RXRα Phosphorylation at Threonine 167 Coordinates Energy Metabolism in Mice

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Threonine 162 constitutes a PKC phosphorylation motif within the DBD of human RXRα. Studies with human RXRα WT and T162A and T162D mutants demonstrated that the phosphomimetic RXRT162D mutant modulates bindings and activities of nuclear receptors differently. For example, RXR T162D repressed PPARα and activated PPARγ in PPRE‐reporter assays in Huh7 cells. Thus, this phosphorylation at T162 may have diverse activities to regulate genes. To investigate physiological significances ofthis phosphorylation in vivo a KI mouseline bearing the mouse homologueT167A mutation (RxraT167A)was established. Western blot analysis with an anti‐phospho‐Thr peptide antibody found that RXRα becomes phosphorylated at T167 in adipocytes in response to fasting; a gene array study revealed that this mutation affects expression of several key genes in lipidmetabolism in response to fasting and feeding. These genes include Mogat2, Dgat2, Acsm3, Acc1, and Fasn. In muscle, genes that maybe involved in body temperature control (Adrb1)and glycogen synthesis (Ppp1r3b) were differentially regulated in KI mice. Conversely, none of these genes observedin adipose and muscles were affected in the liver. Taken all together, RXR phosphorylated at threonine 167 may coordinate multiple organs to regulate energy metabolism in response to fasting and/or feeding in mice.