Our study in middle-aged animals shows significant sex differences in obesity-related inflammation, which was characterized by an augmented age-induced accumulation of CD8+ T cells in the adipose tissue of female animals, higher levels of adipose IFN-γ, TNF-α, GzmB, RANTES, and MIP-1β in female mice, and the absence of an age-related expansion of the adipose tissue Treg population in middle-aged females. Here, IFNG is linked to obesity due to melanocortin 4 receptor deficiency.