Abstract
Magnesium (Mg
2+
) plays pleiotropic roles in cellular biology, and it is essentially required for all living organisms. Although previous studies demonstrated intracellular Mg
2+
levels were regulated by the complex of phosphatase of regenerating liver 2 (PRL2) and Mg
2+
transporter of cyclin M (CNNMs), physiological functions of PRL2 in whole animals remain unclear. Interestingly, Mg
2+
was recently identified as a regulator of circadian rhythm–dependent metabolism; however, no mechanism was found to explain the clock-dependent Mg
2+
oscillation. Herein, we report PRL2 as a missing link between sex and metabolism, as well as clock genes and daily cycles of Mg
2+
fluxes. Our results unveil that PRL2-null animals displayed sex-dependent alterations in body composition, and expression of PRLs and CNNMs were sex- and circadian time–dependently regulated in brown adipose tissues. Consistently, PRL2-KO mice showed sex-dependent alterations in thermogenesis and in circadian energy metabolism. These physiological changes were associated with an increased rate of uncoupled respiration with lower intracellular Mg
2+
in PRL2-KO cells. Moreover, PRL2 deficiency causes inhibition of the ATP citrate lyase axis, which is involved in fatty acid synthesis. Overall, our findings support that sex- and circadian-dependent PRL2 expression alter intracellular Mg
2+
levels, which accordingly controls energy metabolism status.
PRL2 regulates overall cellular energy metabolism by controlling Mg2
2+
fluxes in gender- and circadian rhythm-dependent manner.