Differential effects of central administration of relaxin-3 on food intake and hypothalamic neuropeptides in male and female rats.

Relaxin-3 (RLN3) is an orexigenic neuropeptide that produces sex-specific effects on food intake by stronger stimulation of feeding in female compared with male rats. This study determined which hypothalamic nuclei and associated neuropeptides may be involved in the sex-specific orexigenic effects of RLN3. Relaxin-3 (800 pmol) or vehicle was injected into the lateral ventricle of female and male rats. Food and water intake were measured after the first injection, and rats were euthanized after the second injection to determine the mRNA expression of the hypothalamic neuropeptides. Food but not water intake showed sex-specific effects of RLN3. Stimulation of food intake by RLN3 was significantly higher in female than in male rats. No effect of RLN3 injection was found on c-fos mRNA expression in the arcuate, dorsomedial and ventromedial hypothalamic nuclei. Increased c-fos mRNA expression was observed in the paraventricular hypothalamic nucleus (PVN) in both sexes and in the lateral hypothalamic area (LHA) in female rats. Relaxin-3 injections led to a sex-nonspecific increase in the expression of oxytocin mRNA in the magnocellular PVN. Conversely, RLN3-induced expression of anorexigenic neuropeptide arginine vasopressin (AVP) was significantly higher in the parvocellular PVN in male compared with female rats. Finally, RLN3 administration significantly increased the expression of orexin (ORX) mRNA in the LHA in female but not in male rats. Stronger expression of anorexigenic AVP in the PVN in male rats and increased expression of ORX in the LHA in female rats may contribute to stronger orexigenic effects of RLN3 in female rats compared with male rats.

Sex differences in the effects of chronic stress and food restriction on body weight gain and brain expression of CRF and relaxin-3 in rats.

This study investigated sex-specific effects of repeated stress and food restriction on food intake, body weight, corticosterone plasma levels and expression of corticotropin-releasing factor (CRF) in the hypothalamus and relaxin-3 in the nucleus incertus (NI). The CRF and relaxin-3 expression is affected by stress, and these neuropeptides produce opposite effects on feeding (anorexigenic and orexigenic, respectively), but sex-specific regulation of CRF and relaxin-3 by chronic stress is not fully understood. Male and female rats were fed ad libitum chow (AC) or ad libitum chow and intermittent palatable liquid Ensure without food restriction (ACE), or combined with repeated food restriction (60% chow, 2 days per week; RCE). Half of the rats were submitted to 1-h restraint stress once a week. In total, seven weekly cycles were applied. The body weight of the RCE stressed male rats significantly decreased, whereas the body weight of the RCE stressed female rats significantly increased compared with the respective control groups. The stressed female RCE rats considerably overate chow during recovery from stress and food restriction. The RCE female rats showed elevated plasma corticosterone levels and low expression of CRF mRNA in the paraventricular hypothalamic nucleus but not in the medial preoptic area. The NI expression of relaxin-3 mRNA was significantly higher in the stressed RCE female rats compared with other groups. An increase in the expression of orexigenic relaxin-3 and misbalanced hypothalamic-pituitary-adrenal axis activity may contribute to the overeating and increased body weight seen in chronically stressed and repeatedly food-restricted female rats.

Sucrose modifies c-fos mRNA expression in the brain of rats maintained on feeding schedules.

Food intake is regulated according to circadian activity, metabolic needs and the hedonic value of food. Rodents placed on a fixed feeding schedule show behavioral and physiological anticipation of mealtime referred to as food-anticipatory activity (FAA). FAA is driven by the food-entrainable oscillator (FEO), whose anatomical substrate is not yet known. Recent data have shown that restricted feeding schedules for regular chow and daily limited access to palatable food in free-feeding rats activate distinct brain regions during FAA. The combination of a deprivation regimen and scheduled access to palatable food may give rise to a more global anticipatory mechanism because the temporal cycles of energy balance would be strongly modulated by the incentive properties of palatable food; however, the neuronal response to this combined treatment is not yet known. The present study investigated how adding palatable sucrose to feeding schedules affects the pattern of brain c-fos mRNA expression during FAA (0-3 h) and 1 h following feeding. The rats maintained on scheduled chow access increased their daily chow intake, while the rats maintained on scheduled sucrose and chow mainly increased their daily sucrose intake. Adding sucrose to scheduled feeding displaced c-fos mRNA expression from the dorsomedial and paraventricular hypothalamic nuclei and posterior lateral hypothalamus (LH) to the prefrontal cortex, lateral septum, nucleus accumbens and anterior LH. During refeeding, the rats on scheduled sucrose demonstrated higher activation of the nucleus of the solitary tract. The present results suggest that palatable sucrose combined with restricted feeding schedules activate a distinct neuronal network compared to neuronal activation produced by scheduled access to regular chow. These data provide evidence that the brain may contain different food-oscillatory systems and that food palatability may shift the neuronal activity from the medial hypothalamus to the limbic and reward-related areas even at the negative metabolic state.