Richard D Feinman¹ and Eugene J Fine^1,2

¹Department of Biochemistry, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA

²Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Theoretical Biology and Medical Modelling 2007,
4:27. An open access article.

 

Abstract

Carbohydrate restriction as a strategy for control of obesity is
based on two effects: a behavioral effect, spontaneous reduction in
caloric intake and a metabolic effect, an apparent reduction in energy
efficiency, greater weight loss per calorie consumed. Variable energy
efficiency is established in many contexts (hormonal imbalance, weight
regain and knock-out experiments in animal models), but in the area of
the effect of macronutrient composition on weight loss, controversy
remains. Resistance to the idea comes from a perception that variable
weight loss on isocaloric diets would somehow violate the laws of
thermodynamics, that is, only caloric intake is important ("a calorie
is a calorie"). Previous explanations of how the phenomenon occurs,
based on equilibrium thermodynamics, emphasized the inefficiencies
introduced by substrate cycling and requirements for increased
gluconeogenesis. Living systems, however, are maintained far from
equilibrium, and metabolism is controlled by the regulation of the
rates of enzymatic reactions. The principles of nonequilibrium
thermodynamics which emphasize kinetic fluxes as well as thermodynamic
forces should therefore also be considered.

Here we review the principles of nonequilibrium thermodynamics and
provide an approach to the problem of maintenance and change in body
mass by recasting the problem of TAG accumulation and breakdown in the
adipocyte in the language of nonequilibrium thermodynamics. We describe
adipocyte physiology in terms of cycling between an efficient storage
mode and a dissipative mode. Experimentally, this is measured in the
rate of fatty acid flux and fatty acid oxidation. Hormonal levels
controlled by changes in dietary carbohydrate regulate the relative
contributions of the efficient and dissipative parts of the cycle.
While no experiment exists that measures all relevant variables, the
model is supported by evidence in the literature that 1) dietary
carbohydrate, via its effect on hormone levels controls fatty acid flux
and oxidation, 2) the rate of lipolysis is a primary target of insulin,
postprandial, and 3) chronic carbohydrate-restricted diets reduce the
levels of plasma TAG in response to a single meal.

In summary, we propose that, in isocaloric diets of different
macronutrient composition, there is variable flux of stored TAG
controlled by the kinetic effects of insulin and other hormones.
Because the fatty acid-TAG cycle never comes to equilibrium, net gain
or loss is possible. The greater weight loss on carbohydrate restricted
diets, popularly referred to as metabolic advantage can thus be
understood in terms of the principles of nonequilibrium thermodynamics
and is a consequence of the dynamic nature of bioenergetics where it is
important to consider kinetic as well as thermodynamic variables.