Evidence for a Leptin-Neuropeptide Y Axis for the Regulation of Growth Hormone Secretion in the Rat

Abstract

The obese gene (OB) product, leptin, has been shown to exert control on metabolic processes such as food intake and body weight homeostasis, possibly through a neuropeptide Y (NPY) neurotransmission. More recently, leptin has been shown to control several neuroendocrine axes, modulating pituitary hormone secretions in function of metabolic conditions. Since in the rat growth hormone (GH) secretion is dependent upon prevailing metabolic conditions, and NPY has been shown to be implicated in the feedback mechanisms of this hormone, we reasoned that leptin could also exert control over GH secretion and we examined this hypothesis in male rats submitted to a 3-day fast. Circulating leptin concentrations measured by RIA abruptly fell to low values after 24 h of fasting and remained low thereafter. Upon refeeding, leptin secretion regularly increased. As shown by others, pulsatile GH secretion had disappeared after 3 days of fasting. Centrally administered leptin (10 µg/day, i.c.v. infusion initiated at the beginning of the fasting period) totally prevented the disappearance of pulsatile GH secretion. No leak of centrally administered leptin to the general circulation was observed. Infusing the same amount of leptin intracerebroventricularly to rats receiving ad libitum feeding produced a severe reduction in food intake but maintained a normal GH secretory pattern. In contrast, pair-fed rats, submitted to the same food restriction, exhibited a marked reduction in GH secretion. Hypothalamic NPY gene expression, estimated by Northern blot analysis, was significantly increased in fasting rats, and decreased in leptin-treated, fasting rats. In rats receiving ad libitum feeding, leptin treatment reduced NPY gene expression, consistent with the observed reduction in food intake, whereas pair-fed animals logically exhibited increased NPY gene expression. In both situations with reduced feeding, normal GH secretion was seen in leptin-treated animals exhibiting low NPY gene expression, whereas decreased or abolished GH secretion was seen in animals not receiving leptin and exhibiting increased NPY mRNA levels. Interestingly, despite maintenance of normal GH secretion in leptin-treated, fasting rats, plasma IGF-I levels were low, as in vehicle-treated rats. Indeed, hepatic gene expression for both GH receptor and IGF-I was markedly reduced by fasting, and no correction was seen with leptin treatment. In summary, the regulation of GH secretion, at least the changes linked with malnutrition, appears to be dependent upon a leptin signal, perceived centrally, possibly related to circulating levels of this new hormone. The present data suggest that leptin can rescue normal pulsatile GH secretion by preventing the documented inhibitory action of NPY on GH secretion.

Pituitary Leptin-A Paracrine Regulator of Gonadotropes: A Review

“…The recovery in gonadotropes and somatotropes confirms in vivo studies in which exogenous leptin restored LH or GH pulses [20,58,67,68,76,78]. The assumption has been made, however that leptin acts mainly on the hypothalamus.…”

“…Leptin also directly stimulates LH secretion from pituitary cells in vitro [70][71][72][73][74]. In addition, leptin regulates Growth hormone (GH) [19], although there is lack of agreement about the exact direction of its regulation [19,[75][76][77][78]. Leptin stimulates GH secretion mediated by GH releasing peptide (GHRP [77,79] and restores GH pulses in fasted rats [76,78].…”

“…In addition, leptin regulates Growth hormone (GH) [19], although there is lack of agreement about the exact direction of its regulation [19,[75][76][77][78]. Leptin stimulates GH secretion mediated by GH releasing peptide (GHRP [77,79] and restores GH pulses in fasted rats [76,78]. Luque et al [80] reported that leptin restored GH secretion in ob/ob mice that were infused with exogenous leptin for 7 days.…”

The Neuroanatomical Axis for Control of Energy Balance

“…Reduction in leptin level has been implicated as a critical contributor to all neuroendocrine changes associated with fasting. Thus, the neuroendocrine effects of fasting are reversed by systemic administration of leptin that restores plasma leptin to prefasting levels (2,3,55,129,196). The assumption is that it is the hypothalamus that contains the Ob-Rb that triggers both the effects of deprivation (by reduced stimulation) and their reversal with exogenous leptin treatment.…”

“…However, we think it important to recognize that this circuitry, in its clearest representation, is a neuroendocrine control mechanism linking interoceptive events (especially Ob-Rb stimulation) in the arcuate nucleus to the functional activity of the hypothalamo-pituitary axes (e.g., 2,3,56,129,131,196). In contrast to the clarity of this structurefunction relationship, the manner by which the hypothalamic circuit's defined and no doubt important descending pathways modulate behavioral output is quite vague.…”