Lipotoxic diseases of nonadipose tissues in obesity.
It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes. Excess TG deposition in nonadipocytes leads to impairment of functions, increased ceramide formation, which triggers nitric oxide-mediated lipotoxicity and lipoapoptosis. The fact that TG content in nonadipocytes normally remains within a very narrow range irrespective of excess caloric intake, while TG content of adipocytes rises, is consistent with a system of fatty acid (FA) homeostasis in nonadipose tissues. When leptin is deficient or leptin receptors are dysfunctional, TG content in nonadipose tissues such as pancreatic islets, heart and skeletal muscle, can increase 10-50-fold, suggesting that leptin controls the putative homeostatic system for intracellular TG. The fact that function and viability of nonadipocytes is compromised when their TG content rises above normal implies that normal homeostasis of their intracellular FA is critical for prevention of complications of obesity. FA overload of skeletal muscle, myocardium and pancreatic islets cause, respectively, insulin resistance, lipotoxic heart disease and adipogenic type 2 diabetes. All can be completely prevented by treatment with antisteatotic agents such as troglitazone. In diet-induced obesity, leptin signaling is normal initially and lipotoxic changes are at first prevented; later, however, post-receptor leptin resistance appears, leading to dysfunction and lipoapoptosis in nonadipose tissues, the familiar complications of obesity.
Unger
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Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8854, USA. Runger@mednet.Swmed.edu
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D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D009765:Obesity / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin
D002352:Carrier Proteins; D005227:Fatty Acids; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin