Carbohydrate restriction as a strategy for control of obesity is based on …

• Abstract
• Background
• Discussion
• Emphasis
• Abbreviation
• References
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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 [48] 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[68] 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 muscles [85].

General perspective

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 [86], 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 [87]. 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 [37] 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 conditions.