Dietary carbohydrate provides both an energy source and, through its
effects on insulin and other hormones, regulatory control of
metabolism. In the context of obesity, diabetes and related pathologic
states, it is argued by many researchers that the level of
carbohydrate, by its hormonal effects, controls the disposition of
nutrient intake beyond simple caloric balance [1-11].
From this point of view, fat plays a relatively passive role and the
deleterious effects of high dietary fat are expected only if there is
sufficient dietary carbohydrate to provide the hormonal state in which
the fat will be stored rather than oxidized. In its practical
application, the principle has given rise to several forms of popular
diet strategies which have in common some degree of carbohydrate
restriction [12-14] or effective glycemic level [3,15].
Experimentally, protocols based on carbohydrate restriction do as well
or better than fat reduction for weight loss (reviews: [16-18]),
but because they are somewhat iconoclastic with respect to official
dietary recommendations and because they derive from the popular diets
where discourse is heated, they remain controversial. The extent to
which carbohydrate restriction is successful as a strategy for control
of obesity or diabetes can be attributed to two effects. The strategy
frequently leads to a behavioral effect, a spontaneous reduction in
caloric intake as seen in ad lib comparisons. There is also a
metabolic effect, an apparent reduction in energy efficiency seen in
isocaloric comparisons, popularly referred to as metabolic advantage.
The two are not necessarily independent: an association between
thermogenesis, a reflection of inefficiency, and satiety has been
established by Westerterp, et al., for example .
Experimental demonstrations of energy inefficiency in humans have recently been summarized [16,17,20] and the phenomenon has been demonstrated in animal models (e.g., ref.  and, most dramatically ref. ).
This metabolic effect, however, is not universally accepted as a major
component in human experiments, oddly even by investigators who have
provided experimental support [23-26]. Variable energy efficiency, however, is known in many contexts: hormonal imbalance [27,28], intensive insulin therapy , studies of weight regain [30,31] and particularly knock-out experiments in animals [32-34].
Experiments demonstrating variable energy efficiency in the context of
weight loss, however, remain controversial because of the difficulty in
validating compliance in dietary interventions and because of a
resistance to what is perceived as a violation of thermodynamics, that
is, an intuitive feeling that, in the end, everything must even out.
Thus, progress in this field still depends on a proper understanding of
caloric efficiency and a description of how energy balance can account
for differences in weight loss in isocaloric comparisons.
We have previously described how different isocaloric diets are
actually expected to have different effects on metabolism and therefore
on body mass [16,35,36].
Our previous arguments were largely based on equilibrium thermodynamics
because this is most familiar. However, living systems, and in
particular, TAG stores in adipocytes, are maintained far from
equilibrium and the rates of breakdown of such high energy compounds
are regulated by the kinetics of the enzymes that catalyze hydrolysis
and re-synthesis. Because the system is maintained far from
equilibrium, energy measurements provide values of (∂G/∂ξ)T,P where ξ is the reaction progress coordinate and the path-independence of state variables, that is, ΔG values measured in a calorimeter do not necessarily apply .
In essence, then, the problem is as much one of rates as of free
energy. Much progress has been made in the development of
nonequilibrium thermodynamics for the study of metabolism although
there is no universally accepted approach ([38-40]
and references therein) and the current work is intended to provide a
first step towards developing the problem of energy efficiency in
response to dietary macronutrients.
Here we review the basic ideas of nonequilibrium thermodynamics and
provide an approach to the problem of maintenance and change in body
mass following these ideas. The emphasis is on flux of metabolites in
adipose tissue since, in the end, this is the major reflection of
energy balance and obesity. The work has several goals:
1. To recast the problem of TAG accumulation and breakdown in the
adipocyte in the language of nonequilibrium thermodynamics. In
particular, we want to describe adipocyte physiology in terms of
cycling between an efficient storage mode and a dissipative mode.
