In restrictive type anorexia nervosa (AN), various endocrine, metabolic, and central alterations causing long-term damages for the individuals are observed. The physiological mechanisms involved in the adaptation of the organism to a chronic food restriction before exhaustion are largely unknown. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone, are increased. We have thus developed a mouse model which combined chronic food restriction voluntary activity that mimics most of the alterations observed in AN. After a physiological characterization of the model, we expect to determine the impact of ghrelin both at peripheral and central levels.

Two 8-week old female mice per cage containing a wheel (W) or not were fed ad libitum (AL) or subjected to a progressive food restriction from 30 to 50 % (FR) for a 15-days protocol.

FRW mice showed a 22% decrease of the body weight associated with a shift in physical activity from night to light suggesting an anticipatory behavior to food intake. This phenotype was associated with tissue, metabolic and endocrine alterations. Especially, it appeared a significant increase in the plasma ghrelin levels associated with a better regulation of their glycemia only in FRW mice. At the hypothalamic level and in basal conditions, FR and FRW mice showed a drastic increase in expression of AgRP and NPY mRNA while the POMC (anorexigenic peptide) mRNA was down-regulated only in FRW mice. It appeared also that only FRW mice displayed a decrease of their hypothalamic receptors (MC3R, MC4R, Y1R and Y5R) expression. Physical activity seems to play an essential role in this receptor expression. Finally, acute i.p. injection of ghrelin (2mg/kg) was performed to test the sensitivity to ghrelin. Preliminary data indicated that FRW mice have a differential reactivity at central and peripheral level.