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Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia

View ORCID ProfileMitsugu Shimobayashi, Sunil Shetty, Irina C. Frei, View ORCID ProfileBettina K. Wölnerhanssen, Diana Weissenberger, View ORCID ProfileNikolaus Dietz, Amandine Thomas, Danilo Ritz, Anne Christin Meyer-Gerspach, Timm Maier, Nissim Hay, Ralph Peterli, View ORCID ProfileNicolas Rohner, Michael N. Hall
doi: https://doi.org/10.1101/2019.12.28.887794
Mitsugu Shimobayashi
1Biozentrum, University of Basel, Basel 4056, Switzerland
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  • For correspondence: mitsugu.shimobayashi@unibas.ch m.hall@unibas.ch
Sunil Shetty
1Biozentrum, University of Basel, Basel 4056, Switzerland
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Irina C. Frei
1Biozentrum, University of Basel, Basel 4056, Switzerland
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Bettina K. Wölnerhanssen
2St. Clara Research Ltd, St. Claraspital, Basel 4016, Switzerland
3University of Basel, Basel 4056, Switzerland
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  • ORCID record for Bettina K. Wölnerhanssen
Diana Weissenberger
1Biozentrum, University of Basel, Basel 4056, Switzerland
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Nikolaus Dietz
1Biozentrum, University of Basel, Basel 4056, Switzerland
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Amandine Thomas
1Biozentrum, University of Basel, Basel 4056, Switzerland
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Danilo Ritz
1Biozentrum, University of Basel, Basel 4056, Switzerland
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Anne Christin Meyer-Gerspach
2St. Clara Research Ltd, St. Claraspital, Basel 4016, Switzerland
3University of Basel, Basel 4056, Switzerland
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Timm Maier
1Biozentrum, University of Basel, Basel 4056, Switzerland
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Nissim Hay
4Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA
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Ralph Peterli
5Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, Basel 4016, Switzerland
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Nicolas Rohner
6Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
7Department of Molecular and Integrative Physiology, KU Medical Center, Kansas City, Kansas 66160, USA
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Michael N. Hall
1Biozentrum, University of Basel, Basel 4056, Switzerland
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  • For correspondence: mitsugu.shimobayashi@unibas.ch m.hall@unibas.ch
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Abstract

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.

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Posted March 19, 2020.
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Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia
Mitsugu Shimobayashi, Sunil Shetty, Irina C. Frei, Bettina K. Wölnerhanssen, Diana Weissenberger, Nikolaus Dietz, Amandine Thomas, Danilo Ritz, Anne Christin Meyer-Gerspach, Timm Maier, Nissim Hay, Ralph Peterli, Nicolas Rohner, Michael N. Hall
bioRxiv 2019.12.28.887794; doi: https://doi.org/10.1101/2019.12.28.887794
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Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia
Mitsugu Shimobayashi, Sunil Shetty, Irina C. Frei, Bettina K. Wölnerhanssen, Diana Weissenberger, Nikolaus Dietz, Amandine Thomas, Danilo Ritz, Anne Christin Meyer-Gerspach, Timm Maier, Nissim Hay, Ralph Peterli, Nicolas Rohner, Michael N. Hall
bioRxiv 2019.12.28.887794; doi: https://doi.org/10.1101/2019.12.28.887794

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