Experimentally, this is reflected in the rate of fatty acid flux and
fatty acid oxidation.
2. To provide a plausible mechanism for how different efficiencies
of isocaloric diets can be accounted for by changes in kinetics. To
show that hormonal levels controlled by changes in carbohydrate intake
determine the relative contributions of the efficient and dissipative
parts of the TAG-FA cycle.
Overall, the model is intended to provide a conceptual framework for
energy efficiency in nutrition and to point the way to future research.
We feel that the approach has general implications as well and is tied
to the philosophical position espoused by Prigogine and followers in
emphasizing the dynamic nature of physical processes, that is, the need
to consider kinetics as well as thermodynamics [39,41-44].
We emphasize that metabolic efficiency is not always seen in diet
comparisons. A thermodynamic analysis, however, shows that inefficiency
is to be expected and it is the cases where "a calorie is a
calorie" that need to be explained: it is the unique characteristics of
living systems – maintenance of a steady-state through tightly
controlled feed-back systems – not general physical laws that accounts
for energy balance when it is found. Practically speaking, the
importance of obesity and other metabolic disorders makes it important
to see what the requirements are to break out of these stable states.
It is traditional to separate thermodynamics and kinetics but such a division applies strictly only to equilibrium systems [41,45].
Systems that are far from equilibrium may undergo chemical reactions
that never attain equilibrium and are characterized by the flux of
material as well as energy. In a dietary intervention, the flux of
material must be integrated over time to determine the total change in
weight or fat loss. Thus, accumulated changes may be controlled by the
presence of a catalyst or other factors that affect the rate of
In the case at hand, adipocytes cycle between states of greater or
lower net breakdown of fat (lipolysis and reesterification) depending
on the hormonal state which, in turn, is dependent on the macronutrient
composition of the diet. A hypothetical scheme for changes in adipocyte
TAG and a proposal for how TAG gain or loss could be different for
isocaloric diets with different levels of insulin is shown in Figure 1.
Under normal control conditions of weight maintenance, the breakdown
and utilization of TAG by lipolysis and oxidation is balanced by the
re-synthesis from food intake. Assuming, for simplicity. an
instantaneous spike in food at meals, the curves represent the net flow
of material (possibly through several TAG-FA cycles) within the
adipocyte. In a coarse-grained analysis, the integral over time of the
fluctuations between different states, measures the change in stored
TAG in the time of a dietary experiment. The average is stable, that
is, appears as weight maintenance. If now each meal is maintained at
constant calories but there is an increase in the percentage of
carbohydrate leading to higher insulin levels, the lipases may be
reduced in activity (blue line in Figure 1). The rate of re-synthesis of TAG is less perturbed by the elevated insulin 
and indeed may go the other way. The system may cycle between states,
which, while they never come to equilibrium, have the net affect of
producing changes in the direction of accumulation of TAG.
Figure 1. Hypothetical kinetics of fat storage and hydrolysis.
Model for the effect of insulin on efficiency of storage. Black line
indicates response under conditions of weight maintenance. Blue line
shows the effect of added insulin on hormone sensitive lipase activity.
carbohydrate restriction, the decrease in carbohydrate may be
accompanied by an increase in dietary fat and the relative effect on
rate of TAG accumulation due to disinhibition of lipolysis vs the
effect of increased substrate will determine the efficiency. As noted
below, experiments in the literature 
show that after chronic exposure to a low carbohydrate diet (higher
dietary TAG), the plasma levels of TAG following a high fat meal are
reduced compared to controls. Of course, replacing dietary carbohydrate
with dietary protein at constant lipid will be consistent with the
model in the absence of compensating effects.
In these cases, the integrated change in TAG over the course of a
day (or several days) will no longer be zero. In this way, two diets
may lead to different weight gain (as indicated by accretion of fat),
even though they have the same number of calories, simply because they
affect hormonal levels differently. An analysis based on rates suggests
further that a new steady state may be obtained in which TAG may be
maintained at a higher or lower level even if the hormonal state
returns to one that does not lead to further change. The cell may then
relax from one steady state to another, the observed macroscopic weight
gain or loss. The goal here is to ask what would it take to produce
behavior like that in Figure 1.
