The role of protein translocation in the regulation of glycogen metabolism.

Early biochemical analyses of metabolic pathways assumed that the free diffusion of substrates and enzymes in an evenly mixed cellular space provided the interactions that enabled reactions to proceed. Metabolic complexes have since been shown to assemble and disassemble in response to changes in cellular conditions, and in turn, to channel metabolic intermediates within discreet cellular compartments, allowing for the efficient use or storage of energy. A fundamental component to the formation of metabolic complexes and the channeling of metabolites is the translocation of enzymes in response to specific extra- and intracellular signals. These generalities play an important role in the metabolism of glucose to glycogen within skeletal muscle and liver. In this review, the similarities and differences in skeletal muscle and liver glucose metabolism with regards to glucose transport and intracellular processing will be addressed during the fasted to fed transition. More specifically, the importance of isoform expression and protein translocation in the tissue specific control of glucose homeostasis will be covered.

Transgenic overexpression of protein targeting to glycogen markedly increases adipocytic glycogen storage in mice.

Adipocytes express the rate-limiting enzymes required for glycogen metabolism and increase glycogen synthesis in response to insulin. However, the physiological function of adipocytic glycogen in vivo is unclear, due in part to the low absolute levels and the apparent biophysical constraints of adipocyte morphology on glycogen accumulation. To further study the regulation of glycogen metabolism in adipose tissue, transgenic mice were generated that overexpressed the protein phosphatase-1 (PP1) glycogen-targeting subunit (PTG) driven by the adipocyte fatty acid binding protein (aP2) promoter. Exogenous PTG was detected in gonadal, perirenal, and brown fat depots, but it was not detected in any other tissue examined. PTG overexpression resulted in a modest redistribution of PP1 to glycogen particles, corresponding to a threefold increase in the glycogen synthase activity ratio. Glycogen synthase protein levels were also increased twofold, resulting in a combined greater than sixfold enhancement of basal glycogen synthase specific activity. Adipocytic glycogen levels were increased 200- to 400-fold in transgenic animals, and this increase was maintained to 1 yr of age. In contrast, lipid metabolism in transgenic adipose tissue was not significantly altered, as assessed by lipogenic rates, weight gain on normal or high-fat diets, or circulating free fatty acid levels after a fast. However, circulating and adipocytic leptin levels were doubled in transgenic animals, whereas adiponectin expression was unchanged. Cumulatively, these data indicate that murine adipocytes are capable of storing far higher levels of glycogen than previously reported. Furthermore, these results were obtained by overexpression of an endogenous adipocytic protein, suggesting that mechanisms may exist in vivo to maintain adipocytic glycogen storage at a physiological set point.