Bioactive Lipids in Cancer, Inflammation and Related Diseases

Barbara B. Kahn, M.D.

Barbara B. Kahn, M.D.

Barbara Kahn is the George Minot Professor of Medicine at Harvard Medical School, Vice-Chair for Research Strategy in the Department of Medicine at Beth Israel Deaconess Medical Center (BIDMC), and an Institute Member of the Broad Institute of MIT and Harvard.  She is internationally recognized for her scientific discoveries illuminating the molecular mechanisms underlying obesity and Type 2 diabetes, including the regulation of insulin sensitivity, adipocyte biology, and intertissue communication.  Her pioneering research has elucidated the cellular and physiologic processes that link obesity with diabetes.  Her lab identified novel mechanisms by which adipocytes regulate systemic insulin sensitivity and diabetes risk.  Dr. Kahn’s lab with Dr. Alan Saghatelian’s lab discovered a new class of bioactive lipids with anti-diabetic and anti-inflammatory effects.  



Dr. Kahn received her MD from Stanford University and an MS in Health Sciences from University of California Berkeley. She did her internship and residency in Internal Medicine followed by a General Medicine Fellowship at University of California Davis.  She was an Endocrine Fellowship at NIH where she began her research career studying the cellular mechanisms underlying insulin stimulation of glucose transport.  Dr. Kahn joined the faculty at Harvard Medical School in 1986.  She served as Director of the Diabetes Clinic, Chief of the Diabetes Unit, and Chief of the Division of Endocrinology, Diabetes, and Metabolism at BIDMC. Dr. Kahn recently served on the Advisory Council for the National Institute of Diabetes, Digestive and Kidney Diseases.  She has also served on the Board of Directors of the American Diabetes Association and on the Scientific Advisory Boards of several pharmaceutical and biotech companies.  Dr. Kahn is a founding member of the Mentor Advisory Panel for the American Diabetes Association Pathway to Stop Diabetes, a program to find, fund and mentor the next generation of diabetes researchers.



Dr. Kahn made the seminal discovery that GLUT4, the major insulin-regulated glucose transporter, is down-regulated in adipocytes but not in skeletal muscle in obesity and diabetes.  Around 1990, that created a paradigm-shift since very little glucose is taken up by adipocytes compared to muscle.  To understand this, Dr. Kahn’s lab created one of the first adipose-specific transgenic mice by overexpressing GLUT4 selectively in adipocytes.  Surprisingly, the mice had enhanced glucose tolerance in spite of being obese. Dr. Kahn found that the obesity was characterized by adipocyte hyperplasia without an increase in adipocyte size, laying the groundwork for the concept of “functional” versus “dysfunctional” adipose tissue.



To recapitulate the GLUT4 down-regulation in adipose tissue seen in people with Type 2 diabetes and to determine whether GLUT4 in adipocytes is critical for maintaining insulin sensitivity, Dr. Kahn’s lab knocked out GLUT4 selectively in adipocytes in mice.  Unexpectedly, this impaired insulin action in muscle and liver which resulted in systemic insulin resistance and an increased risk for Type 2 diabetes.  This work was seminal in demonstrating the critical role of adipocytes in regulating systemic insulin sensitivity.  



In the 1990s and early 2000s, Dr. Kahn’s lab also investigated the signaling mechanisms through which the adipocyte-secreted hormone, leptin, regulated systemic energy balance and adiposity.  Among Dr. Kahn’s most highly cited work is her seminal discovery that regulation of the AMP-activated protein kinase pathway (AMP kinase) is critical for leptin action on both fatty acid oxidation in muscle and food intake and body weight control via the hypothalamus.  AMP-kinase was known to be a cellular “fuel gauge”. However, Dr. Kahn’s lab showed for the first time that AMP-kinase regulates fuel supply at the whole-body level. 



Dr. Kahn’s subsequent work was instrumental in uncovering the fundamental mechanisms by which adipocytes regulate glucose homeostasis.  She showed that adipose tissue is not only an endocrine organ but also a metabolic “factory” consuming and producing nutrients and metabolites that have systemic effects on insulin action, energy balance and inflammation.  Her early work using DNA array technology in adipose tissue of adipose-specific GLUT4 knockout and GLUT4 overexpressing mice demonstrated that there were as yet undiscovered, adipocyte-secreted molecules that alter insulin action in other tissues.  For example, her lab showed that Retinol Binding Protein 4 (RBP4) levels are elevated in adipose tissue and serum in insulin-resistant mice and people, and that lowering RBP4 levels in obese mice confers insulin sensitivity. Hundreds of human studies subsequently showed associations of elevated RBP4 with metabolic syndrome components and demonstrated that RBP4 is a strong biomarker for insulin resistance, cardiovascular risk and actual cardiac events (myocardial infarction and stroke) across many ethnic populations. Human genetic data also suggests a causative role for RBP4 in Type 2 diabetes. Dr. Kahn recently showed that RBP4 activates the innate and adaptive immune systems including the NLRP3 inflammasome, thereby increasing the proinflammatory state.  Understanding this dynamic could lead to new therapeutic approaches for Type 2 diabetes.



Dr. Kahn’s lab also showed that de novo lipogenesis in adipocytes driven by Carbohydrate Response Element Binding Protein has a major role in regulating systemic insulin sensitivity and that this is an important mechanism by which increased glucose transport in adipocytes confers enhanced insulin sensitivity.  These studies focused her interest on identifying novel metabolites which regulate glucose homeostasis.  Since the adipose-specific GLUT4-overexpressing mice have markedly enhanced glucose tolerance in spite of obesity and this depends on increasing lipogenesis in adipose tissue, she sought to determine whether specific lipids were being synthesized that have beneficial metabolic effects. 



With Dr. Alan Saghatelian’s lab, Dr. Kahn’s lab discovered a novel class of lipids, branched Fatty Acid Hydroxy Fatty Acids (FAHFAs) that are synthesized in human tissues, correlate highly with insulin sensitivity in humans, and have anti-diabetic and anti-inflammatory effects.  A subfamily of FAHFAs, Palmitic Acid esters of Hydroxy Stearic Acid (PAHSAs) restore normal insulin secretion in pancreatic islets from people with Type 2 diabetes.  They improve insulin sensitivity in insulin-resistant obese mice and protect against inflammatory diseases including autoimmune Type 1 diabetes and colitis in mice. Recently, Dr. Kahn’s lab discovered that the protective effects of PAHSAs on pancreatic beta cells involve preventing and even reversing cellular senescence induced by metabolic stressors and cytokines. In addition, Dr. Kahn’s lab just identified the first biosynthetic enzyme for FAHFAs.  Her lab is determining how to develop FAHFAs into therapeutic agents to treat diabetes and immune-mediated diseases.  



Dr. Kahn is an elected member of the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts and Sciences and a fellow of the American Association for the Advancement of Science.  She received both the Outstanding Scientific Achievement Award and the Banting Medal, the highest award bestowed by the American Diabetes Association.  She also received the Gerald Aurbach Award from the Endocrine Society; the Jacobaeus Prize from the Novo Nordisk Foundation and the Karolinska Institute; the Charles Best Award from University of Toronto; the Excellence in Science Award from the Federation of American Societies for Experimental Biology, and the Naomi Berrie Award from Columbia University. US News and World Report ranked Dr. Kahn in the top 1% of physicians nationwide in Endocrinology and Metabolism.  Dr. Kahn is a devoted mentor who has trained many highly successful leaders in the metabolism field around the world.  She has been an innovative leader in the metabolism field for more than 30 years and a pioneer for women in diabetes research.