For minor perturbations, there will be compensating effects of
competing pathways (increase in insulin secretion due to fatty acid
for example) and one can expect, insofar as the model corresponds to
reality, there may be a threshold effect. This is reflected in the
emphasis on extreme carbohydrate reduction in the early phases of
popular weight loss diets [12-14].
We emphasize that all of the potential sources of metabolic
inefficiency – increased reliance on gluconeogenesis and consequent
increased protein turnover, up-regulation of uncoupling proteins –
described previously [16,36] may still be operative but the net change in fat stores must be the final common output if body mass is to undergo change.
Formalism of nonequilibrium thermodynamics
For systems that are not at equilibrium, changes in entropy will
drive the system towards equilibrium. If the system is close to
equilibrium or, as in the case here, there is a small change in the
total free energy – only a small fraction of TAG is actually hydrolyzed
in the course of a day – then the change in entropy will be due to dSe, the flux of entropy that is exchanged with the environment and dSi, that due to the irreversible effect of the chemical reaction [41,50,51]. We are then interested in the rate of entropy production, Φ, due to chemical reactions at constant T and P:
Φ = dSi/dt = - (1/T) ΣN μk dnk/dt(1)
In nonequilibrium thermodynamics, overall flux of entropy is considered as a product of forces (derivative of the potential), Xk and flows Jk, all forces and flows vanishing at equilibrium. In a chemical system, the force Xk is defined as the negative of the chemical potential of the kth reaction, sometimes referred to as the affinity A = - (∂G/∂ξ)T,P where ξ
is the extent of chemical reaction. In other words, a positive sign of
× indicates spontaneous forward driving force. The force, then, depends
on the concentration of reactants and products, the standard free
energy and the extent of reaction. It is worth noting that for the
systems like the adipocyte that are maintained far from equilibrium the
distinction between ΔG values and (∂G/∂ξ)T,P noted by other authors 
is important, that is, the simple additivity of state variables that
underlies the idea that all calories are equivalent, is not valid.
The flows, Jk, are identified with the flux of the kth reaction. The flux of fatty acid in an adipocyte, for example, J1 = vlipolysis + vsynthesis,
the sum of breakdown and synthesis rates for TAG. In the phenomenologic
approach of nonequilibrium thermodynamics, the forces and flows may be
the sum of several individual processes.
In applying the principles of nonequilibrium thermodynamics, the
analysis will be simplified if we make the assumption that the fluxes
are linear functions of the forces, in analogy with similar linear
equations such as Fick's law of diffusion (diffusion is a linear
function of the concentration gradient), or Ohm's law (current is a
linear function of the potential). The proportionality constant Lkj is called the phenomenological coefficient.
Jk = Σn LkjXj (2)
Although the general requirement that condition (2) hold is that the
system be close to equilibrium, the linear approximation is often
observed to be appropriate for systems very far from equilibrium,
subject to stabilizing feedback and in enzymatic systems operating in
the range of substrate concentrations that are close to KM [52,53]. Further discussion is found in references [54-56].
