biostudies-literatureAuger CNIDDK NIH HHSHoward Hughes Medical Institute1311-1325.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC12137002biostudies-literatureUnknown37(6)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 ofCell metabolismIdentification of a molecular resistor that controls UCP1-independent Ca<sup>2+</sup> cycling thermogenesis in adipose tissue.PMC12137002DP1 DK126160R01 DK097441Fujimoto MShinoda KInaba KVerkerke ARPGriffin PRStimson RHCaycedo MPHLi MO'Leary TRIkeda KAuger CYook JSXiaohan CKajimura SOikawa SfalseIdentification of a molecular resistor that controls UCP1-independent Ca<sup>2+</sup> cycling thermogenesis in adipose tissue.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 of2025-01-01T00:00:00Z2025 Jun2026-06-03T07:54:43.244Z2026-04-26T03:10:37.099ZS-EPMC121370024019932610.1016/j.cmet.2025.03.009