What Ignites UCP1? Cell Metabolism Barbara Cannon, Jan Nedergaard  Cell Metabolism  Volume 26, Issue 5, Pages 697-698 (November 2017) DOI: 10.1016/j.cmet.2017.10.012 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Possible Models of Regulation of UCP1-Mediated Heat Production (A) The standard model for regulation of heat production downstream of the release of fatty acids from lipid droplets in the brown fat cells. Norepinephrine (NE) released from the sympathetic nervous system binds to beta3-adrenergic receptors that, via activation of CGI-58, lead to activation of adipose tissue triglyceride lipase (ATGL). The released free fatty acids (FFAs) are combusted in the mitochondria, but some of them directly activate uncoupling protein 1 (UCP1), which is innately inhibited by cytosolic purine nucleotides such as ATP. The data presented by Schreiber et al. (2017) and Shin et al. (2017) indicate that alternative models may be necessary. (B) In one such model, external fatty acids released from white adipose tissue are both substrates for thermogenesis and activators of UCP1 (but the acute significance of the nervous system is then lost). (C) In another such model, it is necessary to postulate the existence of an NE-induced non-fatty-acid “activator” that activates UCP1 to allow it to uncouple so that external fatty acids can be combusted for thermogenesis. Cell Metabolism 2017 26, 697-698DOI: (10.1016/j.cmet.2017.10.012) Copyright © 2017 Elsevier Inc. Terms and Conditions