Biozentrum, University of Basel, Basel, Switzerland; Department of Chronic Diseases and Metabolism, Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
Amandine Thomas
Biozentrum, University of Basel, Basel, Switzerland
Sunil Shetty
Biozentrum, University of Basel, Basel, Switzerland
Irina C Frei
Biozentrum, University of Basel, Basel, Switzerland
Bettina K Wölnerhanssen
University of Basel, Basel, Switzerland; St. Clara Research Ltd, St. Claraspital, Basel, Switzerland
Diana Weissenberger
Biozentrum, University of Basel, Basel, Switzerland
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium; Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium; Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium; Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
Stowers Institute for Medical Research, Kansas City, United States; Department of Cell Biology and Physiology at the University of Kansas School of Medicine, Kansas City, United States
Michael N Hall
Biozentrum, University of Basel, Basel, Switzerland
Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, Hk2 knockout also promoted glucose production in liver. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of local and systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia.
