Identification of a molecular resistor that controls UCP1-independent Ca²⁺ cycling thermogenesis in adipose tissue.

ABSTRACT: Adipose tissue thermogenesis contributes to energy balance via mitochondrial uncoupling protein 1 (UCP1) and UCP1-independent pathways. Among UCP1-independent thermogenic mechanisms, one involves Ca²⁺ cycling via SERCA2b in adipose tissue; however, the underlying molecular basis remains elusive. Here, we report that an endoplasmic reticulum (ER) membrane-anchored peptide, C4orf3 (also known as another regulin [ALN]), uncouples SERCA2b Ca²⁺ transport from its ATP hydrolysis, rendering the SERCA2b-C4orf3 complex exothermic. Loss of C4orf3/ALN improved the energetic efficiency of SERCA2b-dependent Ca²⁺ transport without affecting SERCA2 expression, thereby reducing adipose tissue thermogenesis and increasing the adiposity of mice. Notably, genetic depletion of

SUBMITTER: Auger C 

PROVIDER: S-EPMC12137002 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature