Ghrelin is a 28-amino acid acylated peptide and is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). The GHS-R is expressed in hypothalamic nuclei, including the arcuate nucleus (Arc) where it is colocalized with neuropeptide Y (NPY) neurons. In the present study, we examined the effects of ghrelin on feeding and energy substrate utilization (respiratory quotient; RQ) following direct injections into either the arcuate or the paraventricular nucleus (PVN) of the hypothalamus. Ghrelin was administered at the beginning of the dark cycle at doses of 15-60 pmol to male and female rats. In feeding studies, food intake was measured 2 and 4 h postinjection. Separate groups of rats were injected with ghrelin, and the RQ (VCO(2)/VO(2)) was measured using an open circuit calorimeter over a 4-h period. Both Arc and PVN injections of ghrelin increased food intake in male and female rats. Ghrelin also increased RQ, reflecting a shift in energy substrate utilization in favor of carbohydrate oxidation. Because these effects are similar to those observed after PVN injection of NPY, we then assessed the impact of coinjecting ghrelin with NPY into the PVN. When rats were pretreated with very low doses of ghrelin (2.5-10 pmol), NPY's (50 pmol) effects on eating and RQ were potentiated. Overall, these data are in agreement with evidence suggesting that ghrelin functions as a gut-brain endocrine hormone implicated in the regulation of food intake and energy metabolism. Our findings are also consistent with a possible interactive role of hypothalamic ghrelin and NPY systems.

FLU suppressed food intake comparably in male and female rats. Dorsal and median raphe injections of 8-OH-DPAT dose dependently reversed the anorectic effect of FLU in male rats. Higher doses of 8-OH-DPAT completely antagonized this response. In female rats, however, 8-OH-DPAT pretreatment was largely ineffective except in ovariectomized females where results were similar to male rats. These findings suggest that male and female rats are differentially sensitive to the ability of 5-HT(1A) receptor agonists to antagonize the feeding suppressive action of FLU and imply a role for neuroendocrine mechanisms in enabling the somatodendritic autoreceptor to control serotonergic neurotransmission under these conditions.

The corticotropin releasing hormone-related ligand, urocortin-I (UcnI), suppresses food intake when injected into multiple hypothalamic and extrahypothalamic areas. UcnI also alters energy substrate utilization, specifically via enhanced fat oxidation as reflected in reductions in respiratory quotient (RQ). In the present study we compared the feeding and metabolic effects of ghrelin and NPY following pretreatment with UcnI. Direct PVN injections of NPY (50 pmol) and ghrelin (50 pmol) were orexigenic while UcnI (10-40 pmol) reliably suppressed food intake. Both ghrelin and NPY increased RQ, indicating enhanced utilization of carbohydrates and the preservation of fat stores. UcnI alone suppressed RQ responses. PVN UcnI attenuated the effects of both ghrelin and NPY on food intake and energy substrate utilization. While ghrelin (5 pmol) potentiated the effect of NPY (25 pmol) on RQ and food intake, these responses were inhibited by pretreatment with UcnI (10 pmol). In conclusion, PVN NPY and ghrelin stimulate eating and promote carbohydrate oxidation while inhibiting fat utilization. These effects are blocked by UcnI which alone suppresses appetite and promotes fat oxidation. Overall these findings are consistent with a possible interactive role of PVN NPY, ghrelin and urocortin in the modulation of appetite and energy metabolism.

In the present study we sought to investigate interactions between hypothalamic nitric oxide (NO) and ghrelin signaling on food intake and energy substrate utilization as measured by the respiratory exchange ratio (RER). Guide cannulae were unilaterally implanted in either the arcuate (ArcN) or paraventricular (PVN) nuclei of male Sprague-Dawley rats. Animals were pretreated with subcutaneous (2.5-10mg/kg/ml) or central (0-100pmol) N-nitro-l-Arginine methyl ester (l-NAME) followed by 50pmol of ghrelin administered into either the ArcN or PVN. Both l-NAME and ghrelin were microinjected at the onset of the active cycle and food intake and RER were assessed 2h postinjection. RER was measured as the ratio of the volume of carbon dioxide expelled relative to the volume of oxygen consumed (VCO/VO) using an open-circuit indirect calorimeter. Our results demonstrated that peripheral and central l-NAME pretreatment dose-dependently attenuated ghrelin induced increases in food intake and RER in either the ArcN or PVN. In fact the 100pmol dose largely reversed the metabolic effects of ghrelin in both anatomical regions. These findings suggest that ghrelin enhancement of food intake and carbohydrate oxidation in the rat ArcN and PVN is NO-dependent.