EVIDENCE FOR A LEPTIN-NEUROPEPTIDE Y-AXIS FOR THE REGULATION OF GROWTH-HORMONE SECRETION IN THE RAT

The obese gene (OB) product, leptin, has been shown to exert control o n metabolic processes such as food intake and body weight homeostasis, possibly through a neuropeptide Y (NPT) neurotransmission. More recen tly, leptin has been shown to control several neuroendocrine axes, mod ulating pituitary hormone secretions in function of metabolic conditio ns. Since in the rat growth hormone (GH) secretion is dependent upon p revailing metabolic conditions, and NPY has been shown to be implicate d in the feedback mechanisms of this hormone, we reasoned that leptin could also exert control over GH secretion and we examined this hypoth esis in male rats submitted to a 3-day fast. Circulating leptin concen trations measured by RIA abruptly fell to low values after 24 h of fas ting and remained low thereafter. Upon refeeding, leptin secretion reg ularly increased. As shown by others, pulsatile GH secretion had disap peared after 3 days of fasting. Centrally administered leptin (10 mu g /day, i.c.v. infusion initiated at the beginning of the fasting period ) totally prevented the disappearance of pulsatile GH secretion. No le ak of centrally administered leptin to the general circulation was obs erved. 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, pai r-fed rats, submitted to the same food restriction, exhibited a marked reduction in GH secretion. Hypothalamic NPY gene expression, estimate d by Northern blot analysis, was significantly increased in fasting ra ts, and decreased in leptin-treated, fasting rats. In rats receiving a d libitum feeding, leptin treatment reduced NPY gene expression, consi stent with the observed reduction in food intake, whereas pair-fed ani mals logically exhibited increased NPY gene expression. In both situat ions with reduced feeding, normal GH secretion was seen in leptin-trea ted animals exhibiting low NPY gene expression, whereas decreased or a bolished GH secretion wets seen in animals not receiving leptin and ex hibiting 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 expr ession for both GH receptor and IGF-I was markedly reduced by fasting, and no correction was seen with leptin treatment. In summary, the reg ulation of GH secretion, at least the changes linked with malnutrition , appears to be dependent upon a leptin signal, perceived centrally, p ossibly 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.