Whereas the assumption of linearity is reasonable for the current model
where small perturbations far from equilibrium occur in a region of
high substrate, in the end, it is a working assumption and experimental
tests of the model will ultimately determine if the assumption is
Qualitative features of the adipocyte model and comparison to glycolysis
F igure 2 shows a simple model that is proposed for adipose tissue
metabolism under conditions bearing on changes in body mass. The flux
of TAG (1) represents the net accumulation or output with respect to
the cell itself. This process driven by (2) the input of
glycerol-3-phosphate from glycolysis or glyceroneogenesis and (3) fatty
acid (FA) from plasma FA. The high energy form of the cycle, TAG, is
stored. From the point of view of the organism, it is the FA output
that provides fuel for oxidation and cell metabolism. This output may
be taken as analogous to the system load as it is usually described in
nonequilibrium thermodynamics. Oxidation and FA uptake are largely
controlled independently, that is, the adipocyte system has high output
conductance and low input conductance, that is, by analogy with an
electronic system, is an ideal amplifier. Because there is effectively
no load on the system and overall metabolic effect is simply to reduce
the affinity of fatty acid, the analysis is greatly simplified. The
flux of FA, J3 is of general physiologic importance and is the most experimentally accessible of the relevant parameters.
In the comparison of different diets, an additional component is (4)
input of fatty acid from TAG-containing lipoproteins. Our treatment of
the problem is to consider fluxes in the absence of this input since
that is how it is usually described in the literature and then to
consider the effect of input from lipoproteins as a perturbation.
Focusing on the reaction in the absence of lipoprotein input, the
overall relations of fluxes and flows:
J1 = L11X1 + L12X2 (3)
J2 = L21X1 + L22X2 (4)
J3 = L13X1 + L33X3 (5)
As an example of the application of these principles, Aledo, et al.
addressed the negative correlation between glycolytic flux and
intracellular ATP concentration in yeast, the so-called ATP paradox [54,57,58].
The paradox was resolved by showing that if ATP-consuming pathways are
more sensitive to glucose than the glycolytic pathway, the cell can
switch from an efficient (ATP-conserving) to a dissipative
(ATP-utilizing) regime [54,58].
The dissipative regime offers higher output at high glucose cost,
whereas the efficient regime has higher accumulation of ATP but lower
In the adipocyte model, periodic switching between dissipative and
conservative regimes is meant to describe the dynamic cycling of TAG.
The goal in development of the model is to show the constraints on the
system for conservation of fat mass, and conversely, how isocaloric
dietary inputs of different composition might plausibly bring about
weight gain or loss, that is, how efficiency is regulated in the TAG-FA
cycle and the activity of the reactants. In essence, we want to know
what it would take for the blue line in Figure 1 to occur.
The major controlling variables will be the Lij, the
phenomenologic constants which depend on hormonal levels, and the
thermodynamic activity of plasma triglyceride (supplying fatty acid).
Looking ahead, the simplest application will be the effect of replacing
dietary carbohydrate with dietary protein at constant lipid where a
semi-quantitative prediction can be made. In the most general case,
however, we also want to know the relative impact of insulin reduction
on the Lij (reduced lipolysis rate) compared to the increase in thermodynamic activity (X4) due to increased dietary fat.
The variables as they apply to the adipocyte model are as follows:
X1 = the output force is the affinity of the
lipolysis-TAG synthesis cycle. The analysis can be simplified by the
assumption that lipolysis of available TAG (and possibly re-synthesis)
in an adipocyte occurs at a heterogeneous interface. We can therefore
take the thermodynamic activity of TAG as 1, that is, although other
concentrations may influence X1, the amount of TAG will not.
(The contribution of TAG activity is unlikely to change in any case
since perturbations in TAG concentrations are extremely small compared
to the total stored TAG).
X1 = -RT (ln (Keq)FA-TAG - ln ([FA]3 [glyc-3-P]/[TAG]) = - 3 RT ln (([FA] [glyc-3-P]/K')
X2 = the driving force for supply of glycerol-3-phosphate
whose major term is normally the availability of carbohydrate. Under
conditions of carbohydrate restriction, however, there is also an
increase in glyceroneogenesis from protein [59,60].
X3 = = the driving force for supply of fatty acid from cellular TAG.
X4 = the force due to the supply of fatty acid from lipoproteins (chylomicrons and VLDL).
