Heads of Laboratories
Investigator, Howard Hughes Medical Institute
Marilyn M. Simpson Professor
Laboratory of Molecular Genetics
Friedman studies the molecular mechanisms that regulate food intake and body weight. Genetic studies in mice led him to identify leptin, a hormone made by fat tissue that plays a key role in controlling appetite and weight. His current work explores the mechanisms by which leptin mediates these functions, and seeks toidentify other key regulators of body weight.
Leptin is a hormone secreted by 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.
The recent identification of the hypothalamic cells that express the leptin receptor is enabling 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. Friedman’s lab has identified a specific neural population in the hypothalamus that expresses a bioactive peptide known as MCH, which plays a key role in sensing the reward value of food. His ongoing studies seek to understand how leptin modulates the activity of these neurons as well as to identify additional neural populations that regulate feeding.
The Friedman lab is also 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 modified a series of leptin bacterial artificial chromosome clones so that the leptin DNA regulatory elements direct the expression of luciferase, enabling them to identify DNA regulatory sequences that control leptin gene expression. The goal of these studies is to identify 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; current data suggest it interferes with both the production and action of glucagon, a hormone that acts to increase blood glucose by opposing the effects of insulin.
In collaboration with Tayfun Özçelik at Bilkent University in Ankara, Turkey, the Friedman lab is conducting studies of consanguineous families that include patients who are either morbidly obese, extremely lean, or have polycystic ovary disease (PCOS), which is associated with resistance to insulin. The team expects that analyses of the DNA sequences from these populations will reveal DNA mutations that contribute to differences in weight or 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
Co-director, Kavli Neural Systems Institute, 2015–2016
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
Harrington Prize for Innovation in Medicine, 2016
National Academy of Sciences
National Academy of Medicine
Fellow, American Association for the Advancement of Science
Ekstrand, M.I. et al. Molecular profiling of neurons based on connectivity. Cell 157, 1230–1242 (2014)
Domingos, A.I. et al. Hypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugar. Elife 2, e01462 (2013).
Stanley, S.A. et al. Radio-wave heating of iron oxide nanoparticles can regulate plasma glucose in mice. Science 336, 604–608 (2012).
Knight Z.A., et al. Molecular profiling of activated neurons by phosphorylated ribosome capture. Cell 151, 1126–1137 (2012).
Domingos, A.I. et al. Leptin regulates the reward value of nutrient. Nat. Neurosci. 14, 1562–1568 (2011).