Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21)1,2 coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing β2 adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.