TY - JOUR TI - Diet-induced loss of adipose hexokinase 2 correlates with hyperglycemia AU - Shimobayashi, Mitsugu AU - Thomas, Amandine AU - Shetty, Sunil AU - Frei, Irina C AU - Wölnerhanssen, Bettina K AU - Weissenberger, Diana AU - Vandekeere, Anke AU - Planque, Mélanie AU - Dietz, Nikolaus AU - Ritz, Danilo AU - Meyer-Gerspach, Anne Christin AU - Maier, Timm AU - Hay, Nissim AU - Peterli, Ralph AU - Fendt, Sarah-Maria AU - Rohner, Nicolas AU - Hall, Michael N A2 - Czech, Michael A2 - Isales, Carlos A2 - Klip, Amira VL - 12 PY - 2023 DA - 2023/03/15 SP - e85103 C1 - eLife 2023;12:e85103 DO - 10.7554/eLife.85103 UR - https://doi.org/10.7554/eLife.85103 AB - 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. KW - obesity KW - glucose KW - lipid metabolism KW - adipose tissue KW - diabetes KW - selective insulin resistance JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -