Identification of a Molecular Resistance that Controls Ucp1-Independent Ca2+ 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 subcutaneous adipose tissue; however, the underlying molecular basis remains elusive. Here, we report that the ER membrane-anchored peptide C4orf3 (also known as another-regulin, ALN) uncouples SERCA2b Ca2+ transport from its ATP hydrolysis, rendering the SERCA2b-C4orf3/ALN complex exothermic. Loss of C4orf3/ALN improved the energetic efficiency of SERCA2b-dependent Ca2+ transport, thereby reducing adipose tissue thermogenesis and increasing the adiposity of mice. Notably, genetic depletion of C4orf3 resulted in compensatory activation of UCP1-dependent thermogenesis following cold challenge. We demonstrated that genetic loss of both C4orf3 and Ucp1 additively impaired cold tolerance in vivo. Together, this study identifies C4orf3/ALN as the molecular resistance to SERCA2b-mediated Ca2+ import that plays a key role in UCP1-independent thermogenesis and energy balance.