Glycogen metabolism: not just a one-trick pony

Prior to the 1940s, glycogen was thought to be stored primarily in the liver and muscles and used during periods of high energy demand and/or low blood glucose availability. In 1942, Tuerkischer and Wertheimer showed that adipose tissue can also produce and store small amounts of glycogen, concurrent with periods of active lipid synthesis. J. M. Friedman and colleagues showed in 2008 that lipid synthesis in adipose tissues occurs via a glycogen intermediate, underlining the importance of glycogen turnover in the regulation of adipocyte energy metabolism. A 2021 Nature paper further extended the role of glycogen metabolism to include thermogenesis in adipocytes.

The low glycogen content in adipocytes was thought to be due to biophysical constraints imposed by the limited cytoplasmic space in these cells, but Tuerkischer and Wertheimer (in 1942) and other researchers later confirmed that glycogen turnover in adipose tissue changes with nutritional status. Glycogen content transiently increases with refeeding after fasting in both brown adipose tissue (BAT) and white adipose tissue (WAT) as well as following cold exposure in BAT, partly due to increased AKT phosphorylation and inactivation of GSK3, resulting in increased glycogen synthesis. Indeed, glycogen metabolism is crucial for BAT development, and abrogating glycogen turnover, either by knocking out (KO) GYS1 (encoding glycogen synthase 1) or blocking glycophagy, prevents lipid droplet formation selectively in BAT.