Our research is directed at the interrelationships between obesity and its most common complications, diabetes and metabolic syndrome. Our laboratory introduced the concept of lipotoxicity, which attributes the diabetes and other metabolic syndrome diseases to ectopic accumulation of lipids. This accumulation leads to apoptosis of the islets by increasing ceramide formation, which results in apoptosis mediated by enhanced peroxynitrite production. This phenomenon, called ?lipoapoptosis?, occurs only in the subset of fat-laden beta-cells. Diabetes results because the reduced population of beta-cells cannot meet the increased demands for insulin imposed by the insulin resistance caused by the increased lipid content of the target tissues of insulin. These abnormalities also occur in other organs. In the heart this leads to congestive failure and dilation. Although not proven, it is possible that lipid overload in the lungs contributes to Pickwickian syndrome, in the gall bladder to bile stasis and gall stones and in the kidneys to hypertension, i. e., the full metabolic syndrome. This laboratory has demonstrated that leptin serves to regulate lipid homeostasis in nonadipose tissues such as the pancreatic islets and liver. The cause of the leptin insensitivity in obesity and ageing, America?s most common health problems, is the focus of the work of this laboratory. Lipotoxicity may have other implication, having recently been identified as a cause of graft failure in islet transplantation, which can be completely prevented by inducing severe lipopenia. The effect of lipopenia on cell survival is an important area of future investigation in the lab.
RESEARCH INTERESTS
Diabetes
Obesity
Metabolic Syndrome
RECENT PUBLICATIONS
Unger RH, "The Physiology of Cellular Liporegulation" Annual Review of Physiology, 65:333-347, 2003
Park BH, Wang MY, Lee Y, Yu X, Ravazzola M, Orci L, Unger RH, "Combined leptin actions on adipose tissue and hypothalamus are required to deplete adipocyte fat in lean rats: Implications for obesity treatment." Journal of Biological Chemistry, 281 (52):40283-91, December 2006
McGavock JM, Victor RG, Unger RH, Szczepaniak LS, "Adiposity of the heart, revisited." Annal of Internal Medicine, 144(7):517-524, April 2006
Unger RH, Elmquist JK, "Movin’ on up: Adipocytes become regulators of nutrient homeostasis." Cell Metabolism, 3(3):147-148, March 2006
Wang MY, Orci L, Ravazzola M, Unger RH, "Fat storage in adipocytes requires inactivation of leptin’s paracrine activity: Implications for treatment of human obesity." PNAS, 102(50):18011-6, December 2005
SIGNIFICANT PUBLICATIONS
Unger RH, Eisentraut AM, McCall MS, Madison LL, "Glucagon antibodies and an immunoassay for glucagon" Journal of Clinical Investigation, 40:1280-1289, 1961
Unger RH, "Glucagon physiology and pathophysiology" New England Journal of Medicine, 285:443-449, 1971
Dobbs RE, Sakurai H, Sasaki H, Faloona GR, Valverde I, Baetens D, Orci L, Unger RH, "Glucagom: Role in the hyperglycemia of diabetes mellitus" Science, 187:544-547, 1975
Shimabukuro M, Zhou Y-T, Levi M, Unger RH, "Fatty acid-induced beta cell apoptosis: A link between obesity and diabetes" Proceedings of the National Academy of Sciences USA, 95:2498-2502, 1998
Unger RH, Zhou Y-T, Orci L, "Regulation of fatty acid homeostasis in cells: Novel role of leptin" Proceedings of the National Academy of Sciences USA, 96:2327-2332, 1999
Point and right click (click and hold for Mac users) your mouse onand select "Save this link (or target) as..." option to save the file to your local computer.
and select "Save this link (or target) as..." option to save the file to your local computer.