Language Barriers: Preferred Fuel
As a linguist, I am often struck by the way phrasing and word choices not only reflect biases, but can actually create them [1]. Again and again in my researches into dietary science, I come upon expressions and turns of phrase that make Low Carb, High Fat diets seem intuitively unhealthy or illogical.
One such phrase is “Preferred Fuel”.
What is a preferred fuel?
Technically, a preferred fuel is simply one that is used first when there is more than one type available.
For many (but not all) of the tissues and organs in the body, glucose is a “preferred fuel”, meaning that if glucose is available, those tissues and organs will use it before using most other fuels, even if they are also present.
People sometimes take this to mean that glucose is the best fuel; the fuel that would make you most healthy. Choosing and preferring are things people do when they have decided that something is “better” than something else. So, whether or not the physiologist who coined the term intended it, this terminology leads the reader to think that the preferred fuel is the one that is inherently a better choice. However, this is not correct. Sometimes the opposite is true. Sometimes it depends on what else is going on.
One analogy I like is that of spending. Many people take a large portion of their hard-earned pay cheques and make a payment on their debts. No matter what else they do, they do that first. Does this mean it is what they “prefer” to spend their money on? In some sense, yes! By the Doctrine of Revealed Preference [2], it is by definition what they prefer. And yet most people would not count this kind of obligation as one of their choices. There is another phrase, “disposable income” for spending associated with choice. The reason paying debts is preferred in this way, is that one seeks to avoid the consequences of not paying. In fact, in most cases, for most people, paying debts is a better choice than not paying them. What it does not mean, however, is that people prefer to have debts to pay in the first place!
To bring this back to the realm of human metabolism, there are several substances that can be used for fuel, including fat, protein, ketones, glucose (which is the kind of fuel carbohydrates provide), and alcohol. Alcohol is a strongly preferred fuel [3]. It is metabolised right away, even if there are other fuel sources around. This is not evidence that alcohol is the best fuel, but rather that it is what the body wants to get rid of immediately. Getting rid of the alcohol is a better choice than leaving it around to do damage. The same is often true of glucose. High blood sugar is toxic, and so whenever there is excess available it will get used or stored as quickly as possible.
We don’t mean to imply that being used for fuel first always means a substance is toxic. What is a good “choice” in a system as complex as the human body is not always obvious. For example, the heart uses acetoacetate (a ketone body) before glucose, but uses primarily fat, even in glucose-based dieters [4].
What about the brain?
It is true that the brain has need for some amount of glucose, even under a ketogenic metabolism. That is one reason why gluconeogenesis (the ongoing production of glucose in the liver) is important, whether you are ketogenic or not. This ensures a steady supply of glucose into the bloodstream, and keeps blood sugar in healthy bounds: enough for the brain, but not too much. Under ketogenic conditions, though, the brain’s need for glucose is drastically reduced, because other fuels, such as ketone bodies and lactate take the place of most of it [5].
Lactate may be preferred over glucose in the brain [6], [7]. Using lactate instead of glucose has neuroprotective properties not unlike those seen with ketosis [8]. It might even be the case that a primary use of glucose in the brain is to be turned into lactate by astrocytes [8], [9]. We still have much to learn.
Next time you see the phrase “Preferred Fuel”, remember that it really just means the order in which different fuels are consumed. There are various context-specific reasons a particular fuel might be used before other ones, and it has nothing to do with its inherent healthiness.
Notes
1. Evidence type: controlled randomised experiment
See for example: Subtle linguistic cues influence perceived blame and financial liability.
Fausey, Caitlin M., and Lera Boroditsky.
Psychonomic bulletin & review 17.5 (2010): 644-650.
“When bad things happen, how do we decide who is to blame and how much they should be punished? In the present studies, we examined whether subtly different linguistic descriptions of accidents influence how much people blame and punish those involved. In three studies, participants judged how much people involved in particular accidents should be blamed and how much they should have to pay for the resulting damage. The language used to describe the accidents differed subtly across conditions: Either agentive (transitive) or non-agentive (intransitive) verb forms were used. Agentive descriptions led participants to attribute more blame and request higher financial penalties than did nonagentive descriptions. Further, linguistic framing influenced judgments, even when participants reasoned about a well-known event, such as the “wardrobe malfunction” of Super Bowl 2004. Importantly, this effect of language held, even when people were able to see a video of the event. These results demonstrate that even when people have rich established knowledge and visual informa – tion about events, linguistic framing can shape event construal, with important real-world consequences. Subtle differences in linguistic descriptions can change how people construe what happened, attribute blame, and dole out punishment.
