Methodological considerations for studies of brain glycogen

Abstract

Glycogen stores in the brain have been recognized for decades, but the underlying physiological function of this energy reserve remains elusive. This uncertainty stems in part from several technical challenges inherent in the study of brain glycogen metabolism. These include low glycogen content in the brain, non-homogeneous labeling of glycogen by radiotracers, rapid glycogenolysis during postmortem tissue handling, and effects of the stress response on brain glycogen turnover. Here we briefly review the aspects of the glycogen structure and metabolism that bear on these technical challenges and present ways they can be addressed.

Keywords: astrocytes; energy metabolism; glycogen.

Figure 1.. Schematic two-dimensional cross-sectional view of glycogen.

A core protein of glycogenin is surrounded by branches of glucose units. The entire globular granule may contain around 30,000 glucose units. The individual glucose moieties of glycogen are linked by α−1, 4 -glycosidic bonds, with branch points at approximately every 10 – 14 glucose residues linked by α−1, 6-glycosidic bonds. The exposed ends of all glycogen chains are non-reducing. Image from (Haggstrom, 2014)

Figure 2.. Bioenergetics and regulation of glycogen metabolism.

Glycogen synthase extends an existing glucosan chain of α−1, 4-glycosidic linkages using UDP glucose as substrate. Glycogen branching enzyme subsequently forms α−1, 6-glycosidic bonds to create branch points every 8 – 12 residues. Glycogen degradation is mediated by glycogen phosphorylase (GP) and debranching enzyme. GP is regulated allosterically in response to hormones, e.g. norepinephrine and vasoactive intestinal peptide (VIP); by changes in energy state (AMP, glucose-6-phosphate (G6P), and others), and by second messengers such as cAMP. The immediate product of glycogen degradation is glucose 1-phosphate which is freely converted to glucose-6-phosphate. Hepatocytes (but not other cell types) can rapidly dephosphorylate glucose-6-phosphate to generate free glucose for export.

Figure 3.. Results of radiolabeling tracer experiments are influenced by the mode of glycogen polymer growth and breakdown.

Schematic diagram showing distribution in glycogen of labeled glucose (filled circles) injected early during glycogen synthesis. Each column of circles represents an individual glycogen polymer. In one scenario, all polymers simultaneously add glucose moieties. In the opposite scenario, each polymer is synthesized to its maximum size before a second one begins to expand. Many other intermediates or more complex patterns are also possible, as are differing patterns of glycogen polymer breakdown. These differing patterns produce a different relationship between rates of glycogen turnover and rates of label release. Redrawn from (Youn & Bergman, 1987).