The adaptive fasting response is invoked as a promising cardiometabolic and neurodegenerative therapeutic pathway. We and others have defined the carbohydrate transporter, GLUT8, as a critical regulator of hepatic and whole-organism metabolic homeostasis in the overfed and diabetic states. However, the functions of this critical transporter in the physiological fasting response remain poorly understood. Here, we tested the hypothesis that GLUT8 modulates the adaptive hepatic fasting response. We demonstrate that mice with targeted Slc2a8 disruption exhibit enhanced thermogenesis, ketogenesis and peripheral lipid mobilization during fasting. These metabolic enhancements were observed in the context of mildly impaired hepatic mitochondrial oxidative metabolism both in vivo and in vitro. Mechanistically, we show that hepatic PPARa and its transcriptional fasting response target hepatokine, FGF21, are cell-autonomously hyperactivated in GLUT8-deficient liver and in isolated primary murine hepatocytes during nutrient depletion. Strikingly, hepatic PPARa knockdown in GLUT8-deficient mice normalized the enhanced ketogenic and FGF21 secretory responses and decreased mitochondrial respiratory function, without altering the hyperthermic response to fasting. Our data demonstrate that hepatocyte GLUT8 regulates adaptive fasting in part through regulation of the PPARa signaling cascade. Moreover, the ketotic and thermic responses to fasting are differentially encoded within the GLUT8-PPARa communication axis. GLUT8 therefore represents a therapeutic target that can be leveraged against cardiometabolic disease.

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