**1. Introduction**

To perform their vital functions, anterior pituitary cells must respond appropriately to their unique hypothalamic releasing hormones, while also responding to extrinsic signals informing them of the body's nutritional and metabolic state. Leptin is one of the most important of these extrinsic signals. However, recent studies show that leptin does more than simply signal levels of fat stores [1–11]. Leptin plays a trophic role that optimizes and maintains differentiation of at least two of these cell types, somatotropes and gonadotropes.

Anterior pituitary somatotropes produce growth hormone (GH) to support growth in muscles and bones before puberty and build muscle, bone, and reduce fat to optimize body composition in the adult [12, 13]. Gonadotropes produce the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), which differentially regulate gonadal functions, ovulation and reproductive cyclicity [14]. Both somatotrope and gonadotrope functions are impacted by the nutritional

state and therefore it is not surprising that they exhibit a dependency on leptin. Early studies showed significant reductions in numbers of gonadotropes in leptin-deficient animals [6, 15–19]. Similarly, rodents that lack leptin or leptin receptors (LEPR) had reduced numbers of somatotropes [20, 21]. Our studies on the distribution of pituitary LEPR showed expression in nearly all cells [1, 22].

A dependency on normal levels of serum leptin was seen in our studies of 24 h fasted rats, when we correlated the reduction in serum leptin with reduced numbers of immunolabeled somatotropes and gonadotropes, along with reduced receptivity for gonadotropin releasing hormone (GnRH) and growth hormone releasing hormone (GHRH) [23]. As these findings pointed to potential trophic actions by leptin, we continued *in vitro* studies to determine if leptin would rescue either cell population, restoring hormone stores lost during the acute fast. We cultured pituitary cells from fasted rats overnight and then incubated them with 10-100 pg./ml leptin for 1 h. This brief treatment rapidly restored stores as detected by increases in numbers of immunolabeled somatotropes and gonadotropes [23], confirming direct effects of leptin on these cell populations.

These findings agree with recent *in vivo* studies of rodents by Luque et al. [24], which showed that both GH secretion and *Ghrhr* mRNA levels were restored by leptin in leptin-deficient *ob/ob* mice. Furthermore, studies of non-human primates by this same group confirmed both somatotropes and gonadotropes as leptin targets in primates [25, 26], reporting that leptin stimulated release of GH and follicle stimulating hormone (FSH) *in vitro* [25].

Leptin's restorative or stimulatory effects directly on somatotropes and gonadotropes have since led to studies that explored the significance of this regulatory influence as well as basic mechanisms of action, including the identification of signaling pathways and transcription factors. This chapter will review the studies which have identified critical leptin target molecules that are vital to the differentiated function of gonadotropes and somatotropes. We will also review signaling pathways used by leptin to stimulate production of these targets. Finally, we will show how leptin may contribute to plasticity of the pituitary by supporting multihormonal cell populations.