In the approach taken here,
L11, L12 are the sensitivities of the flux of
TAG to the levels of TAG and the levels of substrate
(glycerol-3-phosphate) which depend primarily on the hormonal levels (via phosphorylation of the lipases and other enzymes). It is generally assumed on theoretical grounds (Onsager relation) that L12 = L21 although this has to actually be established for systems that are not close to equilibrium.
L22 is the sensitivity of the glycerol-3-phosphate flux
to the availability of carbohydrate (or other sources) which may also
be controlled by hormonal levels.
Although somewhat beyond the level of analysis presented here, it is
worth noting some of the derived parameter that are traditional in a
NET analysis. The degree of coupling, q = L12 /√L11L22 is a dimensionless parameter that indicates how tightly the output process is coupled to the driver process  and takes on values from 0 to 1 in the forward direction. In the model in Figure 2, q will vary with different subjects and different metabolic states, in particular, is strongly under the control of insulin.
Figure 2. Model for adipocyte metabolism. See text for details.
The phenomenological stoichiometry is defined as Z = (√L11/L22)
It should be noted that L11, L12 and L22 and
the derived parameters, q and Z, in general, are where the enzymatic
activity and the effect of hormones reside. It is important to
emphasize that many important variables, such as coenzyme levels are
hidden in the phenomenologic constants. For the adipocyte Z = 1, that
is, TAG synthesis is tightly coupled to glycerol-3-P production. These
parameters hold the promise to quantify insulin resistance, at least in
The experimental parameters that are most frequently determined in
the literature are the rates of appearance in the blood of fatty acid
and glycerol, traditionally written Ra (FA) and Ra (glycerol), and the total rate of TAG oxidation (largely oxidation in non-adipocyte), denoted here as ROX. For the simple two compartment model considered here, there are four species, adipocyte TAG, plasma TAG, FA and CO2 (from oxidation).
The goal is to re-cast the problem of metabolism and regulation of
body mass in the formalism of nonequilibrium thermodynamics, or more
simply, in a way that emphasizes rates in addition to energetics.
Applying the traditional measurements above leads to particularly
simple form. From conservation of carbon mass of fatty acid species, we
can write for the mass fluxes:
0 = d(FA)/dt + d(TAG)/dt + d(CO2)/dt = Ra (FA) + J1 + ROX + J4
or J1 = - (ROX + Ra (FA) + J4)(6)
J3 = Ra (FA)(7)
Although no experiment in the literature has been done that would
allow for a complete quantitative test of the model, further analysis
can support the value of a nonequilibrium approach in understanding
variable efficiency in weight loss experiments. Experiments comparing
the effect of different macronutrient composition, for example, can
allow us to look at the effects on TAG accumulation (J1)
without explicit analysis of the individual reactions. Results from the
literature that support the underlying thesis show that 1) fatty acid
flux and oxidation (ROX + Ra (FA), eq. (6)),
follow the levels of dietary carbohydrate, 2) the effect of
carbohydrate is expressed in the regulation of insulin levels, 3)
lipolysis is the primary target of insulin, 4) the availability of
substrate affects efficiency, 5) insulin increases J4 and finally, 6) chronic diet can affect the force X4 and
thereby the response to dietary input in a single experiment. In the
following sections, we consider these in turn. The net effect is that
accumulated time-dependent changes due to carbohydrate intake control
the efficiency of fat storage and we consider that a nonequilibrium
thermodynamic approach allows clear justification as to how variable
weight gain can be expected on isocaloric diets.
Fatty acid flux and oxidation follow the levels of dietary carbohydrate
Similarity of starvation and carbohydrate restriction
the years, several investigators have made the observation that the
metabolic response to carbohydrate restriction resembles the response
to starvation, in particular, for the current model, increased fatty
acid mobilization and oxidation [61-65]. Perhaps the best example is an elegant study by Klein & Wolfe 
comparing responses of subjects on an 84 hour fast to the same subjects
on a similar fast in which lipids were infused at a level equal to
resting energy requirements. Table 1 shows that the levels of glucose, insulin, the rates of appearance of fatty acid and fat oxidation, ROX + Ra (FA),
were similar in the two groups. For comparison to equation (6), the
molar fluxes would have to be converted to mass and the role of J4 would have to be considered explicitly. In fact, as measured here, J4 is subsumed in the rate of fatty acid appearance and appears to have little effect despite large differences in X4.
