An ER-anchored peptide C4orf3/ALN 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 tissues; however, the molecular underpinnings of this process remain elusive. Here, we report that an ER-membrane anchored peptide C4orf3 (also known as anotherregulin, ALN) uncouples its Ca2+ transport from ATP-hydrolysis by interacting via the cytoplasmic domain, rendering the SERCA2b-C4orf3/ALN complex exothermic. Loss of C4orf3/ALN improved the energetic efficiency of SERCA2-dependent Ca2+ transport, thereby reducing adipose tissue thermogenesis and increasing the adiposity of mice. In turn, overexpression of C4orf3/ALN promotes Ca2+ cycling thermogenesis in the microsomal compartment. Of note, genetic depletion of C4orf3 led to compensatory activation of mitochondrial thermogenesis via UCP1 following cold challenge. We found that genetic loss of both C4orf3 and Ucp1 additively impaired cold tolerance in vivo. Together, this study uncovers the molecular mechanisms and the physiological role of UCP1-independent Ca2+ cycling thermogenesis in adipose tissue. This RNA-seq data set showed that double knockdown (DKO) of UCP1 and C4orf3/ALN increased lipid catabolism in adipose tissue. Overall design: Wild type, UCP1 KO, C4orf3/ALN knockdown (ALN KD) and double knockout mouse (DKO) were exposed to cold for 5 h. Then RNA of white inguinal adipose tissue were isolated from each mouse, and subjected to RNA-seq.