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 sexspecific 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.

This study compared the effects of relaxin-3 (RLN3) on food intake, plasma corticosterone, and the expression of corticotropin-releasing factor (CRF) in male and female rats. RLN3 was injected into the lateral ventricle at 25, 200, and 800 pmol concentrations. RLN3 at 25 pmol increased food intake (grams) at 30 and 60 minutes after injection in female but not male rats. Female rats also showed higher increase in relative to body weight (BW) food intake (mg/g BW) for all RLN3 concentrations at 30 minutes and for 800 pmol of RLN3 at 60 minutes. Moreover, RLN3 at 800 pmol significantly increased 24-hour BW gain in female but not male rats. At 60 minutes after administration, 800 pmol of RLN3 produced a significant increase in plasma corticosterone and in the expression of CRF and c-fos mRNAs in the parvocellular paraventricular hypothalamic nucleus (PVN) in male but not female rats. The levels of c-fos mRNA in the magnocellular PVN were increased by RLN3 but did not differ between the sexes. Conversely, expression of CRF mRNA in the medial preoptic area was increased in female rats but was not sensitive to 800 pmol of RLN3. In the bed nucleus of the stria terminalis, 800 pmol of RLN3 significantly increased CRF mRNA expression in female but not male rats. Therefore, female rats showed more sensitivity and stronger food intake increase in response to RLN3. The differential effects of RLN3 on CRF expression in the PVN and bed nucleus of the stria terminalis may contribute to the sex-specific difference in the behavioral response.

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