Leptin as an Antitorpor Hormone: An Explanation for the Increased Metabolic Efficiency and Cold Sensitivity of ob/ob Mice?

AbstractLeptin is recognized as an anorexigenic hormone. In its absence (e.g., in ob/ob mutant mice), mice become obese, primarily as a result of hyperphagia. A recurrent question is whether, additionally, leptin is thermogenic and thus also an antiobesity hormone in this way. We have earlier reviewed available data and have concluded that most articles implying a thermogenic effect of leptin have based this on a misconstrued division by body weight. Here, we have collected evidence that the remaining observations that imply that leptin is a thermogenic hormone are better understood as implying that leptin is an antitorpor hormone. Leptin levels increase in proportion to the body's energy reserves (i.e., stored lipids in the adipose tissue), and leptin thus serves as an indicator of energy availability. In the absence of leptin, ob/ob mice are exceedingly prone to enter daily torpor, since the absence of leptin causes them to perceive a lack of body energy reserves that, in combination with restricted or no food, induces them to enter the torpid state to save energy. This antitorpor effect of leptin probably explains the following earlier observations. First, ob/ob mice have the ability to gain weight even when pair fed with leptin-treated ob/ob mice. This is understood as follows: In the leptin-treated ob/ob mice, food intake is reduced. Untreated pair-fed mice enter daily torpor, and this markedly lowers total daily energy expenditure; the resulting surplus food energy is then accumulated as fat in these mice. However, ob/ob mice fed ad lib. do not enter torpor, so under normal conditions this mechanism does not contribute to the obesity found in the ob/ob mice. Second, neonatal ob/ob mice have the ability to become obese despite eating the same amount as wild-type mice: this is understood as these mice similarly entering daily torpor. Third, ob/ob mice on the C57BL/6J background have a lower metabolic rate: these mice were examined in the absence of food, and torpor was thus probably induced. Fourth, ob/ob mice have apparent high cold sensitivity: these mice experienced cold in the absence of food and would immediately enter deep torpor. It is suggested that this novel explanation of how the antitorpor effects of leptin affect mouse energy metabolism can open new avenues for leptin research.