Biozentrum, University of Basel, Basel, Switzerland.
Department of Chronic Diseases and Metabolism, Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
Elife. 2023 Mar 15;12:e85103. doi: 10.7554/eLife.85103.
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 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, 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 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of 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.
慢性高血糖（高血糖）会导致糖尿病和脂肪肝疾病。肥胖是高血糖的一个主要危险因素，但潜在的机制尚不清楚。在这里，我们表明高脂肪饮食（HFD）在小鼠中导致糖酵解酶己糖激酶 2（HK2）的表达早期特异性丢失，特别是在脂肪组织中。脂肪组织特异性敲除减少了葡萄糖摄取和脂肪生成，并增强了脂肪组织中脂肪酸的释放。以非细胞自主的方式，HK2 敲除还促进了肝脏中的葡萄糖生成。此外，我们观察到肥胖和糖尿病患者的脂肪组织中己糖激酶活性降低，并在天然高血糖的墨西哥洞穴鱼中鉴定出 基因的功能丧失突变。从机制上讲，HFD 在小鼠中通过抑制 mRNA 的翻译导致 HK2 的丢失。我们的研究结果确定脂肪组织中的 HK2 是局部和全身葡萄糖稳态的关键介质，并表明肥胖诱导的脂肪组织 HK2 丢失是选择性胰岛素抵抗和高血糖发展的一种进化保守机制。