These rather dramatic results were summarized by the authors as
demonstrating that "carbohydrate restriction, not the presence of a
negative energy balance, is responsible for initiating the metabolic
response to fasting." It might be said that this was the fundamental
observation for understanding the role of carbohydrates in energy
balance and the need for a kinetic rather than equilibrium
thermodynamic analysis. The controlling variables are presumed to be
carbohydrate itself which provides substrate for glycerol-3-P synthesis
and insulin which will affect the phenomenologic constants. Bisschop,
et al. 
showed a similar increase in FA rate of appearance and oxidation in a
low carbohydrate, high fat diet (CHO:Lipid:Protein = 2:83:15) compared
to either a high carbohydrate (85:0:15) or control (44:41:15) diets,
and there is agreement with Klein & Wolfe's data (Table 1).
Considering the difference in protocol, the similarity of the response
to carbohydrate restriction, fasting and fasting + lipid is very good.
Although the subjects in Klein & Wolfe's study lost comparable
amounts of weight in the two procedures, the short duration and the
substantial changes in body water make it difficult to accurately
determine whether TAG storage follows the calculated value of J1 .
It is important to point out that in Bisschop's experiment, fatty acid
oxidation does not keep up with the increase in dietary TAG but
according to equations (6) and (7), the flux of TAG is increasing in
the direction of breakdown of TAG and, again, explicit inclusion of J4 would further bias the results in that direction.
it would obviously be difficult to carry out experiments for long
periods of time in humans, studies by Tomé's group have shown that rats
fed a high fat diet without carbohydrate ate less and also gained less
weight per calorie consumed than rats fed a high fat diet that included
Similar results have recently been published by Kennedy, et al. have
shown that a high fat/ketogenic diet could reverse the obesity induced
by an isocaloric high fat diet that also contained sucrose .
The principle that the level of dietary TAG plays a passive role and
that carbohydrate restriction is controlling suggests that evidence
from the older literature showing weight loss on very high fat diets  might be worth re-examining. These were presumably not followed up because they were so counter-intuitive.
Glucose flux regulates TAG flux
Wolfe and Peters  measured the response to infusions of glucose in humans. The data shown in Table 2
indicate that the flux of glucose regulates the rate of TAG synthesis
largely through the inhibition of lipolysis. The effect of glucose, in
turn, is presumed to rest primarily with the effect of insulin.
The effect of carbohydrate is expressed in the regulation of insulin levels
Lipolysis is the primary target of insulin
It is well
established that the primary effect of insulin, both kinetically and in
terms of physiologic effect is on the inhibition of lipolysis and there
is a large literature studying this effect (Review: ). In the language of nonequilibrium thermodynamics, this is expressed in the phenomenologic constant, L11. Campbell, for example, studied fatty acid metabolism in humans infused intravenously with insulin . Figure 3
shows the decline in fatty acid flux as the plasma insulin is
increased. Oxidation of fatty acid was also inhibited but by a much
smaller amount, from 2.7 to 0.9 μmol/kg
lean body mass/min. The total rate of primary reesterification (from
fatty acid that is not released to the plasma after lipolysis) was
similarly increased. Insulin levels further increase the uptake of
plasma TAG due to increase lipoprotein lipase (LPL) activity. Frayn and
have shown how the combination of LPL and lipolysis leads to increase
in flux towards TAG storage. Again, the relative hormonal reduction in
lipolysis and any increase in esterification due to mass action if
plasma TAG is increased will determine if net TAG accumulation will
occur. The importance of insulin can be seen in studies in which
insulin secretion is indirectly inhibited via administration of a
somatostatin antagonist octreotide. This intervention leads to a
reduction in fat mass .
