There are known endogenous and pharmacologic agents, which result in uncoupling the formation of ATP from the dissipation of the gradient. Uncouplers such as 2, 4-dinitrophenol bypass ATP synthase and cause hydrogen ion gradient dissipation without ATP formation that can result in organ dysfunction causing death. More modest degrees of uncoupling may be caused by the class of endogenous compounds we know as uncoupling proteins (UCP's). Three different isoforms, UCP1, UCP2 and UCP3 have been identified thus far in mammalian tissues. While the overall and relative physiologic importance of these proteins remains incompletely understood in human tissues, UCP1 has been shown in mice [8] to result in modest degrees of uncoupling in brown fat. Elevation of fatty acid concentration has been associated with induction of UCP3 and even with pathologic reductions of myocardial efficiency in rat heart [9]. For purposes of illustration, then, we may consider that there may be physiologic triggers that result in oxidative uncoupling, reducing the overall efficiency of glucose metabolism. For example if efficiency is reduced from 40% to 35%, the result will be the production of only 34 moles of ATP instead of the usual 38. While this represents a mechanism better demonstrated in rats than humans, our subject would require more glucose to make 95 moles of ATP. Now 2.9 moles of glucose would be required to produce 95 moles ATP. Our subject would either eat more and stay at the same weight (Figure 1D) or would eat 2.5 moles of glucose, the same amount as previously, but would produce less ATP. By eating only 2.5 moles of glucose our subject's metabolism would enlist oxidation of body stores to make up the additional ATP needed for homeostasis. This would result in weight loss exactly as it did for reduced caloric intake. (Figure 1D).
The essence of the second law of thermodynamics is that it guarantees inefficiency in all metabolic processes. However, variation of efficiency is not excluded. In fact, the laws of thermodynamics are silent on the existence of variable efficiency. If efficiency can vary (as in the example of oxidative uncoupling) then "a calorie is a calorie" is no longer a true statement. The role of uncoupling proteins in humans, as indicated, is as yet incompletely defined [10]. However, thermodynamic principles permit variable efficiency, and its existence must be determined empirically.