Brain glycogen - vestigial no more

Metab Brain Dis (2015) 30:251–253 DOI 10.1007/s11011-014-9596-2 FOREWORD Brain glycogen – vestigial no more Raymond A. Swanson Received: 15 July 2014 / Accepted: 17 July 2014 / Published online: 25 July 2014 # Springer Science+Business Media New York (outside the USA) 2014 Early in my career, in 1991, I was invited to a conference hosted by Leif Herz (a contributor to this issue) to present my studies on neuronal activity and astrocyte glycogen turnover. At one point I was seated near a pre-eminent scientist in the field of brain energy metabolism, and I took that opportunity to ask his thoughts about the role of glycogen in brain. His response was short and deflating: “vestigial, probably; like the appendix”. As evidenced by the contributions to this Special Issue, the notion that brain glycogen is simply an evolutionary remnant, with no physiological function, has long since been put to rest. (Somewhat ironically, it turns out the appendix itself is not just “vestigial”; recent studies show that it serves as an important refuge for normal gut flora during gastroin- testinal infections (Laurin et al. 2011). Nevertheless, many aspects of brain glycogen remain unresolved. Glycogen is present in many tissue types, but it appears to have unique functional roles in brain. Liver contains the largest and most concentrated glycogen store, and this serves to maintain glucose levels in blood. Skeletal muscle contains the second most abundant store of glycogen, where it serves (at least in part) to fuel anaerobic glycolysis when muscle contractions squeeze blood from feeding arterioles and there- by limit the supply of glucose and oxygen (Greenhaff et al. 1993). Brain, however, does not serve as a glucose store for the rest of the body, nor is it is encumbered by contractions that limit blood supply. Moreover, the vast majority of brain R. A. Swanson (*) Department of Neurology, University of California, San Francisco, CA 94143, USA e-mail: Raymond.Swanson@ucsf.edu R. A. Swanson San Francisco Veteran Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121, USA glycogen is localized to astrocytes, rather than neurons (Cataldo and Broadwell 1986). The astrocyte glycogen un- dergoes continuous synthesis and degradation (Swanson et al. 1992; Watanabe and Passonneau 1973), despite the fact that this entails the additional energetic cost of one ATP for every glucose molecule that is shuttled in and out of a glycogen polymer (Obel et al. 2012). Astrocyte glycogen turnover is accelerated by neuronal activity (Cruz and Dienel 2002; Swanson 1992; Swanson et al. 1992), suppressed by anesthe- sia or hibernation (Swanson 1992; Watanabe and Passonneau 1973), and tightly regulated by several intersecting signaling pathways (Cambray-Deakin et al. 1988; Pellerin et al. 1997; Schorderet et al. 1984). Although these features all indicate a dynamic role for glycogen in normal brain function, it has been difficult to identify specific cellular processes that are dependent upon the astrocyte glycogen turnover. One function of brain glycogen has been clearly demon- strated; it can be metabolized to substrates such as lactate for release from astrocytes and subsequent uptake by neurons (Brown et al. 2005; Dringen et al. 1993). This process is likely to be particularly important during severe hypoglycemia, giv- en the unique requirement of brain for glucose as a metabolic substrate (Choi et al. 2003; Suh et al. 2007; Swanson and Choi 1993; Wender et al. 2000). However, this cannot be the whole story; severe hypoglycemia was extraordinarily rare prior to the medical use of insulin and other glucose-lowering agents, and the function of glycogen as a reserve energy supply does not account for the continuous glycogen turnover observed in normal brain. Might glycogen-derived lactate fuel neuronal function during brief, local mismatches between blood supply and energy demand in brain? Perhaps, but metabolism of lactate requires oxygen, and under any condition other than hypoglycemia in which blood delivery of glucose is insuffi- cient to meet demand, blood delivery of oxygen will be even more limited, thus negating any advantage of lactate over blood-borne glucose as a fuel for oxidative metabolism.