Brown adipose tissue (BAT) generates heat during adaptive thermogenesis through a combination of oxidative metabolism and uncoupling protein 1 (UCP1)-mediated electron transport chain uncoupling, using both free fatty acids and glucose as substrates. Previous rat-based work in 1942 showed that prolonged partial fasting followed by refeeding led to a dramatic, transient increase in glycogen stores in multiple fat depots. In the present study, the protocol was replicated in outbred, male CD1 mice, resulting in a 2000-fold increase in interscapular BAT (IBAT) glycogen levels within 4–12 hours (hr) of refeeding, with IBAT glycogen stores reaching levels comparable to fed liver glycogen. Lesser effects occurred in white adipose tissues (WAT). Over the next 36 hr, glycogen levels dissipated and histological analysis revealed an apparent over-accumulation of lipid droplets, suggesting a potential metabolic connection between glycogenolysis and lipid synthesis. 24 hr of total starvation followed by refeeding induced a robust and consistent glycogen over-accumulation similar in magnitude and time course to the prolonged partial fast. Experimentation demonstrated that hyperglycemia was not sufficient to drive glycogen accumulation in IBAT, but that elevated circulating insulin was sufficient. Additionally, pharmacological inhibition of catecholamine production slowed refeeding-induced IBAT glycogen storage, demonstrating the multi-faceted nature of glycogen storage regulation. These findings highlight IBAT as a tissue that integrates both canonically-anabolic and catabolic stimulation for the promotion of glycogen storage during recovery from caloric deficit.
Over-expression of the endogenously-expressed glycogen-binding PP1-regulatory inhibitor subunit, Protein Targeting to Glycogen (PTG), under the control of the aP2 promoter in mice enhanced basal- and starvation-state glycogen storage through inactivation of glycogen phosphorylase (GP). Total IBAT GS was elevated during starvation in aP2-PTG (Tg) mice, along with glucose-6-phosphate (G-6-P) levels, and phosphorylated Akt (pAkt), suggesting that elevated glycogen storage during starvation might enhance glucose uptake. During refeeding, Tg mice reaccumulated glycogen similarly to WT mice despite decreases in the phosphorylation states of GS and GP. All observations during refeeding suggest that glycogen repletion is a substrate-limited process, despite there being a clear balance of kinase and phosphorylase activities mediating the phosphorylation states of key glycogen-metabolic enzymes.
The studies presented here reveal IBAT glycogen storage to be a tightly-regulated process at all levels, with potential effects on insulin signaling and/or nutrient sensing in vivo. Furthermore, the robust glycogen over-accumulation during recovery from starvation across multiple background, transgenes, and species of rodent, combined with the active regulatory mechanisms observed balancing glycogen flux, suggest that the over-accumulation phenomenon plays a critical role in IBAT physiology.
|Advisor:||Brady, Matthew J., Reardon, Catherine A.|
|Commitee:||Cohen, Ron N., Wicksteed, Barton A.|
|School:||The University of Chicago|
|Department:||Molecular Metabolism and Nutrition|
|School Location:||United States -- Illinois|
|Source:||DAI-B 76/11(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Nutrition, Physiology|
|Keywords:||Brown fat, Catecholamines, Glycogen, Glycogen phosphorylase, Glycogen synthase, Insulin|
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