Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia

Shimobayashi, Mitsugu and Shetty, Sunil and Frei, Irina C. and Wölnerhanssen, Bettina K. and Weissenberger, Diana and Dietz, Nikolaus and Thomas, Amandine and Ritz, Danilo and Meyer-Gerspach, Anne Christin and Maier, Timm and Hay, Nissim and Peterli, Ralph and Rohner, Nicolas and Hall, Michael N.. (2020) Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N. and Maier, Timm
Item Type:Working Paper
Number of Pages:50
Note:Publication type according to Uni Basel Research Database: Discussion paper / Internet publication
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Last Modified:01 Jan 2021 04:10
Deposited On:28 Sep 2020 14:14

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