Role of norepinephrine in hepatic gluconeogenesis: Evidence of aging and training effects

This study examined the relationship among the sympathetic neurotransmitter norepinephrine (NE), hepatic gluconeogenesis, and glyconeogenesis in 63 (30 trained and 33 untrained) young (7 mo), middle- aged (15 mo), and old (25 mo) male Fischer 344 rats. Animals were trained 1 h/day, 5 days/wk for 10 wk at treadmill speeds of 75% of age-specific maximal capacity. Liver sections, removed at rest, were sliced and incubated in [¹⁴C]lactic acid and 0, 0.5, 1.0, 3.0, or 6.0 ng/ml NE. The rate of [¹⁴C]lactate incorporation into glucose was significantly greater in young compared with old animals in both training groups and at all NE concentrations. All trained animals had greater rates of glucose production from lactate than their untrained counterparts at 0.5, 1.0, 3.0, and 6.0 ng/ml NE. At each NE concentration, the old rats showed the lowest rates of glycogen synthesis from lactate. The untrained rats in all age groups were the least responsive to increases in NE concentration. Total hepatic glycogen synthase activity exhibited age-related declines as the young and middle- aged had significantly greater total activity compared with the old animals: 620.4 ± 27.5, 590.0 ± 37.9, and 436.3 ± 44.5 disintegrations/min, respectively. No differences with training were found in total activity. The percent of glycogen synthase in the active form was significantly greater in young compared with old in both the trained (48.6 ± 2.0 vs. 40.0 ± 1.3% active) and untrained animals (44.7 ± 2.2 vs. 35.4 ± 1.5% active). Phosphoenolpyruvate carboxykinase activity declined with age as the old animals in both training groups had significantly lower activity compared with the young animals (decreased 42 and 59% in the trained and untrained, respectively). No significant differences in activity existed with training. These data suggest an age-related decline in the ability of the liver to synthesize both glycogen and glucose from lactate. The training effect in glyconeogenesis is most likely occurring in the gluconeogenic pathway as endurance training had little effect on glycogen synthase activity and trained animals had greater rates of lactate incorporation into glucose than untrained at all NE doses.