Insulin-like growth factor 1 regulates developing brain glucose metabolism

Insulin-like growth factor 1 regulates developing brain glucose metabolism

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Edited by Louis Sokoloff, National Institutes of Health, Bethesda, MD, and approved June 16, 2000 (received for review January 7, 2000)

Abstract

The brain has enormous anabolic needs during early postnatal development. This study presents multiple lines of evidence showing that endogenous brain insulin-like growth factor 1 (Igf1) serves an essential, insulin-like role in promoting neuronal glucose utilization and growth during this period. Brain 2-deoxy-d- [1-¹⁴C]glucose uptake parallels Igf1 expression in wild-type mice and is profoundly reduced in Igf1−/− mice, particularly in those structures where Igf1 is normally most highly expressed. 2-Deoxy-d- [1-¹⁴C]glucose is significantly reduced in synaptosomes prepared from Igf1−/− brains, and the deficit is corrected by inclusion of Igf1 in the incubation medium. The serine/threonine kinase Akt/PKB is a major target of insulin-signaling in the regulation of glucose transport via the facilitative glucose transporter (GLUT4) and glycogen synthesis in peripheral tissues. Phosphorylation of Akt and GLUT4 expression are reduced in Igf1−/− neurons. Phosphorylation of glycogen synthase kinase 3β and glycogen accumulation also are reduced in Igf1−/− neurons. These data support the hypothesis that endogenous brain Igf1 serves an anabolic, insulin-like role in developing brain metabolism.

Footnotes

↵ * To whom reprint requests should be addressed at: National Institutes of Health, Building 10/10N262, 10 Center Drive, Bethesda, MD 20892. E-mail: bondyc{at}exchange.nih.gov.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.170008497.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.170008497
Abbreviations:

Igf1,

insulin-like growth factor 1;

2DG,

2-deoxy-d-glucose;

2DGU,

2DG uptake;

WT,

wild type;

PAS,

periodic acid–Schiff;

Pn,

postnatal day n;

GSK3β,

glycogen synthase kinase 3β