Fat accretion and the regulation of insulin-mediated glycogen synthesis after puberty in rats

Peripheral insulin sensitivity decreases after puberty in both humans and rodents and can be explained mostly by a reduction in insulin-mediated glycogen synthesis. We tested the hypothesis that the increase in postpubertal fat mass (FM), reflecting an alternative energy store, regulates a decrease in the capacity to store muscle glycogen. We studied Sprague- Dawley rats (n = 21) before puberty (Pre) or after puberty (at 4 mo of age) in groups that were either ad libitum fed (Post) or moderately caloric restricted (CR). FM (by ³H₂O isotope dilution technique) was decreased by >40% in CR compared with Post. Glucose uptake (R(d), by 18 mU · kg^-1 · min^-1 hyperinsulinemic clamp) was 63 ± 8 mg · kg^-1 · min^-1 in Pre and decreased to 39 ± 2 mg · kg 6-¹ · min^-1 in Post (P < 0.001). However, it increased in CR to 53 ± 2 mg · kg^-1 · min^-1 (P < 0.001 vs. Post). This increase in R(d) was mainly accounted for by an increase in glycogen synthesis (R(d) glycolysis determined by the rate of conversion of ³H-labeled glucose to ³H₂O) from 23 ± 2 in Post to 33 ± 2 mg · kg^-1 · min^-1 in CR (P < 0.001; 38 ± 7 mg · kg^-1. min^-1 in Pre). Correction of glycogen synthesis in CR to near-prepubertal levels was further supported by directly assayed muscle glycogen content after insulin stimulation that was 45% higher and by a 35% enhanced accumulation of [³H]glucose into glycogen. No changes in the enzyme kinetics of glycogen synthase or phosphorylase were observed. An additional group of 2-mo-old postpubertal ad libitum-fed rats was matched with CR for lean body mass but had more FM. This group demonstrated 25% lower rates of insulin-mediated glycogen synthesis compared with CR, further supporting the notion that a moderate reduction of FM prevents the decline in insulin responsiveness and glycogen synthesis occurring after puberty. These data suggest a cause- effect relationship between the increased deposition of fat and the reduced ability to store glucose in skeletal muscle after puberty.