Melanotan II enhances stress-induced anorexia and hypercortisolism in mice via brain melanocortin receptor activation

The brain's melanocortin (MC) system is a well-established regulator of food intake and energy balance under normal, resting conditions. However, various forms of stress are known to potently inhibit appetite, a phenomenon known as stress-induced anorexia. While the link between stress and appetite loss is clear, the specific neural circuits mediating this response are not fully understood. It remains uncertain whether the same melanocortin pathways that control baseline feeding are also recruited to suppress food intake during stressful events. This study investigates if the central MC system is a key player in mediating the anorexic effects of acute stress in mice.

C57Bl/6J male mice were fasted for 17 hours to pre-stimulate food intake. They were then subjected to acute ether stress (a 0.5-minute ether anesthesia exposure). Immediately following the stressor, mice received an intracerebroventricular (ICV) injection into the lateral brain ventricle. The three arms were: a control group receiving saline, a blockade group receiving the non-selective MC receptor antagonist SHU9119, and an activation group receiving the non-selective MC receptor agonist Melanotan II. Food intake was measured 1 hour post-stress. Plasma corticosterone levels and hypothalamic AgRP mRNA levels were also assessed at this time point.

Ether stress alone significantly decreased food intake and increased plasma corticosterone levels 1 hour after exposure. The stress also elevated hypothalamic mRNA levels of AgRP, a natural antagonist of MC receptors. Pharmacological blockade of MC receptors with SHU9119 weakened the stress-induced anorexia, suggesting that endogenous melanocortin signaling is necessary for the full effect. This blockade also decreased the stress-induced rise in hypothalamic AgRP mRNA. Conversely, pharmacological stimulation of MC receptors with Melanotan II enhanced the anorexic effect of the ether stress.

The administration of Melanotan II also exacerbated the stress response itself, leading to significantly enhanced hypercortisolism (elevated plasma corticosterone) compared to stressed mice receiving only saline. This demonstrates a direct, causal link where central melanocortin system activation not only suppresses appetite but also amplifies the physiological stress response.