Author(s): Jane M Johnston 1 , Steven J Greco 1 , Ashkan Hamzelou 1 , J Wesson Ashford 2 , Nikolaos Tezapsidis [[dagger]] 3
Alzheimer'âs disease; cognition; leptin; neurodevelopment; neurons
Leptin is a 16 kDa hormone primarily produced by adipocytes whose name derives from leptos, the Greek word for thin. This hormone is best known for its effects on fat mobilization and energy homeostasis. Numerous studies of human leptin have been reported to date, and leptin deficiencies or resistance have been reported in a variety of disorders ranging from congenital obesity to Alzheimer'âs disease (AD). More than 60 studies, encompassing over a thousand subjects, have involved the administration of leptin to human subjects (PubMed database search using the search terms: 'recombinant leptin'â and 'human clinical trial'â). These studies, which utilized either recombinant methionyl human leptin (r-metHu-Leptin; Amylin Pharmaceuticals) or pegylated recombinant native human leptin (PEG-OB; Hoffman-La Roche), were designed to address dosage, safety and efficacy for the treatment of a number of human conditions, particularly obesity and leptin deficiency, and are discussed below. A major focus of this article is the consideration of leptin replacement for AD patients as an interventional therapeutic as well as a preventative agent for those at risk.
Overview of leptin biology
Leptin is an adipocyte-derived hormone, originally identified in 1994  , with important roles in fat storage and metabolism, immune and reproductive function, bone homeostasis, insulin sensitivity and neuronal protection. Endogenous leptin is secreted in a pulsatile rhythm with the highest levels secreted between midnight and early morning. Circulating leptin levels can vary throughout the day, and are primarily dependent on adipose mass and secondarily on feeding status  . Leptin levels are higher in premenopausal women than in men, and physiological plasma leptin levels vary from 0 ng/ml in congenital leptin deficiency subjects, to more than 100 ng/ml in some morbidly obese subjects.
Leptin exerts activity through signal transduction at the leptin (obesity) receptor (ObR). Six isoforms of the ObR have been identified to date, with signaling pathways associated with the long isoform of the leptin receptor (ObRb)being the best studied  . Leptin receptors are widely distributed throughout the CNS as well as in peripheral tissues. Within the brain, the leptin receptor is highly expressed in the hypothalamus, hippocampus, midbrain and hindbrain  . Leptin from the hypothalamus is linked to a role in feeding behavior  as well as in neuroendocrine function  . Rodents with mutations in the leptin receptor (db/db, fa/fa) and those with two faulty copies of leptin (ob/ob) exhibit an obese phenotype, and only leptin-deficient mice (ob/ob) can attain normal weight following leptin infusion  . Of particular interest is the high expression of the ObRb in the hippocampus, a region of the brain intricately involved in memory and cognition, and which is highly affected by AD pathology.
The leptin receptor is a member of the class 1 cytokine receptor superfamily, which can activate a number of signal transduction components, including JAK2, which subsequently phosphorylates STAT3 to mediate transcription of a number of genes. Leptin has also...