A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes.

Abstract

Uncoupling protein 1 (UCP1)-independent energy dissipation has been proven to serve physiological functions in beige adipocytes. Here we show that a futile sodium/potassium (Na⁺/K⁺) transport cycle is preferentially amplified in mouse and human beige adipocytes and contributes to UCP1-independent energy expenditure. In mice, cold exposure activates a sympathetic-thyroid hormone signaling axis that coordinatedly induces the Na⁺/K⁺-ATPase subunit ATP1A2 together with Na⁺ and K⁺ channels, increasing bidirectional ion flux across the plasma membrane while maintaining ionic balance. Atp1a2⁺Kcnk3⁺ adipocytes are detected in mouse inguinal white adipose tissue after cold exposure. Acute inhibition of Na⁺/K⁺-ATPase reduces energy expenditure in mouse and human beige adipocytes, whereas overexpressing Atp1a2 in murine adipocytes potentiates energy expenditure, independent of UCP1. Adipocyte-specific Atp1a2 deletion impairs thermogenic capacity and exacerbates diet-induced obesity in mice. Expression of a human ATP1A2 missense variant reduces ATP1A2-dependent respiration in mouse adipocytes. Together, these identify ion transport as a tunable ATP-consuming mechanism that expands the thermogenic repertoire of beige adipocytes.