Developing Brain of Moderately Hypothyroid Mice Shows Adaptive Changes in the Key Enzymes of Glucose Metabolism

This study was undertaken to investigate whether the developing brain adapts at biochemical level against neonatal hypothyroidism, as it does so against a variety of physiological disturbances. A moderate hypothyroid state in mice neonates was induced by supplementing 0.05% methimazole in drinking water to the mothers up to suckling period, and its effect on concerted development of the enzymes regulating metabolic channeling of glucose vis a vis glucose phosphorylating activity were studied. In the brain of control mice, the activity of glucose-6-phosphate dehydrogenase (G6PDH), that channels glucose in biosynthetic route (Pentose phosphate pathway, PPP), increased slightly (∼ 1.3 times) from day1 to 10w age. However, glucose phosphorylating activity and the enzymes that commit glucose for energy production, viz phosphofructokinase1 (PFK1), pyruvate kinase (PK) and lactate dehydrogenase (LDH) showed a progressive postnatal increase to attain their respective adult levels (∼ 5-10 times higher than 1day value) by 3-10w ages of mice. In comparison to the control, in the brain of age matched neonatal hypothyroid mice, glucose phosphorylating activity, G6PDH and PFK1 increased significantly (p<0.001) at day1. Thereafter, though, glucose phosphorylating activity continued to increase up to 1w age and remained static thereafter, G6PDH declined significantly (p<0.001) from 1w onward ages. On the other hand, as PFK1 activity increased significantly up to 10w age (p<0.001), the ratio of G6PDH/PFK1 showed a marked decline from 1w onward ages. PK and LDH also showed increasing trend up to 3w age in the brain of hypothyroid mice pups. The results suggest that a moderate hypothyroid state, during the period of rapid brain growth (day 1-1w age), stimulates all the enzymes that regulate channeling of glucose in both, the energy yielding and biosynthetic paths. However, the later postnatal ages, it modulates these enzymes in a metabolic path dependent manner.