Grant: Project Grant

Current understanding of the pathophysiological events linking obesity to type 2 diabetes (T2DM) is predicated on a body of data generated predominately in male animals. The default use of male animals has led to a paucity of knowledge in sex-specific mechanisms and the development of "one-size-fits-all" treatments that fail to account for the influence of sex hormones. T2DM risk in obesity is not driven by the absolute amount of body fat, but rather by its distribution and function. Males tend to accumulate fat around internal (visceral) organs, which increases the risk for T2DM. In contrast, expansion of fat located beneath the skin (subcutaneous) is characteristic of females and associated with a favourable metabolic profile. After menopause, a shift towards the male-like pattern of body fat distribution coincides with an increase in the risk for T2DM. Our preliminary data suggest that estrogen-mediated responses of fat-residing stem cells underlie sex differences in fat distribution and T2DM risk. Thus, we will probe the molecular mechanisms by which sex and estrogen influence site-specific stem cell responses and metabolic health. We will use a mouse model of diet-induced obesity. The role of estrogen will be determined by removing the ovaries, with a subset of ovariectomized females supplemented with estrogen. The response of stem cells to obesogenic conditions will be measured using a state-of-the-art transgenic model that permits the identification of new fat cells in the whole animal. The role of immune cells in governing sex-specific stem cell behaviour will be determined by assessing stem cell responses to an obesogenic environment after pharmacological or genetic ablation of immune cells. Single cell sequencing will measure stem cell abundance to determine if female mice are protected against obesity-induced exhaustion of the stem cell pool.