Female animals have a well-documented and persistent history of being excluded from preclinical biomedical research. Because preclinical research is the foundation of medical treatment development, male bias at the preclinical level contributes to persisting inequities of medical treatment in women: women are more likely to be misdiagnosed in a wide array of medical conditions and are more likely to suffer from adverse drug reactions than men. Therefore, it is critical that preclinical researchers thoughtfully consider sex as a biological variable (SABV) in experimental designs and analyses.

This dissertation discusses the importance of considering SABV in metabolism-related endpoints. First in chapter one, we give a perspective on the current state of male bias in preclinical research with an emphasis on metabolism research. We discuss recent progress in studies including SABV, as well as practical and cultural barriers that keep investigators from conducting sex-inclusive research. Next, we thoroughly investigate SABV in the three data chapters that follow. In chapter two, we report that the melanocortin-4 receptor, a well-known regulator of energy balance, modulates the hypothalamic-pituitary-adrenocortical axis tone in a markedly sex-dependent manner. In chapter three, we report that the hormone fibroblast growth factor-21 (FGF21) decreases liver triglyceride content in a sex-dependent manner. In chapter four, we take a multi-omics analyses approach to investigate potential molecular pathways underlying the effects of FGF21 on hepatic metabolism. Thus, through the data discussed in this dissertation, we hope to highlight the importance of considering SABV in preclinical research and contribute robust data to the body of knowledge aiding in making scientific translation more effective and equitable.