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The mammalian lipidome consists of a vast array of molecules that provide structural components of cell membranes; or can be metabolized to generate cellular energy; or act as signaling molecules that mediate critical biological processes. Branched Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs) are a structurally novel family of bioactive lipids which are synthesized in mammalian tissues in vivo. FAHFAs are present in all mammalian tissues tested. In humans, adipose tissue and serum levels of one FAHFA family, Palmitic Acid Esters of Hydroxystearic Acids (PAHSAs) correlate highly with insulin sensitivity. PAHSA levels in serum and subcutaneous white adipose tissue are lower in insulin-resistant compared with insulin-sensitive people and in obese mice on HFD compared to lean mice. PAHSA isomers have multiple effects which result in improved glucose tolerance and insulin sensitivity in insulin-resistant and diabetic mice. PAHSAs also have anti-inflammatory and immunomodulatory effects which delay the onset and reduce the severity of colitis in mice and prevent autoimmune Type 1 diabetes in NOD mice. The striking prevention of Type 1 Diabetes involves alterations in immune cell profiles and reduction in senescence in pancreatic islet cells. We recently discovered that the first biosynthetic enzyme for FAHFAs - Adipose Triglyceride lipase (ATGL), which was known as a key regulator of lipolysis. We found that ATGL also synthesizes FAHFAs in vivo using a previously unrecognized transacylase activity. Understanding the regulation of FAHFAs could uncover new therapeutic opportunities for people with Type 2 Diabetes and with immune-mediated diseases such as Type 1 Diabetes and colitis.
Bio: 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 recognized internationally 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 seminal studies demonstrated that expression of the insulin-regulated glucose transporter, GLUT4, is down-regulated in adipocytes in insulin-resistant states. Mechanistically, her lab discovered metabolically important adipose-secreted molecules that alter insulin sensitivity and the risk for Type 2 diabetes. She and her lab also discovered, with collaborator Alan Saghatelian, a novel class of signaling lipids (FAHFAs) with anti-diabetic and anti-inflammatory actions which are tightly linked with insulin-sensitivity in humans and rodents. These potentially therapeutic lipids augment insulin secretion and action, and protect against Type 2 diabetes in mice. FAHFAs also dramatically reduce Type 1 diabetes risk by preserving pancreatic b-cell mass and preventing cellular senescence.
Prof. Kahn is an elected member of the National Academy of Sciences, and she received both the Outstanding Scientist Award from the American Diabetes Association and the Banting Medal, the highest award bestowed by the American Diabetes Association. The US News and World Report has ranked Dr. Kahn in the top 1% of physicians nationwide in Endocrinology and Metabolism.
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