Vulnerability to psychological stress-induced anorexia in female mice depends on blockade of ghrelin signal in nucleus tractus solitarius

Abstract

Background and purpose: Women have a higher incidence of eating disorders than men. We investigated whether the effects of ghrelin on feeding are affected by sex and stress, and to elucidate the mechanisms that may cause sex differences in stress-mediated anorexia, focusing on ghrelin.

Experimental approach: Acylated ghrelin was administered to naïve and psychologically stressed male and female C57BL/6J mice, followed by measurements of food intake and plasma hormone levels. Ovariectomy was performed to determine the effects of ovary-derived oestrogen on stress-induced eating disorders in female mice. The numbers of Agrp or c-Fos mRNA-positive cells and estrogen receptor α/c-Fos protein-double-positive cells were assessed.

Key results: Ghrelin administration to naïve female mice caused a higher increase in food intake, growth hormone secretion, Agrp mRNA expression in the arcuate nucleus and c-Fos expression in the nucleus tractus solitarius (NTS) than in male mice. In contrast, psychological stress caused a more sustained reduction in food intake in females than males. The high sensitivity of naïve females to exogenous ghrelin was attenuated by stress exposure. The stress-induced decline in food intake was not abolished by ovariectomy. Estrogen receptor-α but not -β antagonism prevented the decrease in food intake under stress. Estrogen receptor-α/c-Fos-double-positive cells in the NTS were significantly increased by stress only in females.

Conclusion and implications: Stress-mediated eating disorders in females may be due to blockade of ghrelin signalling via estrogen receptor-α activation in the NTS. Targeting the ghrelin signal in the brain could be a new treatment strategy to prevent these disorders.

Keywords: anorexia; ghrelin; mice; rikkunshito; sex differences; stress.