Development of Obesity in Zucker Rats: Early Insulin Resistance in Muscles But Normal Sensitivity in White Adipose Tissue

Abstract

Euglycemic-hyperinsulinemic clamps were performed on 4- and 12-wk-old anesthetized lean and obese Zucker rats. During the clamp studies, total glucose production and utilization were assessed with a 3-[3H]glucose perfusion, whereas local glucose utilization was determined by measuring 2-deoxy-1-[3H]glucose 6-phosphate accumulation in various tissues. In the basal state, 4 wk-old obese rats were hyperinsulinemic (159 ± 8 vs. 82 ± 9 μU/ml), whereas glucose turnover rate was similar to that observed in lean rats (14.9 ± 1.9 vs. 12.5 ± 1.9 mg · min−1 · kg−1). Glucose utilization was identical in skeletal muscles, whereas it was increased in white adipose tissue of obese rats (22 ± 4 vs. 8 ± 2 ng · min−1 · mg−1). At plasma insulin level of 500 μU/ml, glucose production was totally suppressed in both groups, whereas overall glucose utilization was slightly less in 4-wk-old obese than in lean rats. This was due to a reduced stimulation of glucose utilization in skeletal muscles and brown adipose tissue. In contrast, glucose utilization in periovarian white adipose tissue was similarly increased in lean and obese rats. For a maximal insulin concentration (1500 μU/ml), all the differences were abolished between lean and obese young Zucker rats. In older (12-wk-old) obese rats, glucose utilization in various tissues was markedly reduced at maximal insulin level compared with that observed in age-matched lean animals. Thus, a decreased insulin sensitivity in skeletal muscles and brown adipose tissue with a normal insulin sensitivity in white adipose tissue could contribute to the development of obesity in young Zucker rats by preferentially channeling glucose toward this tissue.