Leptin and the leptin receptor : Molecular and genetic studies.

Leptin, a 16kDa protein, is secreted primarily by adipose tissue. Its effects are pleiotropic, with known roles in body mass regulation, haematopoiesis, immune function and reproduction.Studies of the leptin system in females were undertaken to complement existing animal and human studies. Serum leptin levels were found to increase in the luteal phase of the menstrual cycle raising the possibility of a role for leptin at the time of implantation. RT-PCR studies showed that leptin receptors were expressed in the human endometrium throughout the menstrual cycle. In these preliminary studies, these receptors appeared to be functional in response to leptin; increasing proliferation and decreasing TNF-a production in cultured endometrial cells. This implies that leptin has a local effect at the level of the endometrium.Many cytokines are bound to proteins in serum; a proportion of this binding can be attributed to a soluble cytokine receptor. Soluble receptors and binding proteins have a variety of roles, acting as scavengers, carriers, agonists and antagonists. In order to investigate this phenomenon in the leptin system, a radio-receptor assay was developed to measure leptin-binding activity (LBA). The leptin receptor has an extracellular domain that is common to all isoforms and therefore, LBA may also reflect the binding parameters of cell surface receptors. Serum leptin levels of LBA were found to be low at birth, high in early childhood, to fall steadily through puberty and remain at the post-pubertal levels throughout adult life. This suggests that leptin and LBA has an important role in the initiation of puberty. There was no significant variation in LBA during the menstrual cycle.Several single nucleotide polymorphisms (SNP) exist in the leptin receptor gene. Studies of two of these SNPs, GLN223ARG and LYS656ASN, present in the extracellular domain of the receptor were undertaken to assess if genetic changes are associated with differences in phenotype or effect ligand binding. Homozygosity of the G allele of GLN223ARG is associated with lower fat mass, BMI and leptin levels in postmenopausal Caucasian females. This polymorphism changes the binding characteristics of the receptor, with a higher LBA being associated with homozygosity of the G allele. This suggests that the actual binding of leptin to its receptor may be an important factor in the regulation of body weight and adiposity.