High fat diet is commonly used to model obesity and prediabetes in mice. Prior work had shown that young female mice are generally protected from the detrimental metabolic effects of high fat diet relative to young males. However, how these effects change with age had never been examined. Zuloaga and colleagues demonstrated (International Journal of Obesity) that if the high fat diet is initiated in middle-age, when females are perimenopausal, that this sex difference is reversed and females have greater metabolic impairment compared to males. This work made a critical contribution to the field by highlighting sex and age as key biological variables in metabolic disease research.