| First Author | Sueyoshi T | Year | 2019 |
| Journal | Lab Invest | Volume | 99 |
| Issue | 10 | Pages | 1470-1483 |
| PubMed ID | 31152145 | Mgi Jnum | J:282714 |
| Mgi Id | MGI:6383949 | Doi | 10.1038/s41374-019-0266-1 |
| Citation | Sueyoshi T, et al. (2019) A phosphorylation-deficient mutant of retinoid X receptor alpha at Thr 167 alters fasting response and energy metabolism in mice. Lab Invest 99(10):1470-1483 |
| abstractText | Retinoid X receptor alpha (RXRalpha) has a conserved phosphorylation motif at threonine 162 (humans) and threonine 167 (mice) within the DNA-binding domain. Here we have generated RXRalpha knock-in mice (Rxralpha(T167A)) bearing a single mutation of Thr 167 to alanine and examined the roles of Thr 167 in the regulation of energy metabolism within adipose, muscle, and liver tissues. Rxralpha(T167A) mice exhibited down-regulation of metabolic pathways converting glucose to fatty acids, such as acetyl-CoA carboxylase in the white adipose tissue (WAT) and ATP citrate lyase in the 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 beta1 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 RXRalpha Thr 167 mutation and by some secondary effect of the mutation. Blood glucose levels remained normal in Rxralpha(T167A) during feeding, as observed with RXRalpha wild-type mice. However, Rxralpha(T167A) mice exhibited an attenuated decrease of blood glucose levels that occurred after fasting. This attenuation correlated with a concomitant down-regulation of lipid metabolism in WAT and was associated with RXRalpha phosphorylation at Thr 167. Thus, Thr 167 enabled RXRalpha to coordinate these three organs for regulation of energy metabolism and maintenance of glucose homeostasis. |
