The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic.

The hypothalamic circuits controlling food intake and body weight receive and integrate information from circulating satiety signals such as leptin and insulin and also from ghrelin, the only known circulating hormone that stimulates appetite following systemic injection. Activation of arcuate neurons by ghrelin and ghrelin mimetics (the growth hormone secretagogues) is augmented in 48-h-fasted rats compared with fed rats, as reflected by a greater number of cells expressing Fos protein in response to administration of the same maximally effective dose. Here we sought to determine whether this increased responsiveness in fasting might reflect or be influenced by low levels of circulating satiety factors such as leptin or insulin. Chronic central infusion of insulin or leptin during a 48-h fast suppressed the threefold increase in the Fos response to intravenous injection of a maximally effective dose of growth hormone-releasing peptide (GHRP)-6, a synthetic growth hormone secretagogue. This appears to be a direct central action of insulin and leptin because the marked decrease in plasma levels of insulin, leptin, and glucose during fasting were unaffected by central administration of either hormone. Furthermore, the GHRP-6-induced Fos response was twofold greater in obese leptin- and insulin-resistant Zucker rats compared with lean controls. These data provide evidence that the ghrelin-sensitive circuits in the hypothalamus are dynamically regulated by central insulin and leptin action.

Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection.

Beneficial effects of GH on memory, mental alertness, and motivation have been documented. Many actions of GH are mediated through IGF-I; hence, we investigated whether systemic administration of GH or GH-releasing peptide (GHRP)-6 modulates the brain IGF system. Treatment of adult male rats with GHRP-6 or GH for 1 wk significantly increased IGF-I mRNA levels in the hypothalamus, cerebellum, and hippocampus, with no effect in cerebral cortex. Expression of the IGF receptor and IGF-binding protein (IGFBP)-2 were not affected. Phosphorylation of Akt and Bad was stimulated in areas where IGF-I was increased, with no change in MAPK or glycogen synthase kinase-3beta. This suggests that GH and GHRP-6 activate phosphatidylinositol kinase intracellular pathways involved in cell survival in response to growth factors. Indeed, the antiapoptotic protein Bcl-2 was augmented in these same areas, with no change in the proapoptotic protein Bax. IGFBP-5, also reported to be involved in neuron survival processes, was increased mainly in the hypothalamus, suggesting a possible neuroendocrine role. In conclusion, GH and GHRP-6 modulate IGF-I expression in the central nervous system in an anatomically specific manner. This is coincident with activation of intracellular signaling pathways used by IGF-I and increased expression of proteins involved in cell survival or neuroprotection.

Intracerebroventricular injection of apelin-13 reduces food intake in the rat.

Apelin is a peptide recently identified as a ligand for the APJ receptor, a receptor located in tissues such as the small intestine and in the hypothalamus. Apelin has been detected in adipose tissue, gastrointestinal tract, heart and stomach. Recent reports suggest a role for apelin in the regulation of blood pressure and the control of body fluid homeostasis. The present studies examined the consequences on food intake of intravenous (IV) and intracerebroventricular (ICV) injection of apelin-13 in the Wistar rat. IV injection of 10 nmol of apelin-13 did not cause any change in food intake in either fed or 24-h fasted rats. ICV injection of 1 and 3 nmol of apelin-13 resulted in a reduction in food intake in both fed and fasted rats. The earliest reduction in food intake occurred at 4 h post-injection in fed rats. In fasted rats, food intake was reduced at 24-h post-injection only. These data provide evidence of a possible role for apelin-13 in the control of food intake.