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Hormone Resistance in Diabetes and Obesity: Insulin, Leptin, and FGF21

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Hormone Resistance in Diabetes and Obesity: Insulin, Leptin, and FGF21 Hormone Resistance in Diabetes and Obesity: Insulin, Leptin, and FGF21 The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Flier, Jeffrey S. 2012. Hormone resistance in diabetes and obesity: insulin, leptin, and fgf21. The Yale Journal of Biology and Medicine 85(3): 405-414. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:10436248 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA YALE JOURNAL OF BIOLOGY AND MEDICINE 85 (2012), pp.405-414. Copyright © 2012. LEE E. FARR LECTURE Hormone resistance in diabetes and obesity: insulin, Leptin, and FGF21 Jeffrey S. Flier Dean of the Faculty of Medicine, Harvard University, Harvard Medical School, Boston, Massachusetts This an edited transcript of the Lee E. Farr Lecture given by Dr. Jeffrey Flier on May 8, 2012, at the culmination of the annual Student Research Day at the Yale School of Medicine. In this presentation, Dr. Flier discusses his and his wife’s research on insulin, leptin, and FGF21 in the context of his reflections upon his life’s work and his advice for young investigators. introduction Chief Academic Officer for Beth Israel Deaconess Medical Center (BIDMC), a Dr. Jeffrey S. Flier was named the 21st Harvard teaching affiliate. Dean of the Faculty of Medicine at Harvard Flier was born in New York City. He University on July 11, 2007. Flier, an en - received a BS from City College of New docrinologist and an authority on the mo - York in 1968 and an MD from Mount Sinai lecular causes of obesity and diabetes, is School of Medicine in 1972, graduating also the Caroline Shields Walker Professor with the Elster Award for Highest Aca - of Medicine at Harvard Medical School demic Standing. Following his residency (HMS). Previously, he served as HMS Fac - training in internal medicine at Mount Sinai ulty Dean for Academic Programs and Hospital from 1972 to 1974, Flier moved To whom all correspondence should be addressed: Jeffrey S. Flier, MD, Dean of the Fac - ulty of Medicine, Harvard University, Harvard Medical School, 25 Shattuck St. – Gordon Hall, Room 111, Boston, MA 02115; Email: [email protected]. †Abbreviations: HMS, Harvard Medical School; BIDMC, Beth Israel Deaconess Medical Center; NIH, National Institutes of Health; NIDDM, non-insulin-dependent diabetes melli - tus; NAFLD, non-alcoholic fatty liver disease. Keywords: Farr Lecture, insulin, leptin, FGF21, obesity, diabetes 405 406 Flier: Lee E. Farr lecture to the National Institutes of Health (NIH) as Endocrine Society and the Banting Lecture a Clinical Associate. In 1978, he joined the of the American Diabetes Association, its Faculty of Medicine at HMS, serving as highest scientific honor. In 2010, Flier was Chief of the Diabetes unit at Beth Israel awarded an Honorary Doctor of Science De - Hospital until 1990, when he was named gree from the University of Edinburgh and chief of the hospital’s Endocrine Division. last year was awarded the 2011 Rolf Luft In 2002, Flier was named Chief Aca - Award for Metabolic Research by the demic Officer of BIDMC, a newly created Karolinska Institute in Stockholm, Sweden. senior position responsible for research and We are delighted and honored that he academic programs. He worked with Beth delivered the 25th Lee E. Farr Lecture, and Israel Deaconess academic department his doing so is a testament to how meaning - chairs to ensure the quality and breadth of ful medical student research is to him. academic programs at the Medical Center, through which most of HMS students pass. Lee e. Farr Lecture He also served as the formal liaison to HMS, sitting on the Council of Academic Deans. It is a distinct pleasure and honor to be Flier is one of the country’s leading in - asked to give the Farr lecture, which has a vestigators in the areas of obesity and dia - tradition of excellent speakers and is espe - betes. His research has produced major cially meaningful for its focus on medical insights into the molecular mechanism of in - students’ research. My own research career sulin action, the molecular mechanisms of began when I was a medical student, and the insulin resistance in human disease, and the state of medical student research at HMS, molecular pathophysiology of obesity. He the school that I now lead, is something to was one of the first to demonstrate that diet- which I have given much attention. Re - induced obesity in rodents is associated with search is an aspect of medical education that increased leptin expression and leptin re - has been prominent at Yale for more than a sistance, and that short-term starvation is as - century. Harvard