We herewith present results with 3xTg-AD mice, with and without transgenic sgp130Fc expression by astrocytes, and challenged with a high-fat diet to elicit obesity, which suggest that IL-6 trans-signaling modulates some of the hypermetabolic traits presented by the 3xTg-AD mice in a sex-dependent manner. Here, IL6 is linked to obesity due to melanocortin 4 receptor deficiency.