Thermodynamics is not the limiting factor behind the concept of metabolic advantage. On the contrary, thermodynamics guarantees inefficiency in all metabolic processes and is silent on the possibility that inefficiency may be augmented in some instances. A familiar example of inefficiency is thyrotoxicosis, with attendant weight loss and heat generation despite unchanged or increased caloric consumption. The theoretical possibility of inefficiency and metabolic advantage due to macronutrient compositional change exists, but demonstration of the phenomenon can only be resolved experimentally. Isocaloric dietary studies with a low vs. a higher carbohydrate arm support the experimental possibility of metabolic advantage. A formal meta-analysis would be required to evaluate this more objectively. Further studies, including tracer methods, would be required to establish mechanisms. The presence of high quantities of dietary protein (often a feature of low carbohydrate diets) is known to stimulate protein turnover, an energetically costly process. However, it is unclear whether this is the only factor, or whether it is necessary for metabolic advantage to occur. In particular, obligate gluconeogenesis from endogenous sources may also contribute to induction of protein turnover.