Summary: Metabolic diseases (e.g., obesity and type 2 diabetes) along with their serious sequelae such as non-alcoholic fatty liver disease (NAFLD) have reached epidemic proportions in the developed world due to excess nutrient intake and increasingly sedentary lifestyles. It is now well recognized that skeletal muscle significantly modulates systemic metabolic status through its roles in fatty acid uptake and oxidation, insulin-mediated glucose uptake, glycogen storage, and amino acid catabolism. Additionally, its ability to crosstalk with other metabolic organs has significant effects on influencing nutrient homeostasis. Unsurprisingly, aberrant skeletal muscle metabolism is closely associated with metabolic diseases. The transcription factor family known as Kruppel-like factors (KLFs) have emerged as crucial regulators of metabolism, and this dissertation work focuses on KLF15 in particular. In Chapter 3, we show that KLF15 controls muscle lipid uptake and oxidation, and the absence of muscle KLF15 confers a profound metabolic disease phenotype, including obesity and the development of NAFLD. In Chapter 4, we take a deeper dive into the molecular mechanisms of KLF15 action and demonstrate that it not only coordinates with PPARδ to orchestrate lipid flux but is necessary for PPARδ's proper binding to DNA and transcriptional activity. In Chapter 5, we turn our attention to a highly metabolic tissue that is closely related to muscle: brown adipose tissue (BAT). We uncover the transcriptional adaptions BAT undergo in response to states of high energy demand and demonstrate that KLF15 is necessary in regulating this transcriptional nutrient switch. And finally, we end with Chapter 6, where we present interesting findings that muscle KLF15 seems to be a regulator of arterial and venous thrombosis, both pathologies that frequently co-occur with metabolic disease. Together, these studies highlight the interconnectedness of metabolic processes across different tissues and place KLF15 at the center of critical metabolic networks necessary for daily adaptation.