Growth hormone and IGF-I modulate local cerebral glucose utilization and ATP levels in a model of adult-onset growth hormone deficiency.
Decreases in plasma IGF-I levels that occur with age have been hypothesized to contribute to the genesis of brain aging. However, support for this hypothesis would be strengthened by evidence that growth hormone (GH)/IGF-I deficiency in young animals produces a phenotype similar to that found in aged animals. As a result, we developed a unique model of adult-onset GH/IGF-I deficiency by using dwarf rats specifically deficient in GH and IGF-I. The deficiency in plasma IGF-I is similar to that observed with age (e.g., 50% decrease), and replacement of GH restores levels of IGF-I to that found in young animals with normal GH levels. The present study employs this model to investigate the effects of circulating GH and IGF-I on local cerebral glucose utilization (LCGU). Analysis of LCGU indicated that GH/IGF-I-deficient animals exhibit a 29% decrease in glucose metabolism in many brain regions, especially those involved in hippocampally dependent processes of learning and memory. Similarly, a high correlation between plasma IGF-I levels and glucose metabolism was found in these areas. The deficiency in LCGU was not associated with alterations in GLUT1, GLUT3, or hexokinase activity. A 15% decrease in ATP levels was also found in hippocampus of GH-deficient animals, providing compelling data that circulating GH and IGF-I have significant effects on the regulation of glucose utilization and energy metabolism in the brain. Furthermore, our results provide important data to support the conclusion that deficiencies in circulating GH/IGF-I contribute to the genesis of brain aging.
Sonntag
William E
WE
Dept. of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157-1083, USA. wsonntag@wfubmc.edu
Bennett
Colleen
C
Ingram
Rhonda
R
Donahue
Ashley
A
Ingraham
Jeremy
J
Chen
Haiying
H
Moore
Tracy
T
Brunso-Bechtold
Judy K
JK
Riddle
David
D
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D013006:Growth Hormone / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011922:Rats, Mutant Strains
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; C495679:Slc2a1 protein, rat; C495690:Slc2a3 protein, rat; D007334:Insulin-Like Growth Factor I; D000255:Adenosine Triphosphate; D013006:Growth Hormone; D005947:Glucose