The Leptin System in Patients with Classical Galactosaemia - Putative Role and Clinical Consequences

Abstract

The hormone leptin is a polypeptide of 146 amino acids which is predominantly secreted by adipose tissue. Leptin has distinct effects on energy homeostasis, metabolism, neuroendocrine function and other systems through its interactive effects on the central nervous system (CNS) and peripheral tissues. It has a critical role on regulation of body weight, fat reserves and reproductive function. The leptin receptor (LepR, Ob-R) is expressed in different isoforms, with the main signaling carried out by its long glycosylated isoform, Ob-Rb. Soluble leptin receptor (sOb-R) represents the main binding protein for leptin in human blood and increases its bioavailability. There are numerous N-glycosylation sites which are of physiological relevance for receptor function. Galactose and other sugar moieties are physiologically relevant for glycosylation of complex molecules for a wide range of biological processes.This review considers how leptin signaling pathways are dysregulated in the rare inherited disorder of carbohydrate metabolism, Classical Galactosaemia. This disease is caused by profound deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). Classical Galactosaemia may cause significant morbidity and even mortality in neonates and long-term complications later in life, including pubertal delay and primary ovarian insufficiency (POI). The immediate removal of galactose from the diet is lifesaving in affected infants. The pathophysiology of its long-term complications is incompletely understood. Underlying mechanisms comprise intoxication with galactose and its metabolites together with altered glycosylation pathways and disruption of signaling pathways.Here we discuss how interaction of leptin with the hypothalamic pituitary gonadal axis (HPG) and other circuits is potentially dysregulated in Classical Galactosaemia with clinical consequences for puberty and reproductive capacity, particularly in females. We have identified defective N-glycosylation as a major factor implicated in disrupted leptin-HPG signaling resulting from distorted receptor function. Finally, we speculate how leptin dysregulation may affect cognitive function and neuroprotection in patients with Classical Galactosaemia.