It is also important in the discussion of biological systems to understand that they are open systems, i.e. they take in nutrients and oxygen and excrete carbon dioxide, water, urea and other waste products, as well as heat. The importance with respect to weight considerations is that mass and energy are conserved (the more general statement of the first law of thermodynamics), but they are not conserved entirely within the organism.
To illustrate the proper interpretation of the first law of thermodynamics consider a subject whose resting energy expenditure is met by the production of 95 moles of ATP. Since oxidation of a single mole of glucose provides 38 moles of ATP, 2.5 moles of glucose will be needed to meet this individual's resting energy requirements. It is important to note that the resultant carbon dioxide, water, and heat are not retained within the organism. The useful retained energy is in the 95 moles of ATP (Figure ). (Similar equations could be written for lipid or protein but we restrict our discussion to glucose for simplicity).
Figure 1 A: Oxidation of glucose in a calorimeter is completely inefficient. The products of oxidation are carbon dioxide and water, and all of the energy produced is released as heat. 1B: To illustrate the proper interpretation of the first law of thermodynamics (more ...)
The illustration above can be compared to the oxidation of glucose in a calorimeter in which no useful energy is obtained and the total energy of oxidation is measured as the heat produced. This process is completely inefficient. A traditional (Atwater) value for glucose obtained in the calorimeter is approximately 4 kilocalories of energy per gram (Figure ). By contrast, the living organism above metabolizes and oxidizes glucose so that approximately forty percent of the energy of oxidation is retained as useful ATP (38 moles per mole of glucose)) whereas sixty percent is released as heat, the inefficiency in this mode of oxidation. The entropy (i.e. the second law of thermodynamics) shows up in this inefficiency. The calorimeter heat can no longer be interpreted in a simple way. The energy stored in useful ATP represents the efficiency of 40% (neglecting the difference in entropy between the structures of the products and reactants). This value approximates the efficiency for oxidation of carbohydrate as well as lipid, whereas proteins are generally oxidized at a lower value of approximately 30–35% (Figure ).
Summary of thermodynamics in living organism
1. The second law of thermodynamics dictates that there is an inevitable metabolic inefficiency in all biological and biochemical processes with heat and high entropy molecules (carbon dioxide, water, urea) as the most common products.
2. The first law of thermodynamics is satisfied in living (open) systems by properly accounting for the mass excreted and the heat radiated and exported in high entropy molecules.
Weight loss due to reduced caloric intake
The most common example of weight loss is reduction of caloric intake. At the risk of oversimplification, if our subject ingests fewer than 2.5 moles of glucose and produces, for example, only 90 moles of ATP from food, then homeostasis would require enlisting endogenous body stores for further oxidation. This oxidation would then provide the additional 5 moles of ATP required. Oxidation of body stores (lipid or lean body mass) will result in production of additional carbon dioxide, urea, water and heat. The excretion of these products will result in weight loss. (Figure ).
Weight loss due to increased metabolic inefficiency
The implication of the first and second laws of thermodynamics is that reduced efficiency has precisely the same result as reduced caloric intake. One conceptually simple means of reducing efficiency involves the process of uncoupling in mitochondria. ATP is produced in a variety of cellular locations. Glycolysis produces a net of two ATP's per molecule of glucose, in the cell cytoplasm. On the other hand, we recall that 36 additional molecules of ATP are produced from glucose as a result of the mitochondrial TCA cycle and electron transport. A critical part of the process involves the development of a hydrogen ion gradient across the mitochondrial membrane. This concentration gradient provides the energy that is converted into ATP as hydrogen ions pass down the gradient through the ATP synthase particle, entirely analogous to the energy in a high-pressure gas in a cylinder with a movable piston. (The expansion of the gas is like diffusion down a gradient: It does work against the piston). In the mitochondrion the energy of moving down the gradient is captured in ATP, the medium of exchange for the performance of work within cells. This capture of energy, referred to as coupling the energy to the formation of ATP, is the essential process permitting work to be done by living systems.
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 ) 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 ).
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.