Leptin physiology: a second look.

It is widely believed that the primary physiologic role of leptin is to prevent obesity by regulating food intake and thermogenesis through actions on hypothalamic centers. Here we sugest that the first premise, the anti-obesity role, is untenable, and present evidence for an alternative physiologic role, namely antisteatotic activity in which fatty acid overaccumulation in nonadipose tissues is prevented by leptin-mediated regulation of beta-oxidation. The second premise, namely that leptin acts exclusively on the hypothalamus, is confirmed in normal lean animals with plasma leptin concentrations below 5 ng/ml; their correlation with cerebrospinal fluid levels supports the classical concept of leptin-mediated hypothalamic regulation of food intake. However, when chronic hyperleptinemia exceeds 15 ng/ml, as in obesity, a further rise in plasma leptin does not raise cerebrospinal leptin levels or reduce food intake. Nevertheless, the peripheral antisteatotic action of leptin in acquired obesity continues, suggesting that at chronically hyperleptinemic levels the hormone acts primarily on peripheral tissues and that its hypothalamic action has reached a plateau.