Does hypoleptinemia trigger entrapment in anorexia nervosa? Etiological and clinical considerations

Abstract

Based on the recent observation that human recombinant leptin (r‐Met‐hu‐leptin; metreleptin) may induce a profound alleviation of the complex symptomatology of patients with anorexia nervosa (AN), we examine the implications for our conceptualisation of this eating disorder. Hypoleptinemia as a core endocrine feature of AN serves as a central and peripheral trigger of tissue‐specific adaptations to starvation. In this narrative review, we argue that leptin deficiency may explain many of the puzzling features of this eating disorder. Weight loss can be viewed as a two‐step process, with only the second step entailing hypoleptinemia and thereby the entrapment characteristic of AN. We discuss the central and peripheral distribution of leptin receptors and consider possible functional implications of hypoleptinemia. We contrast the slow psychological recovery of patients with AN and of people who experienced starvation upon weight recovery with the rapid onset of improvements upon off‐label metreleptin treatment. Characteristics of the sex and age dependent secretion of leptin may contribute to the elevated vulnerability of young females to develop AN.

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder

“…The attainment of an absolute or relative deficiency of the circulating level of the adipokine leptin has been hypothesized to trigger entrapment (Hebebrand et al, 2024). In brief, only the free leptin index is relevant for its biological action; a proportion of circulating leptin is bound to the soluble leptin receptor (Hebebrand et al, 2024). Circulating leptin levels are positively correlated with BMI and more so with percent fat mass (Considine et al, 1996).…”

Anorexia-Induced Hypoleptinemia Drives Adaptations in the JAK2/STAT3 Pathway in the Ventral and Dorsal Hippocampus of Female Rats

“…Leptin plays a significant role in the clinical symptomatology and the progression of AN; indeed, it is also considered a risk factor for relapse episodes [ 14 , 95 ] and four variants in the sequence of the coding region of the leptin gene have been identified in acutely ill AN patients [ 96 ]. Our data add evidence to the hypothesis that hypoleptinemia could be an initial driver of the adaptations set in motion by the body in a condition of starvation.…”