Protecting the Heart From Lipid Overload

In this review, we attempt to deduce teleologically the physiological mission of leptin. Because overnutrition and diet-induced obesity are the only known causes of hyperleptinemia, we contrast the differences in overnutrition in normally leptinized rodents, in which the added lipids are confined to adipocytes, with those of unleptinized rodents, in which the added lipids are distributed in liver, pancreatic islets, and heart and skeletal muscle, causing organ dysfunction and cell death with a disease cluster resembling metabolic syndrome. We focus here on lipid-induced cardiac dysfunction and the remarkable ability of hyperleptinemia to prevent it. We conclude that the hyperleptinemia of overnutrition prevents the ectopic lipid deposition by: (1) acting on hypothalamic appetite centers to limit the caloric surplus to fit the available adipocyte storage capacity and, (2) upregulating of fatty acid oxidation and downregulating lipogenesis in peripheral tissues to minimize ectopic lipid deposition. The causes of failure of this system and its clinical consequences are discussed. (Hypertension. 2005;45:1031-1034.) Deducing the Function of Hyperleptinemia One decade after its discovery,1 the precise physiological function of the adipocyte hormone leptin has still not been unequivocally established. Nonetheless, there are potentially important clues. The physiological mission of a hormone can often be deduced from its secretory behavior (ie, an analysis of factors or situations that elicit its hypersecretion). Because the only known cause of leptin hypersecretion is diet-induced obesity (DIO), it can be inferred that hyperleptinemia plays an important physiological role in DIO. The storage of surplus calories as fat provides a vital means of prolonging survival during famine,2 so long as the caloric surplus does not jeopardize health before the famine has even begun. The putative tradeoff is as follows. To survive famine, one must have stored a stockpile of calories in the form of triglycerides. Yet most cells in our body are intolerant to lipid overload and are seriously damaged by certain lipid metabolites.3 The evolution of the adipocyte, a cell that is uniquely adapted to store enormous quantities of triacylglycerol (TG), resolved this critical problem by providing the requisite caloric storage compartment. However, there remained the problem of protecting nonadipose tissues from lipid-induced trauma during the period of overnutrition by partitioning the surplus calories into the adipose tissue compartment. Evidence for Leptin-Dependent Lipid Partitioning The problem of lipid partitioning was resolved through the evolution of leptin. Leptin achieves compartmentalization of surplus lipids in 2 ways: (1) it limits the level of overnutrition via hypothalamic action on appetite centers to keep the intake of surplus calories from exceeding the slowly expanding lipid storage capacity of adipocytes and; (2) it upregulates the fatty acid oxidative capacity in nonadipose tissues so as to oxidize any lipid spillover that may have occurred during the period of overnutrition, while reducing their lipogenic capability.4 The fact that lipotoxicity is usually absent early in the course of DIO is consistent with the idea that the hyperleptinemia generated by overnutrition is effectively protecting the nonadipose tissues from lipid overaccumulation as adipocytes undergo expansion through hypertrophy and hyperplasia in the defense against famine. This concept of the role of leptin is supported by the fact that in syndromes of congenital leptin deficiency and leptin resistance, widespread ectopic lipid deposition and severe lipotoxicity appear early in life and can be ameliorated by restoring leptin action.4–8 Leptin deficiency states are extremely rare, the most common form being congenital generalized lipodystrophy, which is caused by the lack of leptin-secreting adipocytes. Early in life, patients develop a severe facsimile of metabolic syndrome, or with insulin resistance, hyperleptinemia, severe diabetes, cardiomyopathy, and fatty liver. These abnormalities can be dramatically ameliorated with leptin treatment.8 A second, much rarer form of leptin deficiency is caused by a mutation in the leptin gene.9 It is associated with severe obesity. Leptin-resistant states are far more common. Although congenital leptin resistance attributable to a loss-of-function Received February 10, 2005; first decision February 28, 2005; revision accepted April 1, 2005. From the Gifford Laboratories, Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, and Veterans Affairs Medical Center, Dallas, Tex. Correspondence to Roger H. Unger, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8854. E-mail [email protected] © 2005 American Heart Association, Inc. Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000165683.09053.02