Leptin and the pituitary.

Although leptin was originally viewed as an antiobesity hormone, it is now evident that it may have more pleiotropic actions. Experiments in rodents have shown that leptin activates the sympathetic nervous system, is involved in regulation of blood pressure, hematopoiesis, immune function, angiogenesis and brain, bone and pituitary development. Some biological effects expected based on observations in rodents, have so far not been seen in humans. Thus due to species differences in the role of leptin it is difficult to translate the data from rodents to human physiology. Hypothalamus is the primary brain site targeted by circulating leptin, secreted by fat cells. Leptin receptor has homology to members of class I cytokine receptor family, which may imply similarities in molecular events engaged by cytokines and leptin. In view of its cytokine-like properties it is likely that leptin produced and secreted outside of fat tissue i.e. in other tissues (CNS, pituitary, ovary, placenta, etc), is a paracrine regulator. Leptin receptor isoforms, long-signaling and short-nonsignaling, have been recently localized in human pituitaries. This opens the possibility of a direct action of leptin on the pituitary. However this appears to be quite complex and is species dependent. Leptin can be synthesized by normal and tumorous pituitary cells. Leptin protein expression in pituitary adenomas is decreased compared to that in normal pituitaries. Colocalization studies with leptin and anterior pituitary cells showed that 70% of ACTH cells are positive for leptin, 21% of GH cells, 29% of LH cells, 33% of FSH cells, 32% of TSH cells, 64% folliculo-stellate cells whereas very few PRL cells were positive (3%). Leptin is stored in secretory granules and secretory cells retain leptin in granules until stimulated. This follows a different secretory pathway than in adipocytes where upon synthesis leptin is immediately released. Question to be raised is does the pituitary contribute to the body leptin pool or is its action predominantly paracrine/autocrine? Clinically based evidence from studies performed in patients harboring different functional pituitary tumors causing a state of hormonal hypersecretion (acromegaly, prolactinomas, Cushing's disease) or hypopituitarism (due to non-functioning pituitary adenomas), are in favor of a paracrine/autocrine role of the pituitary leptin. Most of the studies have shown that the link between leptin, body composition and hormones of the pituitary is indirect. Thus changes in levels of circulating leptin are most likely due to changes in the metabolic and hormonal milieu during the chronic course of the disease or chronic treatment. Furthermore, circadian rhythm of leptin, its pulsatility and gender difference are preserved in hypopituitarism as well as in patients with functional pituitary adenomas implying that intact hypothalamic-pituitary function is not essential for leptin's circadian rhythm.