Adipose tissue stores energy in the form of triglycerides. The ability to regulate triglyceride synthesis and breakdown based on nutrient status (e.g., fed versus fasted) is critical for physiological homeostasis and dysregulation of this process can contribute to metabolic disease. Whereas much is known about hormonal control of this cycle, transcriptional regulation is not well understood. Here, we show that the transcription factor Kruppel-like factor 15 (KLF15) is critical for the control of adipocyte lipid turnover. Mice lacking Klf15 in adipose tissue (AK15KO) display decreased adiposity and are protected from diet-induced obesity. Mechanistic studies suggest that adipose KLF15 regulates key genes of triglyceride synthesis and inhibits lipolytic action, thereby promoting lipid storage in an insulin-dependent manner. Finally, AK15KO mice demonstrate accelerated lipolysis and altered systemic energetics (e.g., locomotion, ketogenesis) during fasting conditions. Our study identifies adipose KLF15 as an essential regulator of adipocyte lipid metabolism and systemic energy balance. Display omitted •Adipose-specific Klf15 deletion results in decreased adiposity•KLF15 regulates genes important for lipogenesis and inhibits lipolysis in adipocytes•Adipose KLF15 is induced by insulin to orchestrate metabolic homeostasis The ability of adipose tissue to store and release energy is essential for the maintenance of metabolic homeostasis. Matoba et al. demonstrate that KLF15 is a critical regulator of adipose lipid handling. Adipocyte KLF15 is downregulated by fasting and enhances lipid mobilization, leading to systemic alteration in energy substrate utilization.