Leptin and the Pituitary Popovic et al. V. Popovic, S. Damjanovic, C. Dieguez, and F. F. Casanueva Institute of Endocrinology, University Clinical Center Belgrade, Yugoslavia and Dept. of Physiology Medical Faculty and Dept. of Medicine, Endocrine Division Complejo Hospitalario, University Santiago de Compostela, Santiago de Compostela, Spain Abstract. Although leptin was originally viewed as an an- tiobesity 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 pitui- tary 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 dif~cult 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 fam- ily, which may imply similarities in molecular events en- gaged 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 recep- tor 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 tumor- ous pituitary cells. Leptin protein expression in pituitary adenomas is decreased compared to that in normal pituitar- ies. Colocalization studies with leptin and anterior pitui- tary 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 secre- tory granules and secretory cells retain leptin in granules until stimulated. This follows a different secretory pathway than in adipocytes where upon synthesis leptin is immedi- ately released. Question to be raised is does the pituitary contribute to the body leptin pool or is its action predomi- nantly paracrine/autocrine? Clinically based evidence from studies performed in patients harboring different func- tional pituitary tumors causing a state of hormonal hyper- secretion (acromegaly, prolactinomas, Cushing’s disease) or hypopituitarism (due to non-functioning pituitary ade- nomas), 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 hy- popituitarism as well as in patients with functional pitui- tary adenomas implying that intact hypothalamic-pituitary function is not essential for leptin’s circadian rhythm. Key Words. leptin, pituitary, paracrine action Leptin and hypothalamus Leptin, the ob gene product, is secreted almost exclu- sively by fat cells and the circulating leptin level is proportional to total fat mass. Leptin gene is over-ex- pressed in adipose tissue in obese subjects [1]. Fur- thermore obese subjects have been found to be resis- tant to the regulatory function of circulating leptin. In addition, there is a gender difference in circulating leptin levels, being higher in women than men, even after correcting serum leptin levels for percent or total body fat indicating that an endocrine involvement may be at the basis of this gender difference [2]. Apart from fat mass and gender, there are a number of other pos- tulated in_uences on the circulating leptin level. Thus there is a negative relationship between circulating testosterone and leptin [3], growth hormone and leptin [4], while there is a positive relationship between glucocorticoids [5], insulin [6], and estrogens [7] with leptin levels. However the respective roles of these hormonal factors in the overall regulation of leptin pro- duction have not been fully ascertained [8]. Leptin most likely exerts its most important effects through CNS speci~cally within the hypothalamus. Al- though several lines of evidence suggest that the hypo- thalamus is the primary brain site targeted by leptin [9] the precise site within the hypothalamus cannot be ascertained at present. Perhaps the most revealing ~nding is the subpopulation of NPY-producing cells in hypothalamus which may be one of the targets of leptin action. Besides hypothalamus, leptin receptors and leptin m RNA have been identi~ed in the placenta, ovary, T-cells, gastric mucosa, mammary epithelial cells, myocytes, pituitary and the brain. Leptin receptor (OB-R) has homology to members of class I cytokine receptor fam- Pituitary 4: 7–14, 2001 © 2001 Kluwer Academic Publishers. Manufactured in The Netherlands. Address correspondence to: Professor dr. Vera Popovic, Institute of Endocrinology, University Clinical Center, dr Subotic 13, 11000 Belgrade, Yugoslavia Fax: 381 11 685 357, e-mail: popver@ Eunet.Yu