Variable metabolic efficiency due to the macronutrient composition
of the diet is plausibly explained in terms of nonequilibrium
thermodynamics by a shift in the cycling between dissipative lipolytic
modes and efficient storage modes. Such a mechanism is consistent with
experimental data on the effect of diet on metabolism. The
nonequilibrium thermodynamic approach and the application to the FA-TAG
cycle may raise general questions about metabolism.
Fatty acid flux, insulin resistance
There is an increasing perception that circulating fatty acids are
critical in metabolic responses and, in particular, in the development
of insulin resistance and type 2 diabetes [81-83].
The effect of insulin resistance on the disinhibition of lipolysis and
an increase in fatty acid flux may be as important for the adipocyte as
the effect on glucose uptake. In combination, the two effects may
reduce TAG storage and may represent a down-regulation in response to
excess insulin. As such, it may be thought of as beneficial for obesity
and, at the same time, suggests that reduction in insulin directly or
via carbohydrate restriction will improve insulin resistance.
The increase in circulating fatty acid remains problematical in
that, whereas it does indicate that less TAG is stored, it is generally
considered deleterious and may lead to peripheral insulin resistance.
In addition, fatty acids are known to stimulate insulin secretion. On
the other hand, the effects of high plasma FA may be different under
conditions of low carbohydrate: FA-induced insulin secretion, for
example, is strongly dependent on carbohydrate levels 
and is probably not a factor at all if plasma glucose is low. In
practice, carbohydrate restriction improves insulin resistance and the
increased fatty acids may be considered a reflection of a more general
paradox: it is observed that fatty acid levels are increased in obesity
and references therein), diabetes and insulin resistance but are also
elevated by those conditions that mediate against these conditions:
exercise, starvation and carbohydrate restriction. It is also
paradoxical that the TZD's increase insulin sensitivity but also
pre-dispose to obesity. The latter effect has been shown to be due at
least partly to the increase in glyceroneogenesis (X2) [59,84].
It could also be argued that the high levels indicate that FA is not
being taken up by peripheral tissues as happens in insulin-resistant
states. A recent review by Westman argues similarly that a so-called
glycolytic pressure controls the disposition of fatty acid as fuel in
Animal models provide very clear-cut demonstrations of inefficiency
as a function of macronutrient composition and therefore it seems there
is no theoretical barrier to accepting demonstrations in humans where
ideal control is not possible. The driving force for TAG flux in the
proposed model is the availability of carbohydrate and the key
regulating phenomenologic constant depends on insulin and other
hormones. Of course, the system is going to be subject to other cells
and processes. De novo fatty acid synthesis is a significant effect.
Moreover, this simple model makes no attempt to account for
compensatory processes and the nonlinear effects that are ultimately
expected in complex biological systems. For example, hepatic production
of β-hydroxybutyrate, which increases twenty-fold during very low carbohydrate diets, inhibits lipolysis ,
likely blunting the effects of reduced insulin concentrations. The
increased fatty acid flux under carbohydrate restriction will lead to
increased insulin secretion and, at some point, these process would
have to be added back into the model.
Relation to previous arguments on reduced energy efficiency
We previously pointed out a number of errors in the idea that weight
regulation is necessarily independent of diet composition (and
therefore insulin levels) [16,35,36].
We proposed several mechanisms and, in a practical sense, all of these
– increased gluconeogenesis and associated increased protein turnover,
increased mitochondrial uncoupling and increased substrate cycling –
must be reflected in the flux of TAG if fat loss is to be effected. We
have also pointed out that in a dietary intervention it is important to
be specific about changes in fat mass not simply weight loss .
The mechanism is ultimately through fatty acid oxidation which, again,
will be under separate control of glucose and hormones.
From a theoretical standpoint, the simplest objection to the idea
that calorimeter values are sufficient to understand processing of food
is that it assumes that no process other than complete oxidation takes
place, that is, that metabolic reactions are the same as calorimeter
reactions. This is obviously not generally true since living organisms
use other reactants and make all kinds of products, proteins, ATP, etc.
In comparing two diets of different macronutrient composition each diet
itself must conform to the first law, but because they may be carrying
out different overall chemical reactions, there is no requirement that
the energy changes are the same in the two biological reactions just
because the reference calorimeter values are the same. In addition, it
is expected that different pathways will have different efficiencies as
dictated by the second law. Thus, it is not thermodynamics, but the
special characteristics of living systems that explain why energy
balance is usually observed. Under most conditions, a steady state can
be attained in which oxidation of food to CO2 and water is the major process, and the differences between the diets in the other reactions are small.
Finally, as noted above, application of thermodynamic laws is
limited in systems that do not come to equilibrium. This has been
described in the literature as the inappropriate use of ΔG values  when what is really measured under conditions where equilibrium is not attained is (∂G/∂ξ)T,P where ξ
is the reaction progress coordinate. In the end, a thorough going
analysis of the potential for inefficiency must consider nonequilibrium