Grant: Catalyst Grant: NWHRI: Innovation Fund - Biomedical Discovery Grants

Reproduction, mood and nutrition are naturally intertwined throughout life, to coordinate food intake behavior with fluctuating energy needs & changing environment. As a direct consequence of this synchronization, female mammals are partially protected against metabolic & mood disorders such as obesity and depression during reproductive life, while showing increased propensity to develop these diseases after menopause. These effects are largely due to the major reduction of sex hormone secretion by the ovaries after menopause. Indeed, sex hormones such as estradiol has been shown to be protective against weight gain and mood disorders in both humans and preclinical rodent models. While it is now known that estradiol limits weight gains due to its ability to sensitize the brain to "metabolic" cues, it is not known whether estradiol improves mood via the same means. Overall, neither these metabolic cues -a hormone named leptin- nor estradiol are used therapeutically to treat durably postmenopausal obesity and mood disorders, due to resistance to their actions or to their long-term side-effects. Meanwhile, we have discovered a new protein in the brain named Cited1 that acts as a molecular bridge between sex hormones and metabolic cues. This protein is crucial for estradiol protective effects on weight, as female mice deficient in this protein are as sensitive to develop obesity than male mice. In this project, we propose to investigate Cited1 under a therapeutic, preclinical angle. This protein will be used as a molecular tool to treat both metabolic and mood disorders in mouse models of menopause. The overarching goal of this proposal is to investigate a novel molecular approach that can alleviate metabolic and mood disorders in menopause, and obtain robust results that will form the basis of a clinically-relevant, larger-scale project in the future.