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We previously described a colocalization between arginine vasopressin (AVP) and the chemokine stromal cell-derived factor-1alpha (SDF-1) in the magnocellular neurons of both the hypothalamic supraoptic and paraventricular nucleus as well as the posterior pituitary. SDF-1 physiologically affects the electrophysiological properties of AVP neurons and consequently AVP release. In the present study, we confirm by confocal and electron microscopy that AVP and SDF-1 have a similar cellular distribution inside the neuronal cell and can be found in dense core vesicles in the nerve terminals in the posterior pituitary. Because the Brattleboro rats represent a good model of AVP deficiency, we tested in these animals the fate of SDF-1 and its receptor CXCR4. We identified by immunohistochemistry that both SDF-1 and CXCR4 immunoreactivity were strongly decreased in Brattleboro rats and were strictly correlated with the expression of AVP protein in supraoptic nucleus, paraventricular nucleus, and the posterior pituitary. We observed by real-time PCR an increase in SDF-1 mRNA in both heterozygous and homozygous rats. The effect on the SDF-1/CXCR4 system was not linked to peripheral modifications of kidney water balance because it could not be restored by chronic infusion of deamino-8D-ariginine-vasopressin, an AVP V2-receptor agonist. These original data further suggest that SDF-1 may play an essential role in the regulation of water balance.

Peptide S (NPS or PEPS) and its cognate receptor have been recently identified both in the central nervous system and in the periphery. NPS/PEPS promotes arousal and has potent anxiolytic-like effects when it is injected centrally in mice. In the present experiment, we tested by different approaches its central effects on feeding behaviour in Long-Evans rats. PEPS at doses of 1 and 10 microg injected in the lateral brain ventricle strongly inhibited by more than 50% chow intake in overnight fasted rats with effects of longer duration with the highest dose (P<0.0001). A similar decrease was observed for the spontaneous intake of a high-energy palatable diet (-48%; P<0.0001). This anorexigenic effect was comparable to that induced by corticotropin-releasing hormone in fasted rats at equimolar doses. However, peptide S did not modify food intake stimulated by neuropeptide Y (NPY) at equimolar doses. It also did not affect the fasting concentrations of important modulators of food intake like leptin, ghrelin, and insulin in circulation. This study therefore showed that peptide S is a new potent anorexigenic agent when centrally injected. Its inhibitory action appears to be independent of the NPY, ghrelin, and leptin pathways. Development of peptide S agonists could constitute a new approach for the treatment of obesity.

In this study, we measured the ghrelin, leptin, and insulin variations in lean and obese Zucker fa/fa rats during the acute phase of body weight gain. At 2 months of age, plasma insulin and leptin concentrations in fa/fa rats were, respectively, 470% and 3700% higher than in lean rats (p <0.0001). Plasma ghrelin was significantly lower (-24.6%; p <0.02) than in lean rats. At 6 months of age, ghrelin increased in both genotypes but the difference was no more significant. The inverse correlations existing between ghrelin and either body weight (BW), insulin or leptin at 2 months of age were no more observable in 6-month-old rats. At 6 months of age, the lean rats had the same body weight as the 2-month-old obese rats. In these body weight-matched rats, ghrelin was not correlated with BW but it remained negatively correlated with insulin and leptin. At the same body weight, obese rats had a much lower plasma ghrelin than lean rats (717+/-42 vs. 1754+/-83 pg/ml; p <0.0001). These data indicate that body composition rather than body weight is the primary factor for the down-regulation of the ghrelin system. This down-regulation constitutes a mechanism of defense of the organism against the development of obesity at least during the first part of life.

Fischer rats show a low or absent basal salt appetite and a reduced intake of salt solutions in response to peripherally administered angiotensin II (AII) when compared to other strains. We investigated spontaneous sodium intake, and sodium intake after intracerebroventricular (i.c.v.) AII and losartan, and septo-preoptic neuronal responses to AII and losartan, in age-matched male Fischer and Wistar rats. Spontaneous intake of 1.8% NaCl was lower in Fischers, but i.c.v. injection of 10 pmol AII produced similar 2 h intakes in a 2 h test period. Iontophoretic application of AII and losartan onto neurons in the septo-preoptic continuum revealed differences between the two strains of rat. In the Fischer rats only 11% of the spontaneously active neurons were sensitive to locally applied AII compared to approximately 30% in the Wistar. Local application of losartan produced neuronal inhibition in Fischer rats but neuronal excitation in Wistars. The central AII system appears to be regulated differently in these two strains, and may be related to the differences in their spontaneous sodium intake, but not to AII aroused sodium appetite.

