Maturation of brain energy metabolism under normal conditions

The Human Brain

In human neonates, cerebral glucose utilization, measured by positron emission tomography with [¹⁸F]fluorodeoxyglucose, is at 71%–93% of the adult level in most brain regions, with values ranging from 13 to 25µmol/100g/min (13, 14, 43, 98). Adult cerebral metabolic rates for glucose (LCMRglcs, 19–33µmol/100g/min) are reached by 2 years. Thereafter, LCMRglcs continue to rise until 3–4 years to values ranging from 49 to 65µmol/100g/min that are maintained at that high level until approximately 9 years. Then LCMRglcs start to decline and reach adult levels by the end of the second decade of life. The high levels of brain energy metabolism in children during the first decade of life underwrite the basal energetic and biosynthetic needs required by the very active maturational processes occurring during that period.

The Rat Brain

In contradistinction to what is seen in the human brain, glucose consumption in the whole rat brain is very low at birth, about 2–4µmol/100g/min. It undergoes a sigmoidal rise from birth to adulthood, reaching 65–72µmol/100g/min in the adult rat brain (67, 92). The measurement of LCMRglcs in the developing rat brain assessed by the quantitative autoradiographic [¹⁴C]2-deoxyglucose (2-DG) method (86) adapted to the immature rat in our laboratory shows that LCMRglcs are low and quite homogeneous between postnatal day 10 (P10) and P17, with the exception of higher rates in some posterior regions (67). Most of the significant increases in LCMRglcs occurring between P10 and P17 correlate with the acquisition of specific functions, such as audition, vision, and locomotion (64, 67). LCMRglcs undergo a widespread increase of about 50% between P17 and P21, then further increase until the adult stage is reached (67). Conversely to the human brain, LCMRglcs do not exhibit a peak during maturation in the rat and are never higher in pups than in the adult brain. However, the postnatal evolution of LCMRglcs in the rat parallels that of the cerebral metabolic rate of oxygen and the activity of the enzymes of oxidative glucose breakdown (9, 49, 50).

Simultaneously, because of the high lipid and low carbohydrate content of maternal milk, shortly after birth the rat pup develops a nutritional ketosis that lasts throughout the suckling period (for a review, see ref 64). During that period, ketone bodies constitute up to 22%–76% of the total energy metabolism balance of the brain, and positive cerebral arteriovenous differences for β-hydroxybutyrate and acetoacetate proportional to their concentration in arterial blood are recorded (16, 35, 44, 45). The uptake of β-hydroxybutyrate by the immature rat brain as measured by autoradiography is high during suckling, reaching peak levels at P14 and P17 (21, 62, 63). Between P17 and P21, regional rates of β-hydroxybutyrate uptake largely decrease in all brain regions (62, 63), concurrently with the marked increase in LCMRglcs (67).

In the immature rat brain, which is dependent on glucose and β-hydroxybutyrate for its energy metabolism and biosynthesis needs, changes in LCMRglcs are region-specific and underlie functional changes (67), as in the human brain (13, 14), whereas ketone bodies appear to be oriented toward more general purposes shared by all brain regions, namely, cellular build-up (62). Conversely, in the human brain, active growth occurs mainly between 3 and 9 years of age, when glucose is the sole cerebral substrate under normal conditions.