which leptin controls feeding behavior, body weight and glucose metabolism, as well as to identify other key regulators.
Leptin is a hormone secreted by the adipose tissue, in proportion to its mass, that modulates food intake relative to energy expenditure, maintaining weight within a relatively narrow range. Increased fat mass increases leptin levels, which reduces body weight; decreased fat mass leads to a decrease in leptin levels and an increase in body weight.
Defects in the leptin gene are associated with severe obesity in animals and humans. Leptin acts on neurons in brain centers that control energy balance, and it plays a general role in regulating many of the physiologic responses observed with changes in nutritional states, with clear effects on female reproduction, immune function and the function of other hormones, including insulin.
Using a novel system that employs an engineered virus to trace the neural circuit modulated by leptin, Dr. Friedman and his colleagues have found that a number of brain regions, including those known to regulate emotional behavior and higher brain functions, modulate leptin signaling in the hypothalamus. The lab also has shown that these leptin-responsive circuits are extremely dynamic and that leptin has rapid and dramatic effects on the number of synapses found on key neural pathways that regulate feeding. Using laser photostimulation, they mapped with great precision the inputs to leptin-responsive neurons.
Most recently, the Friedman lab has used channel rhodopsin to modulate the activity of neurons that regulate ingestive behavior. They showed that light activation of dopaminergic neurons in reward centers of mice, coupled to licking using a “lickometer,” markedly increased ingestive behavior and altered an animal’s preference for sucrose over sucralose, a non-nutritive sweetener.
A new line of research is aimed at elucidating the molecular mechanisms responsible for the regulation of leptin gene expression associated with weight changes. The amount of leptin expressed from fat is strongly regulated, which suggests that the fat cell knows how much fat it has. To address this question, the lab is using transgenic mice to identify DNA regulatory elements that change expression of a receptor gene controlled by the leptin gene in parallel with changes in adipose tissue mass.
The Friedman lab has shown that leptin’s effects on fat deposition resulted from the downregulation of stearoyl-CoA desaturase (SCD-1), an enzyme that plays an important role in fat metabolism. Studies with Markus Stoffel’s group, formerly at Rockefeller, have shown that leptin’s antidiabetic effects are independent of SCD-1 and in part are a result of activation of the FoxA2 transcription factor. Recently the lab showed that leptin increases the expression of IGF Binding Protein 2 (IGFBP2), a plasma protein produced by the liver. Overexpression of IGFBP2 can improve insulin resistance in a number of animal strains that develop diabetes.
Diet-induced weight loss in humans decreases leptin concentration, which may explain dieting’s high failure rate. Data is now being analyzed from recently completed clinical studies at The Rockefeller University Hospital that explored the possibility that leptin administered to dieting patients can alter the biologic response to weight.
The Friedman lab has been conducting genetic studies in collaboration with the Department of Health on the Pacific island of Kosrae in Micronesia and with the laboratories of Dr. Stoffel and Jan Breslow. The citizens of Kosrae have a high incidence of obesity, the basis of which is not understood. The researchers genotyped the entire population and identified a number of genetic loci responsible for aspects of human metabolic disease. Dr. Friedman and his colleagues plan to impute the sequence of everyone on the island by sequencing about 50 “key” individuals. These studies are being performed in collaboration with Itsik Pe’er at Columbia University.
Dr. Friedman graduated from Rensselaer Polytechnic Institute and, in 1977 at the age of 22, received his M.D. from Albany Medical College of Union University. After completing two residencies at Albany Medical Center Hospital, Dr. Friedman came to Rockefeller as a postgraduate fellow and associate physician in 1980. In 1986 he received his Ph.D., working in the lab of James E. Darnell Jr., and was appointed assistant professor. In 1991 he was named head of laboratory, and in 1995 he was promoted to professor. He was appointed the Marilyn M. Simpson Professor in 1999. He has been an investigator at the Howard Hughes Medical Institute since 1986.
A member of the National Academy of Sciences and its Institute of Medicine, his honors include the 2010 Albert Lasker Award for Basic Medical Research, the Shaw Prize in Life Science and Medicine, the Keio Medical Science Prize, the Jessie Stevenson Kovalenko Medal, the Danone International Prize for Nutrition, the Gairdner Foundation International Award and the Passano Foundation Award.
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