Now UCP(rotein), Now You Don’t: UCP1 Is Not Mandatory for Thermogenesis  Ildiko Szabo, Mario Zoratti  Cell Metabolism  Volume 25, Issue 4, Pages 761-762 (April 2017) DOI: 10.1016/j.cmet.2017.03.013 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Schematic Illustration of the Two Futile Cycles Characterized So Far in Beige Adipocytes The circular contour of the wheels represents both the biochemical cycle and the inner mitochondrial membrane separating the mitochondrial matrix and the intermembrane space (IMS). Front wheel: the creatine cycle. The ATP synthase produces ATP from ADP and phosphate in the matrix. ATP is then exported in exchange for ADP and is used by creatine kinase (CK) to phosphorylate creatine (Cr) to give phosphocreatine (PCr) and ADP (reimported). A phosphatase, likely phospho 1 (Kazak et al., 2015), then completes the futile cycle by dephosphorylating PCr. Rear wheel: the UCP1 cycle. In this case, it’s the transmembrane proton electrochemical gradient to be directly dissipated. The respiratory chain ejects protons, which are then brought back into the matrix by a long-chain fatty acid associated with UCP1, using a seesaw re-orientation mechanism. Given the negative-inside transmembrane voltage gradient, the carboxylate terminus of the acid can only diffuse inward when in its neutral, protonated form. As soon as it loses the proton, by normal acid-base dissociation, on the matrix side, it is driven to the outside face in a voltage-dependent, rate-limiting step. Kirichok, Spiegelman, and coworkers now report that the UCP1 cycle is not present in all beige adipocytes. Those lacking it would therefore be better represented by a monocycle. Both energy-dissipation mechanisms may be exploitable against obesity, which clearly afflicts the bicycle rider. Artwork by Matteo Simonetti. Cell Metabolism 2017 25, 761-762DOI: (10.1016/j.cmet.2017.03.013) Copyright © 2017 Elsevier Inc. Terms and Conditions