The hypothalamo-pituitary-adrenal (HPA) axis plays a central role both in the regulation of the stress response, and in the control of feeding behaviour. Sensitivity of the HPA axis to respond to stress varies both during ontogeny and between individuals, and can be altered by neonatal events. The aim of our experiments was to determine whether early events that affect the HPA axis could also induce persistent modifications in food intake (quantitatively and qualitatively), as well as alterations of anxiety-related behaviour. Twenty-four-hour maternal deprivation was introduced at two different periods of HPA maturation, on day 5 (DEP5) or day 14 (DEP14) after birth. Sequential measurements of plasma levels of adrenocorticotropin hormone (ACTH) and corticosterone showed that this deprivation altered the HPA axis of adults; the response to restraint stress was prolonged in DEP5 and a higher ACTH peak appeared in DEP14. The neonatal stress also produced long-lasting modifications of rat behaviour, as DEP14 adults became more anxious. Standard food intake decreased in both groups of deprived rats. Diet preferences also changed, as carbohydrate intake decreased in DEP5 rats. Corticosteroid receptor binding did not vary in the hippocampus of the deprived rats. The modifications of the stress response and the behaviour parameters could be due to the alteration of corticosteroid receptors in the hypothalamic paraventricular nucleus and/or corticotropin-releasing hormone or vasopressin function, but these parameters have yet to be determined. This early stress paradigm altering feeding behaviour could become an interesting model for research into human eating disorders.

Arginine vasopressin (AVP) produced in the hypothalamic suprachiasmatic nuclei (SCN) plays a role in establishing neuroendocrine rhythms and, in particular, in regulating the corticotrope axis rhythm. It has recently been shown that AVP from SCN inhibits corticosteroid release. In order to investigate the influence of suprachiasmatic AVP on the different peptidergic systems through the hypothalamus, SCN neurons containing AVP were functionally lesioned by using toxins associated with a cytotoxic monoclonal antibody (MAb) raised against AVP. Six days later, the AVP contents and AVP mRNA were measured in different hypothalamic and extrahypothalamic sites. Adrenocorticotrophic hormone (ACTH) concentration was also measured in plasma. Microinjection of the AVP-MAb/toxin mixture into SCN brought about a significant decrease in the AVP expression in SCN. This is demonstrated by the decrease in the AVP immunoreactive content (24%, P < 0.01) and the decrease of AVP hybridized mRNA (33%, P < 0.01). This points to the efficiency of the microinjection in decreasing the production of AVP in the injection area. Modifications of the AVP contents in the two subdivisions of the hypothalamic paraventricular nucleus (PVN) were also observed. AVP contents decreased in the parvocellular subdivision (pPVN); this is coherent with the AVP depletion in SCN since pPVN is the major site of the SCN hypothalamic efferences. AVP content and AVP mRNA increased in the magnocellular subdivision (mPVN); this also confirms the difference in AVP synthesis regulation according to the PVN subdivisions. The microinjection did not modify AVP expression in supraoptic nuclei or oxytocin (OT) immunoreactive content in the main hypothalamic OT containing sites. Plasma ACTH values were double (P < 0.02) the values measured under non-specific IgG treatment 10 hr after lights on. This probably resulted from the stimulation of the hypothalamo-pituitary-adrenal system since corticotrophin-releasing hormone (CRH) mRNA increased simultaneously by 24% (P < 0.05) in the PVN and the immunoreactive CRH content of the median eminence significantly decreased (26%, P < 0.05). Overall, our data confirm that AVP produced in the SCN inhibits the CRH-adrenocorticotrope axis in normal conditions, probably because of SCN projections of AVP neurons on the PVN.