Glucocorticoids decrease thermogenic capacity and increase triacylglycerol synthesis by glycerokinase activation in the brown adipose tissue of rats

Abstract

Although it is well established that glucocorticoids inactivate thermogenesis and promote lipid accumulation in interscapular brown adipose tissue (IBAT), the underlying mechanisms remain unknown. We found that dexamethasone treatment (1 mg/kg) for 7 days in rats decreased the IBAT thermogenic activity, evidenced by its lower responsiveness to noradrenaline injection associated with reduced content of mitochondrial proteins, respiratory chain protein complexes, noradrenaline, and the β 3 -adrenergic receptor. In parallel, to understand better how dexamethasone increases IBAT lipid content, we also investigated the activity of the ATP citrate lyase (ACL), a key enzyme of de novo fatty acid synthesis, glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, and the three glycerol-3-P generating pathways: (1) glycolysis, estimated by 2-deoxyglucose uptake, (2) glyceroneogenesis, evaluated by phosphoenolpyruvate carboxykinase activity and pyruvate incorporation into triacylglycerol-glycerol, and (3) direct phosphorylation of glycerol, investigated by the content and activity of glycerokinase. Dexamethasone increased the mass and the lipid content of IBAT as well as plasma levels of glucose, insulin, non-esterified fatty acid, and glycerol. Furthermore, dexamethasone increased ACL and G6PD activities (79% and 48%, respectively). Despite promoting a decrease in the incorporation of U-[ 14 C]-glycerol into triacylglycerol ($54%), dexamethasone increased the content ($55%) and activity ($41%) of glycerokinase without affecting glucose uptake or glyceroneogenesis. Our data suggest that glucocorticoid administration reduces IBAT thermogenesis through sympathetic inactivation and stimulates glycerokinase activity and content, contributing to increased generation of glycerol-3-P, which is mostly used to esterify fatty acid and increase triacylglycerol content promoting IBAT whitening.

Impact of divergence of residual feed intake on triglyceride metabolism-related gene expression in meat-type ducks

“…GYK and GK2 are the enzymes responsible for converting glycerol into glycerol 3-phosphate (G3P), the substrate for glycolysis and lipid synthesis [ 11 , 12 , 24 ], as glycerol levels are elevated in the absence of GK [ 49 ]. Considering that glycerol levels usually reflect the state of fat mobilization, Assis et al [ 50 ] found that glucocorticoids decrease thermogenic capacity and increase TG synthesis by GK activation in the brown adipose tissue of rats. In our study, GK2 was negatively correlated with MBW 0.75 , RFI, ADFI, and FCR.…”

Dexamethasone Inhibits White Adipose Tissue Browning

“…Regarding thermogenesis, very little is known about DXM’s effects on WAT browning. Most reports have described GCs effects in BAT thermogenesis, showing tissue remodelling from BAT to WAT-like phenotype in DXM treated mice, including increased lipid droplet content, decreased mitochondrial number and lower respiratory complexes levels [ 21 ], as well as decreased Ucp-1 mRNA levels [ 22 ]. Additionally, DXM inhibits the norepinephrine stimulated Ucp-1 mRNA expression in a dose-dependent manner in HIB-1B brown adipose cells [ 23 ].…”