Enhanced hepatic PPARa activity links GLUT8 deficiency to augmented peripheral fasting responses in male mice

Allyson L. Mayer, Yiming Zhang, Emily H. Feng, Cassandra B. Higgins, Oyinkansola Adenekan, Terri A. Pietka, Wandy L. Beatty, Brian J. DeBosch

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The adaptive fasting response is invoked as a promising cardiometabolic and neurodegenerative therapeutic pathway. We and others have defined the carbohydrate transporter glucose transporter 8 (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 in vivo and in vitro. Mechanistically, we show that hepatic peroxisome proliferator–activated receptor a (PPARa) and its transcriptional fasting response target hepatokine, fibroblast growth factor (FGF)21, are cell-autonomously hyperactivated in GLUT8-deficient liver and in isolated primary murine hepatocytes during nutrient depletion. 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.

Original languageEnglish
Pages (from-to)2110-2126
Number of pages17
JournalEndocrinology
Volume159
Issue number5
DOIs
StatePublished - May 1 2018

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