“…Futile substrate cycles are a long-standing concept and various examples have been showcased in an array of different invertebrate and vertebrate species. Several glycolytic substrate cycles in insects [ [6] , [7] , [8] ], a futile calcium (Ca 2+ ) cycle in the heater organ of a large pelagic predatory fish, the blue marlin [ 9 ], an extracellular inter-organ lipid cycle between liver and adipose tissue as well as an intracellular adipocyte-specific triglyceride/fatty acid (TG/FA) cycle in rodents and humans [ [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] ], futile substrate cycling between de novo FA synthesis and FA oxidation in skeletal muscle of mice [ 21 ], and futile Ca 2+ cycling mediated by sarcoplasmic reticulum calcium ATPase (SERCA) pump activity in skeletal muscle of mammals, reviewed in [ 22 ]. For thermogenic adipocytes, there has been a recent revival of interest in futile substrate cycles [ 23 ], since ATP driven cyclic Ca 2+ pumping [ 24 ] and cyclic interconversion of creatine/creatine-phosphate [ 25 ] were discovered as contributors to NST in murine adipose tissues and the control of whole-body energy homeostasis.…”