2. From Investopedia
“Definition of ‘Revealed Preference’
“An economic theory of consumption behavior which asserts that the best way to measure consumer preferences is to observe their purchasing behavior. Revealed preference theory works on the assumption that consumers have considered a set of alternatives before making a purchasing decision. Thus, given that a consumer chooses one option out of the set, this option must be the preferred option.
“Revealed preference theory was introduced by Paul Samuelson in 1938. Since then it has expanded upon by a number of economists and remains a major theory of consumption behavior. The theory is especially useful in providing a method for analyzing consumer choice empirically.”
3. See for example:
Ethanol and lipids.
Lieber CS, Savolainen M.
Alcohol Clin Exp Res. 1984 Jul-Aug;8(4):409-23.
“The interaction of ethanol with lipid metabolism is complex. When ethanol is present, it becomes a preferred fuel for the liver and displaces fat as a source of energy.”
Or
Ethanol Causes Acute Inhibition of Carbohydrate, Fat, and Protein Oxidation and Insulin Resistance.
John J. Shelmet, George A. Reichard, Charles L. Skutches, Robert D. Hoeldtke, Oliver E. Owen, and Guenther Boden
J Clin Invest. 1988 April; 81(4): 1137–1145.
“We conclude that ethanol was a preferred fuel preventing fat, and to lesser degrees, CHO and protein, from being oxidized. It also caused acute insulin resistance which was compensated for by hypersecretion of insulin.”
4. Evidence type: authority
Section 30.2, Each Organ Has a Unique Metabolic Profile.
Biochemistry. 5th edition.
Berg JM, Tymoczko JL, Stryer L.
New York: W H Freeman; 2002.
“Unlike skeletal muscle, heart muscle functions almost exclusively aerobically, as evidenced by the density of mitochondria in heart muscle. Moreover, the heart has virtually no glycogen reserves. Fatty acids are the heart’s main source of fuel, although ketone bodies as well as lactate can serve as fuel for heart muscle. In fact, heart muscle consumes acetoacetate in preference to glucose.”
Public Note to Self: “functions almost exclusively aerobically, as evidenced by the density of mitochondria” is relevant to the idea that ketogenic diets increase mitochondrial number. There is preliminary evidence of this, as discussed previously. This statement leads me to believe that it should be unsurprising if decreased reliance on glucose had this effect.
5. Evidence type: controlled experiment
Brain Metabolism during Fasting
O. E. Owen, A. P. Morgan, H. G. Kemp, J. M. Sullivan, M. G. Herrera, and G. F. Cahill, Jr.
J Clin Invest. 1967 October; 46(10): 1589–1595. doi: 10.1172/JCI105650 PMCID: PMC292907
(Measurements on three people after 38-41 days of fasting)
“Turning to Table V, the average glucose uptake, after subtracting the amount glycolyzed to lactate and pyruvate, is 0.145 mmole/liter (2.6 mg/100 ml). This is markedly less than the usual 9-10 mg/100 ml observed in our laboratory while the techniques which little or no production of lactate or pyruvate was observed (25-28). Similar data were observed in our laboratory while the techniques and methods used to study these fasted subjects were validated. With measured cerebral blood flow of 45 ml/100 g of tissue per min, and assuming a brain size of 1400 g the 24 hr glucose oxidation would approximate 24 g, which agrees well with the theoretical maximum of 33 g calculated from nitrogen execretion and glycerol from adipose tissue as described above. The third confirmatory evidence for this marked reduction in glucose metabolism has been data, which obtained from hepatic and renal vein catheterization studies, demonstrated that the liver almost totally ceases to synthesize glucose from amino acids and that the kidney assumes the role of the major source of this diminished amount of glucose daily produced and consumed during starvation.”