has always had many stu - sociated with decreased leptin expression dents who do research, but as of this past and blood levels. His proposal that leptin year, it is now a requirement for every en - level serves as a switch from the fed to the tering student to complete a scholarly proj - starved state has fundamentally shaped dis - ect, and this is an exciting initiative for the course in the field. school. Flier has authored more than 200 schol - This lecture will not focus in great de - arly papers and reviews and has held many tail on the most recent work in my labora - editorial positions, including Associate Edi - tory. Rather, my goal is to use some research tor of the Journal of Clinical Investigation , vignettes to illustrate aspects of my own ap - and has served on the Editorial Boards of proach to research over the years. I will Molecular Endocrinology , the Journal of begin with the start of my own research dur - Clinical Endocrinology and Metabolism , ing medical school, how I continued this at and the American Journal of Medicine . He the NIH and then through a long career on served on the Board of Consulting Editors the HMS faculty at Beth Israel and then of Science Magazine . BIDMC. I won’t speak much about being An elected member of the Institute of the dean of HMS, but I will speak about Medicine and a fellow of the American family and the bigger picture of “what it’s Academy of Arts and Sciences, Flier’s hon - all about.” ors also include the Eli Lilly Award of the I entered the Mount Sinai School of American Diabetes Association, the Berson Medicine in 1968, in the first entering class Lecture of the American Physiological So - of the school. I was one of 36 entering stu - ciety, and an Honorary Doctorate from the dents. One of the reasons I decided to go to University of Athens. He delivered the 2003 Mount Sinai was that I thought being part of Edwin B. Astwood Lecture Award from the this new school would be an adventure. I Flier: Lee E. Farr lecture 407 also was impressed with the people named had been Dr. Berson’s first student. At that as chairs of the major departments. As it time, the Roth group was leading the world turned out, working with two of them in par - in the identification and characterization of ticular influenced me greatly. cell surface receptors. At that time, the struc - The chair of Biochemistry, P.G. Kat - ture of such receptors was unknown, either soyannis, led a group that was the first to biochemically or genetically. Were they on synthesize insulin through peptide synthesis the membrane? Were they inside the cell? and then show it to be biologically active. What kind of molecules were they? How did He and his colleagues made an enormous they generate signals? Jesse Roth’s group number of insulin analogues with varying had terrific science and many smart people, properties that represented an important and the atmosphere was quite electric. body of work. I got to know him, and I be - I was very fortunate in my research at came interested in insulin during my first NIH, but during my first 6 months of re - few months at Mount Sinai. search, literally nothing worked. I had begun The chairman of Medicine was to think that I would leave for some further Solomon Berson. He became my personal clinical training when I had one opportunity hero. He and his research partner, Rosalyn to pursue a good idea, and everything just Yalow, developed the technique of radioim - sort of fell into place. A few months later, munoassay, and though he unfortunately that idea evolved in a paper in the journal died prematurely during my senior year of Science [1] in which we showed that some medical school, Dr. Yalow went on to win patients with extreme insulin resistance had the Nobel Prize in 1977 for their joint dis - autoantibodies against their insulin receptor. covery, which had many practical implica - The paper also showed for the first time that tions, notably providing the first ability to the receptor we identified with this antibody quantitate levels of insulin, growth hor - was truly critical for insulin’s action. We mone, and many other molecules. So I were able to show that the patient’s own worked with the person who first synthe - cells ― removed and studied ex vivo ― had sized insulin and the person who first meas - reduced insulin binding, and we could re - ured it. I was clearly destined for a career produce this by exposing normal cells to studying insulin. serum and eventually to purified im - I had other mentors. Dr. Kurt Hirschhorn munoglobulin. I also thought for one intense was an immunologist and the head of genet - weekend that perhaps similar antibodies ics, and I spent most afternoons working in might be the cause of type II diabetes.
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