Heads of Laboratories
Investigator, Howard Hughes Medical Institute
Marilyn M. Simpson Professor
Laboratory of Molecular Genetics
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. Current studies explore the mechanisms by which leptin controls feeding behavior and body weight. Studies to identify other key regulators are also under way.
Numerous lines of evidence have suggested that energy balance in animals and humans is tightly controlled. With the identification of leptin and its receptors by the Friedman laboratory, two of the molecular components of a system that maintains constant weight have been identified. Leptin is a hormone secreted by the adipose (fat) tissue in proportion to its mass that in turn modulates food intake relative to energy expenditure. Increased fat mass increases leptin levels, which in turn reduces body weight; decreased fat mass leads to a decrease in leptin levels and an increase in body weight. By this mechanism, weight is maintained within a relatively narrow range. Defects in the leptin gene are associated with severe obesity in animals and in humans.
Leptin acts on sets of neurons in brain centers that control energy balance to regulate appetite. Leptin also plays a general role in regulating many of the physiologic responses that are observed with changes in nutritional state, with clear effects on female reproduction, immune function and the function of many other hormones, including insulin.
Current research in the Friedman lab focuses on a series of questions pertinent to the regulation of body weight: How does the fat cell regulate how much leptin is made — i.e., how does the fat cell know how fat it is? How does a single molecule (leptin) change feeding, a complex behavior? How do brain pathways that are modulated by leptin in turn regulate peripheral metabolism and insulin action? Does variation in the genes that compose the physiologic circuit of which leptin is a component explain differences in body weight?
The recent identification of the hypothalamic cells that express the leptin receptor is enabling Dr. Friedman and his colleagues to delineate the precise neuronal effects of leptin and the mechanisms by which this single molecule can alter a complex behavior. Recent studies have revealed that leptin reduces food intake by decreasing the pleasure associated with food. This finding suggests that the pleasure derived from eating is not fixed but rather reflects the status of metabolic signals.
The lab has also identified a specific neural population in the hypothalamus that expresses a bioactive peptide known as MCH, which plays key role in sensing the reward value of food. Ongoing studies seek to understand how leptin modulates the activity of these neurons. In addition, several new methods have also been developed for identifying additional neural populations that regulate feeding. In the first, a novel gene profiling technology can be used to define neural populations whose activities are regulated by a stimulus. In the second, gene profiling technology is used to define specific neural populations based on their anatomic connections. Finally, the lab has developed a new method for probing neural function using magnets or radiowaves to remotely modulate the activity of specific neural populations in vivo.
The Friedman lab is also studying the molecular mechanisms responsible for changes of leptin gene expression associated with changes in fat mass. The amount of leptin that is expressed from fat is strongly regulated, with a more than 100-fold increase in expression from ob/ob adipose tissue compared to adipose tissue of a lean or fasted animal, suggesting that fat cells know how much fat they have and adjust leptin expression accordingly. To identify the underlying mechanism responsible for this regulation, Dr. Friedman and his colleagues are using transgenic mice to identify DNA regulatory elements that change expression of a reporter gene controlled by the leptin gene proportionately with changes in adipose tissue mass. They have thus modified a series of leptin bacterial artificial chromosome (BAC) clones so that the leptin DNA regulatory elements direct the expression of luciferase. This has enabled the researchers to identify DNA regulatory sequences that control leptin gene expression as well as protein factors binding to these sequences. Studies to elucidate how the activity of these factors changes, as fat is gained or lost, are underway. Dr. Friedman hypothesizes that these studies will lead to the identification of a novel lipid sensing signaling pathway in adipocytes and possibly other cell types.
Leptin has potent metabolic effects to improve insulin action and reduce the lipid content of peripheral tissues as retained and is now an FDA-approved drug for the treatment of severe lipodystrophy, a form of diabetes. The Friedman lab is studying the mechanism responsible for leptin’s antidiabetic function in this and other forms of diabetes. Current data suggests that leptin interferes with both the production and the action of glucagon, a hormone that acts to increase blood glucose by opposing the effects of insulin. The cellular mechanisms responsible for this are under investigation.
In collaboration with Tayfun Ozcelik at Bilkent University in Ankara, Turkey, the Friedman lab is conducting studies of consanguineous marriages that include patients who are either morbidly obese, extremely lean or have polycystic ovary disease (PCOS), which is associated with extreme resistance to insulin. Whole genome sequencing is now underway on more than 50 families, with the expectation that analyses of the DNA sequences from patients who are lean and obese will reveal DNA mutations that contribute to differences in weight, or, in other families, that lead to PCOS.
Renssalaer Polytechnic Institute
Albany Medical College, Union University
The Rockefeller University
Internship in medicine, 1977–1978
Residency in medicine, 1978–1980
Albany Medical Center Hospital
Assistant Professor, 1986–1991
Associate Professor, 1991–1995
The Rockefeller University
Associate Physician, 1980–1983
The Rockefeller University Hospital
Assistant Investigator, 1986–1992
Associate Investigator, 1992–1996
Howard Hughes Medical Institute
Canada Gairdner International Award, 2005
Passano Award, 2005
Jessie Stevenson Kovalenko Medal, 2007
Danone International Prize, 2007
Shaw Prize, 2009
Keio Medical Science Prize, 2009
Albert Lasker Basic Medical Research Award, 2010
BBVA Frontiers of Knowledge Award, 2012
Fondation IPSEN Endocrine Regulation Prize, 2012
King Faisal International Prize, 2013
National Academy of Sciences
National Academy of Medicine
Fellow, American Association for the Advancement of Science
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Domingos, A.I. et al. Leptin regulates the reward value of nutrient. Nat. Neurosci. 14, 1562–1568 (2011).