Thermodynamics of Low Carbohydrate Diets Eugene J. Fine, M.D. (Jacobi Medical Center, Bronx, NY) and Richard D. Feinman, Ph.D. (SUNY Downstate Medical Center, Brooklyn, NY) Low carbohydrate diets raise an interesting problem in bioenergetics: the so-called metabolic advantage, greater weight loss than on isocaloric diets. Such an effect has been disputed even in the face of supporting experimental evidence and it is claimed that it is thermodynamically impossible, that “a calorie is a calorie.” Three questions bear on metabolic advantage: 1. Is it theoretically possible or is it really a violation of the laws of thermodynamics ? 2. What is the experimental evidence that it actually occurs? 3. What are the underlying mechanisms that could account for an effect of macronutrient composition on weight loss? 1. There are two laws of thermodynamics. Whereas the first law is a conservation (of energy) law, the second law is a dissipation law: something is unrecoverable. It is the misunderstanding of the second law that has given rise to the notion that “a calorie is a calorie.” The second law says that there is a parameter, the entropy, which we identify with disorder or inefficiency and that the entropy always increases in any real (irreversible) process. In addition, living systems are open systems (exchange energy and material) and excrete high entropy products that result from inefficiencies. Therefore if variation of macronutrient composition in one diet compared to another can reduce metabolic efficiency, that diet will lead to greater weight loss. 2. Does it happen? Many tests of low carbohydrate diets when compared to isocaloric diets of different composition, show significantly greater weight loss. Homeostatic mechanisms insure that, most of the time, body mass is stable and some experiments may not bring out the effect but methodological error has not been demonstrated in numerous studies that do show metabolic advantage. Further, the differential weight loss appears to correlate with the decrement in carbohydrate. 3. Inefficiency in metabolic processes appears for a variety of reasons: an increased frequency of metabolic cycles (macromolecule synthesis and breakdown); energetically costly pathways (gluconeogenesis and protein synthesis), rearrangements in tissue composition and oxidative uncoupling. The choice of pathways is determined by hormones and allosteric controls which in turn depend on diet composition. A major candidate for metabolic advantage is gluconeogenesis and/or associated protein turnover that is required to supply the obligate glucose for brain, CNS and erythrocytes under conditions where carbohydrate is absent or reduced in the diet.