TY - JOUR T1 - Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia JF - bioRxiv DO - 10.1101/2019.12.28.887794 SP - 2019.12.28.887794 AU - Mitsugu Shimobayashi AU - Sunil Shetty AU - Irina C. Frei AU - Bettina K. Wölnerhanssen AU - Diana Weissenberger AU - Nikolaus Dietz AU - Amandine Thomas AU - Danilo Ritz AU - Anne Christin Meyer-Gerspach AU - Timm Maier AU - Nissim Hay AU - Ralph Peterli AU - Nicolas Rohner AU - Michael N. Hall Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/03/19/2019.12.28.887794.abstract N2 - Chronically high blood glucose (hyperglycemia) leads to diabetes, fatty liver disease, and cardiovascular 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 caused enhanced gluconeogenesis and lipogenesis in liver, a condition known as selective insulin resistance, leading to glucose intolerance. 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 systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved, non-cell-autonomous mechanism for the development of hyperglycemia.One Sentence Summary Loss of the glycolytic enzyme Hexokinase 2 in adipose tissue is a mechanism underlying high blood glucose levels. ER -