6. Evidence type: non-human animal experiments
In Vivo Evidence for Lactate as a Neuronal Energy Source
Matthias T. Wyss, Renaud Jolivet, Alfred Buck, Pierre J. Magistretti, and Bruno Weber
The Journal of Neuroscience, 18 May 2011, 31(20): 7477-7485; doi: 10.1523/JNEUROSCI.0415-11.2011
“Cerebral energy metabolism is a highly compartmentalized and complex process in which transcellular trafficking of metabolites plays a pivotal role. Over the past decade, a role for lactate in fueling the energetic requirements of neurons has emerged. Furthermore, a neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported. The majority of the current evidence concerning lactate metabolism at the cellular level is based on in vitro data; only a few recent in vivo results have demonstrated that the brain preferentially utilizes lactate over glucose. Using voltage-sensitive dye (VSD) imaging, beta-probe measurements of radiotracer kinetics, and brain activation by sensory stimulation in the anesthetized rat, we investigated several aspects of cerebral lactate metabolism. The present study is the first in vivo demonstration of the maintenance of neuronal activity in the presence of lactate as the primary energy source. The loss of the voltage-sensitive dye signal found during severe insulin-induced hypoglycemia is completely prevented by lactate infusion. Thus, lactate has a direct neuroprotective effect. Furthermore, we demonstrate that the brain readily oxidizes lactate in an activity-dependent manner. The washout of 1-[ 11C]L-lactate, reflecting cerebral lactate oxidation, was observed to increase during brain activation from 0.077 Ϯ 0.009 to 0.105 Ϯ 0.007 min Ϫ1. Finally, our data confirm that the brain prefers lactate over glucose as an energy substrate when both substrates are available. Using [18F]fluorodeoxyglucose (FDG) to measure the local cerebral metabolic rate of glucose, we demonstrated a lactate concentration-dependent reduction of cerebral glucose utilization during experimentally increased plasma lactate levels.”
7. Evidence type: review of experiments
Lactate utilization by brain cells and its role in CNS development.
Medina JM, Tabernero A.
J Neurosci Res. 2005 Jan 1-15;79(1-2):2-10.
“Lactate metabolism is particularly relevant in the brain, in which lactate is preferred over glucose, glutamine, or ketone bodies (Arizmendi and Medina, 1983; Fernandez and Medina, 1986; Vicario et al., 1991).”
Note that the references in this passage are either in rat brains or in glucose-6-phosphatase deficient children, so the unqualified generalisation as stated here is not warranted.
8. Evidence type: non-human animal experiments
Regulation of oligodendrocyte development and myelination by glucose and lactate
Johanne E. Rinholm, Nicola B. Hamilton, Nicoletta Kessaris, William D. Richardson, Linda H. Bergersen, and David Attwell
J Neurosci. 2011 January 12; 31(2): 538–548. doi: 10.1523/JNEUROSCI.3516-10.2011
“In the brain’s grey matter, astrocytes have been suggested to export lactate (derived from glucose or glycogen) to neurons to power their mitochondria. In the white matter, lactate can support axon function in conditions of energy deprivation, but it is not known whether lactate acts by preserving energy levels in axons or in oligodendrocytes, the myelinating processes of which are damaged rapidly in low energy conditions. Studies of cultured cells suggest that oligodendrocytes are the cell type in the brain which consumes lactate at the highest rate, in part to produce membrane lipids presumably for myelin. Here we use pH imaging to show that oligodendrocytes in the white matter of the rat cerebellum and corpus callosum take up lactate via monocarboxylate transporters (MCTs), which we identify as MCT1 by confocal immunofluorescence and electron microscopy. Using cultured slices of developing cerebral cortex from mice in which oligodendrocyte lineage cells express GFP under the control of the Sox10 promoter, we show that a low glucose concentration reduces the number of oligodendrocyte lineage cells and myelination. Myelination is rescued when exogenous L-lactate is supplied. Thus, lactate can support oligodendrocyte development and myelination. In CNS diseases involving energy deprivation at times of myelination or remyelination, such as periventricular leukomalacia leading to cerebral palsy, stroke, and secondary ischaemia following spinal cord injury, lactate transporters in oligodendrocytes may play an important role in minimising the inhibition of myelination that occurs.”
9. Evidence type: conceptual integration of experiments
The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect.
Yudkoff M, Daikhin Y, Melø TM, Nissim I, Sonnewald U, Nissim I.
Annu Rev Nutr. 2007;27:415-30.
“The oxidation of glucose provides essentially all energy needed to maintain cerebral function. Glycolysis may be relatively more prominent in some cells or in specific sub-cellular compartments. Thus, the filopodia of astrocytes are too narrow to accommodate mitochondria, and these cells will activate glycolysis (and glycogenolysis) in order to provide the energy that maintains their vital function of removing from the synaptic cleft much of the glutamate and K+ that presynaptic neuronal terminals release upon depolarization (24, 46). The fate of the pyruvate generated via glycolysis remains a topic of active inquiry and debate. It may be that astrocytes do not immediately oxidize all pyruvate produced via glycolysis. Instead, they may convert some pyruvate to lactate and release the latter to the extracellular fluid, from which neurons extract it and oxidize it as a fuel. Neurons can respire on lactate (102), but they may require glucose as a substrate if they are to maintain large internal pools of glutamate and aspartate (125). Astrocytic release of lactate and sub-sequent neuronal oxidation may constitute a mechanism by which neuronal and metabolic activity are effectively coupled (33, 66). “