Conversely, it has long been known that chronic insulin therapy for
diabetes leads to weight gain and decreased flux of fatty acids
compared to isocaloric controls.
Figure 3. Effect of insulin on fatty acid flux.
Free fatty acid appearance in plasma R(a) were examined in healthy
humans infused intravenously with insulin. Data from reference .
Units converted for comparison to figure 5.
dramatic if abstract demonstration of the potential effect of
carbohydrate restriction on insulin stimulation of fat cells comes from
the study of the adipose-specific insulin receptor knockout mice FIRKO
mouse of Bluher & Kahn [32,71].
These animals have a knockout of the insulin receptor specific to the
adipocyte. Widely discussed because of their increased longevity they
also show greatly reduced efficiency in the storage of lipid and are
significantly thinner than the wild type even though both groups
consumed the same amount of food (Figure 4).
Figure 4. Weight change and food intake of the FIRKO mouse.
Data from reference [71, 88] Adipose-specific insulin receptor knockout
(FIRKO) mice have normal or increased food intake but are protected
The flux of insulin for diabetic patients under two dietary conditions is shown in Figure 5.
A consistently lower level of insulin throughout the day is seen under
conditions of lower carbohydrate intake. In addition, Such behavior has
been measured frequently in the literature. Chronic carbohydrate
restriction means that this reduced insulin never catches up with
control. The study from Gannon & Nuttal 
was carried out under conditions of weight maintenance so that there is
presumably a compensating fatty acid oxidation but it is clear that
insulin flux is controlled by dietary carbohydrate which, in turn,
reduces the flux of fatty acid.
Figure 5. Effect of diet on serum insulin concentration.
Mean serum insulin concentration before (red) and after (blue) 5 weeks
on a reduced carbohydrate diet (CHO:Lipid:Protein = 20:50:30) using a
randomized crossover design with a 5-week washout period. Data from
reference . The control diet was (55:30:15). As noted in the text,
the insulin values are in the linear range of the dependence of fatty
acid flux on insulin and the pattern roughly proportional to the flux
of fatty acid.
Availability of substrate affects efficiency
Glycerol-3-phosphate: PEPCK overexpression
The key substrate
for TAG synthesis is glycerol-3-phosphate. Because adipocytes normally
have very low levels of glycerol kinase, the flux of TAG is dependent
on processes (J2) that supply glycerol-3-phosphate:
glycolysis or, under conditions of starvation or glucose deprivation,
glyceroneogenesis, a truncated form of gluconeogenesis .
These processes are dependent on the composition of the diet and the
hormonal state of the organism. One approach to separating the effect
of glucose from the effect of glucose-induced insulin, is the genetic
manipulation of the level of enzymes under conditions of low glucose.
Such a strategy allows one to isolate the driving force from the
effects of hormone on the phenomenologic constants, L22 and L21. Franckhauser 
overexpressed phosphoenolpyruvate carboxykinase (PEPCK) in mice
adipocytes. Under conditions of starvation, transgenic mice showed
increased glyceroneogenesis which was accompanied by increased
reesterification of free fatty acids (FAs), and a corresponding
decrease in circulating FAs, both reflecting an increase in stored TAG
In fact, the transgenic mice showed increased adipocyte size and fat
mass, and higher body weight. Insulin sensitivity was preserved. When
fed, nutrient consumption was the same for the experimental animals and
the wild type. Thus, the change in the enzymatic activity of PEPCK
affects the accretion of fat in the absence of any change in caloric
intake or change in hormonal level that normally triggers changes in
PEPCK levels. An overall change in the efficiency of food utilization
is 2-fold for the heterozygotes and almost 4-fold for the homozygotes.
