A phosphorylation-deficient mutant of retinoid X receptor α at Thr 167 alters fasting response and energy metabolism in mice

Abstract

Retinoid X receptor α (RXRα) has a conserved phosphorylation motif at threonine 162 (humans) and threonine 167 (mice) within the DNA binding domain. Here we have generated RXRα knockin mice (Rxrα T167A) bearing a single mutation of Thr167 to alanine and examined the roles of Thr167 in the regulation of energy metabolism within adipose, muscle and liver tissues. Rxrα T167A mice exhibited down-regulation of metabolic pathways converting glucose to fatty acids, such as acetyl-CoA carboxylase in white adipose tissue (WAT) and ATP citrate lyase in muscle. They also reduced gene expression for genes related to fatty acid catabolism and triglyceride synthesis in WAT and controlled heat factors such as adrenergic receptor β1 in muscles. In contrast, hepatic gluconeogenic pathways and synthetic pathways related to fatty acids remained unaffected by this mutation. Expression of multiple genes that were affected by the Thr 167 mutation in adipose tissue exhibited clear response to LG100268, a synthetic RXR agonist. Thus, the altered gene expression in mutant mice adipose appeared to be a direct effect of RXRα Thr 167 mutation and by some secondary effect of the mutation. Blood glucose levels remained normal in Rxrα T167A during feeding, as observed with RXRα WT mice. However, Rxrα T167A mice exhibited an attenuated decrease of blood glucose levels that occurred after fasting. This attenuation was correlated with a concomitant down-regulation of lipid metabolism in WAT and was associated with RXRα phosphorylation at Thr167. Thus, Thr167 enabled RXRα to coordinate these three organs for regulation of energy metabolism and maintaining glucose homeostasis.

Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

“…Once ERα is confirmed in human microglia, therapeutic drugs which selectively target phosphorylated ERα over nonphosphorylated ERα. Together with our investigations using ERα S216A KI mice and RXRα T167A KI mice [8], we demonstrated the possibility that phosphorylation of the conserved motif within the DBD can be a common signal for nuclear receptors to diverge their functions.…”

“…These extremely high cross-species conservations strongly suggest critical regulatory functions this motif may plays for nuclear receptor actions. In fact, In addition to Ser216 of ERα, the corresponding residues of four other nuclear receptors have been reported to be phosphorylated in mouse tissues in vivo and to confer specific function to them, which include Thr38, Ser100, Ser154 and Thr167 of constitute active/androstane receptor (CAR), retinoid-related orphan receptors α (RORα), farnesoid X receptor (FXR) and retinoid X receptor α (RXRα), respectively [4,5,6,7,8]. For example, phosphorylation of Thr38 presses the constitutive activity of CAR, providing it with the response ability to its activator [5,6].…”

“…RXRα was found to be phosphorylated at Thr167 in mouse adipose tissues in response to fasting. We generated RXRα T167A knock-in mouse and demonstrated that this phosphorylation regulates blood glucose levels by altering energy metabolism in adipose tissues [8].…”

Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

“…RXRα was found to be phosphorylated at Thr167 in mouse adipose tissues in response to fasting. We generated RXRα T167A knock-in mouse and demonstrated that this phosphorylation regulates blood glucose levels by altering energy metabolism in adipose tissues [9]. These observations confirmed that phosphorylation of this conserved motif can be a common regulatory factor of nuclear receptors.…”

“…These extremely high cross-species conservations strongly suggest critical regulatory functions this motif may plays for nuclear receptor actions. In fact, In addition to Ser216 of ERα, the corresponding residues of four other nuclear receptors have been reported to be phosphorylated in mouse tissues in vivo and to confer specific function to them, which include Thr38, Ser100, Ser154 and Thr167 of constitute active/androstane receptor (CAR), retinoid-related orphan receptors α (RORα), farnesoid X receptor (FXR) and retinoid X receptor α (RXRα), respectively [4,5,6,7,8,9]. For example, phosphorylation of Thr38 presses the constitutive activity of CAR, providing it with the response ability to its activator [6,7].…”