17a-Estradiol alleviates high-fat diet-induced inflammatory and metabolic dysfunction in skeletal muscle of male and female mice

17a-estradiol (17a-E2) is a naturally occurring nonfeminizing diastereomer of 17b-estradiol that has life span-extending effects in rodent models. To date, studies of the systemic and tissue-specific benefits of 17a-E2 have largely focused on the liver, brain, and white adipose tissue with far less focus on skeletal muscle. Skeletal muscle has an important role in metabolic and age-related disease. Therefore, this study aimed to determine whether 17a-E2 treatment has positive, tissue-specific effects on skeletal muscle during a high-fat feeding. We hypothesized that male, but not female, mice, would benefit from 17a-E2 treatment during a high-fat diet (HFD) with changes in the mitochondrial proteome to support lipid oxidation and subsequent reductions in diacylglycerol (DAG) and ceramide content. To test this hypothesis, we used a multiomics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. Unexpectedly, we found that 17a-E2 had marked, but different, beneficial effects within each sex. In male mice, we show that 17a-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAG), and inflammatory cytokine levels, and altered the abundance of most of the proteins related to lipolysis and b-oxidation. Similar to male mice, 17a-E2 treatment reduced fat mass while protecting muscle mass in female mice but had little muscle inflammatory cytokine levels. Although female mice were resistant to HFD-induced changes in DAGs, 17a-E2 treatment induced the upregulation of six DAG species. In female mice, 17a-E2 treatment changed the relative abundance of proteins involved in lipolysis, b-oxidation, as well as structural and contractile proteins but to a smaller extent than male mice. These data demonstrate the metabolic benefits of 17a-E2 in skeletal muscle of male and female mice and contribute to the growing literature of the use of 17a-E2 for multi tissue health span benefits. NEW & NOTEWORTHY Using a multiomics approach, we show that 17a-E2 alleviates HFD-induced metabolic detriments in skeletal muscle by altering bioactive lipid intermediates, inflammatory cytokines, and the abundance of proteins related to lipolysis and muscle contraction. The positive effects of 17a-E2 in skeletal muscle occur in both sexes but differ in their outcome.