Year: 2023
Type: peer-review
Abstract: 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-cellautonomous 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. Editor's evaluationThis study reveals that expression of the glycolytic enzyme hexokinase 2 (HK2) in adipocytes is decreased in obesity and is associated with glucose intolerance and insulin resistance.The authors then show that adipose selective depletion of HK2 in mice causes systemic glucose intolerance, suggesting that the decreased HK2 may contribute to metabolic dysfunction in obese humans.These studies point to a potentially important new pathway that contributes to the regulation of metabolic health.
Authors: Mitsugu Shimobayashi, Amandine Thomas, Sunil Shetty, Irina C Frei, Bettina K Wölnerhanssen, Diana Weissenberger, Anke Vandekeere, Mélanie Planque, Nikolaus Dietz, Danilo Ritz, Anne Christin Meyer-Gerspach, Timm Maier, Nissim Hay, Ralph Peterli, Sarah-Maria Fendt, Nicolas Rohner, Michael N Hall
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Awards: G1454342856, Fat primes the liver for hepatocellular carcinoma development by inducing a Warburg metabolism, G3736690102, mTOR signaling in growth and metabolism, NCCR RNA & disease: The role of RNA biology in disease mechanisms, Identification of an mTORC2-regulated adipokine that improves ß cell function in diabetes
OpenAlex ID: W4324342771