The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: Implications for anorexia nervosa.

This narrative review aims to pinpoint mental and behavioral effects of starvation, which may be triggered by hypoleptinemia and as such may be amenable to treatment with leptin receptor agonists. The reduced leptin secretion results from the continuous loss of fat mass, thus initiating a graded triggering of diverse starvation related adaptive functions. In light of leptin receptors located in several peripheral tissues and many brain regions adaptations may extend beyond those of the hypothalamus-pituitary-end organ-axes. We focus on gastrointestinal tract and reward system as relevant examples of peripheral and central effects of leptin. Despite its association with extreme obesity, congenital leptin deficiency with its many parallels to a state of starvation allows the elucidation of mental symptoms amenable to treatment with exogenous leptin in both ob/ob mice and humans with this autosomal recessive disorder. For starvation induced behavioral changes with an intact leptin signaling we particularly focus on rodent models for which proof of concept has been provided for the causative role of hypoleptinemia. For humans, we highlight the major cognitive, emotional and behavioral findings of the Minnesota Starvation Experiment to contrast them with results obtained upon a lesser degree of caloric restriction. Evidence for hypoleptinemia induced mental changes also stems from findings obtained in lipodystrophies. In light of the recently reported beneficial cognitive, emotional and behavioral effects of metreleptin-administration in anorexia nervosa we discuss potential implications for the treatment of this eating disorder. We postulate that leptin has profound psychopharmacological effects in the state of starvation.
Competing Interests: Conflict of interest statements Johannes Hebebrand, Gertraud Gradl-Dietsch, and Jochen Antel declare that they will be named as inventors in a patent application that the University of Duisburg-Essen prepares to file on the use of leptin analogues for the treatment of depression. Johannes Hebebrand and Jochen Antel declare that were named as inventors in a patent application that the University of Duisburg-Essen had filed on the use of leptin analogues for treating anorexia nervosa and related conditions. Johannes Hebebrand received speaker’s honoraria from Amryt Pharmaceuticals and from Novo-Nordisk. Haiko Schlögl has consulted for Aegerion Pharmaceuticals. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)