In similar experiments, Shepherd, et al. 
overexpressed adipocyte GLUT4 in transgenic mice. Body lipid was
increased 2–3 fold in these mice compared to wild-type and the mutants
had increased insulin sensitivity. Direct comparison to the simple
model in Figure 2 is complicated by the fact that the transgenic mice showed fat cell hyperplasia rather than a simple increase in size.
Dietary fat and the effect of chronic carbohydrate restriction
key question in the application of the model is the extent to which
lipolysis and other catabolic processes that are increased by
reductions in insulin are compensated for by the increased availability
of dietary TAG (X4) if carbohydrate in the diet is replaced by fat. At this point, we can consider the process indicated by J4, the influx of plasma FA from plasma TAG, as a perturbation on overall TAG storage. The activity of lipoprotein lipase (J4) is increased by higher insulin and will be reduced by chronic carbohydrate restriction . The effect of chronic diet on the response to dietary fat challenge can provide further data on this point. Sharman, et al. 
showed that six weeks on a low carbohydrate ketogenic diet led to a
substantially reduced postprandial serum triacylglycerol (TAG) response
in normal-weight men (Figure 6).
The low carbohydrate group, in distinction to controls, showed
drastically reduced (-34 %) insulin levels. Thus, despite the higher
fat intake, the rate of lipolysis increased and the contribution of
activity of TAG (X4) went down.
Figure 6. Effect of chronic diets on postprandial response to high fat meal.
Responses to high fat meal before and after 6 weeks on low carbohydrate
(< 10% energy) ketogenic diet in overweight men. Data from reference
The bottom line: efficient and dissipative modes
While no experiment in the literature measures all the relevant variables, comparisons of Figures 3, 5 and 6
give a sense of the difference in time dependent responses on low
carbohydrate and high carbohydrate (high insulin) diets. The individual
components that contribute are as follows:
1. Rate of lipolysis. Insulin represses lipolysis as shown in Figure 3.
This is true even in insulin-resistant states such as diabetes.
Carbohydrate restriction reduces insulin fluxes as indicated in Figure 5.
2. Figure 6 shows that the effect of chronic carbohydrate restriction compared to controls is to reduce plasma triglycerides (X4)
in response to a fat challenge, reducing the activity of FA in the
carbohydrate-restricted state compared to the higher carbohydrate state.
3. Lipoprotein lipase is known to be up-regulated by higher insulin increasing the flux of FA into the adipocyte (J4) under conditions of high carbohydrate.
4. Carbohydrate represses per cent fat oxidation.
Thus, all of the differences in high and low insulin states are in
the direction of efficient modes in the former and toward more
dissipative modes in the latter.
As a guide to future research, then, the continuous monitoring of FA
flux and oxidation, or other variables that allow determination of TAG
flux can be done with current technology and it is possible to test the
role of kinetic regulation in different weight loss strategies and to
rationalize variable efficiency. It is important to point out that a
thermodynamic analysis explains the potential for the metabolic
advantage for particular diets but can, as well, point the way to
identifying other factors that maintain homeostasis. In other words,
isocaloric diets do not always show differences in efficiency and the
thermodynamic analysis suggests that it is as important to explain
cases where metabolic advantage does not occur as those where it does.
A metabolic scheme of the type considered here is traditionally
evaluated in terms of the effect of the demand on the output by the
load, or conductance matching by analogy with electronic systems [54,58]. The assumptions of the model in Figure 2
is that there is effectively no load on the adipocyte: output of fatty
acid and its subsequent utilization by other tissues, are independently
regulated and the adipocyte, in effect, has very high output
conductance, that is, supplies whatever fatty acid is required. Wolfe
and coworkers [76-78]
have emphasized the extent to which glucose controls fatty acid
metabolism rather than the other way around as originally suggested in
the Randle cycle [79,80].
From the perspective of further metabolic analysis, the adipocyte may
be considered a discrete modular element and could be patched into a