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. We found that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in white adipose tissue (WAT). Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in the 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 a loss of HK2 by inhibiting the elongation of Hk2 mRNA translation.  Thus, 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 mechanism for the development of selective insulin resistance and thereby hyperglycemia. Here, we propose to investigate the mechanism of translational regulation of Hk2 mRNA in adipose tissue.