Chemotherapy-induced anorexia is accompanied by activation of brain pathways signaling dehydration

Background and aimsCancer chemotherapy is accompanied by anorexia and mucositis. To clarify the mechanisms of chemotherapy-induced anorexia, we studied the expression of c-fos and appetite-regulating neuropeptidergic and inflammatory mediators in the hypothalamus of rats treated with methotrexate (MTX).MethodsSprague-Dawley rats received MTX (2.5 mg/kg, subcutaneously) on three consecutive days and were compared with ad libitum- and pair-fed control rats five days after the first injection.ResultsMTX administration inhibited food and water intake and induced lean and fat mass losses. MTX also induced mucositis and diarrhea without changes in plasma osmolality. Pair-fed rats lost a similar amount of body weight but had no mucositis or diarrhea. Increased number of c-fos positive hypothalamic vasopressin neurosecretory neurons as well as numerous c-fos positive cells in the subfornical organ and in the organum vasculosum of the lamina terminalis were found in MTX-treated as compared to control or pair-fed rats. In both MTX and pair-fed rats, a decrease of hypothalamic proopiomelanocortin mRNA expression and low plasma levels of interleukin-1β (IL-1β) were found reflecting probably the energy deficit. No significant changes of IL-1β mRNA expression and intensity of microglial staining in the hypothalamus were found in MTX-treated rats.ConclusionThe pattern of c-fos expression in the hypothalamus during MTX treatment is similar to that seen with systemic dehydration, which is known to cause anorexia. No evidence of inflammatory origin of anorexia was found, suggesting that chemotherapy accompanied by mucositis and diarrhea may cause anorexia associated with systemic dehydration.

Research Highlights
► Methotrexate induces intestinal mucositis and diarrhea.
► Diarrhea causes systemic hypovolemic dehydration.
► Dehydration is perceived by the brain pathways involved in water balance control.
► Brain perception of dehydration triggers anorexia and weight loss.