The question of “is a calorie a calorie?” is as old as nutrition research, and it frequently surfaces in modern low carb diet research.
Understanding the factors regulating energy intake and energy expenditure is fundamental to understanding human nutrition.
Seemingly lost in this longstanding debate is that a calorie is simply a unit of energy [specifically heat]; it has no value beyond this.
Nevertheless, the simple unit of energy has been at the centre of one of the longest debates in nutrition: “calories in, calories out” or “CICO”.
“CICO” is a basic proposition: body mass is ultimately influenced by the balance of energy consumed [“calories in”] vs. the level of energy expended [“calories out”].
This longstanding debate has also centred on low-carbohydrate diets, popularised by the claims of Dr Robert Atkins in the early 1970’s and frequently examined in low carb diet research.
Atkins proposed that anyone restricting carbohydrates would be able to consume as much dietary fat as possible and not gain weight.
In fact, Atkins proposed that this would result in weight loss no matter how many calories someone ate from dietary fat.
David Ludwig and the “Metabolic Advantage”
This hypothesis that low-carbohydrate diets conferred a “metabolic advantage” gathered momentum again in the early 21st Century.
The evidence from initial low carb diet research seemed to suggest that low-carb diets resulted in greater weight loss compared to low-fat diets, at the same amount of calories.
However, there was an issue with this evidence.
Closer scrutiny of these trials revealed a significant confounder in that dietary protein intake was often significantly higher on the low-carb diets, compared to the LF diets.
For example, the average dietary protein content of low-carb diets ranged from 30-35%, while the comparative low-fat diets ranged from 15-18%.
The higher dietary protein, in free-living studies, may also have facilitated reductions in energy intake.
Thus, it may simply have been that a calorie is indeed a calorie.
But Harvard’s Dr David Ludwig has always begged to differ.
In 2018 his group published a paper which suggested that, compared to a high-carbohydrate diet, energy expenditure on a low-carbohydrate diet was 209kcal greater per day.
That’s a fairly whopping increase in energy expenditure.
True Effect or Artefact of Measurement Error?
There were several major issues with that 2018 paper, but the primary limitation was the use of doubly-labelled water DLW to assess energy expenditure in the context of the low-carbohydrate diet. Let’s explain this.
As a method, doubly-labelled water has been the gold standard for assessing human energy expenditure in free-living conditions.
However, the method has only been validated in humans consuming a moderate degree of carbohydrate intake and has never been validated against a low-carbohydrate diet.
This is important because the doubly-labelled water method relies on carbon dioxide [CO2] production in its calculations.
However, CO2 production can vary between diets with different carbohydrate levels.
The net effect is that doubly-labelled water may overestimate CO2 production during low-carbohydrate diets.
Methodological Messing in Meta-Analysis
Ludwig is generally impervious to evidence against his hypothesis, and continues to produce research inattentive to these limitations.
In 2021, his group published a meta-analysis of trials examining the effects of lower carbohydrate diets on energy expenditure.
To be included, studies had to have used either whole-room calorimetry or doubly-labelled water to measure energy expenditure, aiming to clarify ongoing low carb diet research.
The main difference is that whole-room calorimetry allows for the calculation of a metric respiratory quotient” [RQ], which is the ratio of oxygen [O2] to CO2 produced from metabolising macronutrients.
The advantage of RQ is that it allows for a correction to the potential misestimation of energy expenditure on low-carb diets from doubly-labelled water.
In this meta-analysis, studies were stratified by whether they were under or over 17 days duration.
In the analysis of studies <17 days, there was no significant effect on energy expenditure of varying levels of carbohydrates in the diet.
However, in the analysis of trials > 17 days duration low-carb diets showed an increased TEE by 135kcal/d.
Still seems like a “metabolic advantage”, right?
In fact, there were some pretty clear differences between studies that measured energy expenditure using whole-room calorimetry and RQ, and studies using doubly-labelled water.
Appearances May Be Deceptive…
Six studies were included in the analysis of trials of >17 days duration.
Of these, two had measures of RQ available, and the magnitude of effect was far smaller than the estimates from the doubly-labelled water studies.
In these studies, energy expenditure was higher on low-carb diets, but by ~70kcal/d.
But happens if the other studies are corrected for measurement error using RQ?
This was undertaken by Kevin Hall and Stephan Guyenet in a re-analysis of the studies included in the Ludwig meta-analysis.
For example, in the Ludwig group 2018 study mentioned above, adjustment for RQ lowered the energy expenditure estime by 50%.
The Hall & Guyenet reanalysis indicated that low-carb diets over 14 days duration increased energy expenditure by 63kcal/d.
This estimate is right in line with the two studies in the original meta-analysis that used whole-room calorimetry to assess energy expenditure.
Final Thoughts
Do low-carb diets truly confer a “metabolic advantage”?
The first question to ask is whether there is any true difference in energy expenditure on a low-carb diet, and it does appear that there is.
One of Kevin Hall’s metabolic ward studies illustrates this difference, where energy expenditure increased by an average of ~57kcal/d on a ketogenic diet.
If the Ludwig meta-analysis had corrected for the measurement error of doubly-labelled water on low-carb diets using RQ in the calculations, it would have yielded results of a similar magnitude to the prior metabolic ward study from Hall’s group.
The next question is, if there is a difference, does it lead to meaningful differences in human outcomes?
And the answer to that, both in relation to measured fat oxidation and weight loss compared to a low-fat diet, is “no”.
Given that any magnitude of increased energy expenditure is likely <100kcal/d, this is unsurprising.
So, there may be some elevation in energy expenditure on a low-carb diet that is measurable scientifically within low carb diet research, but of little clinical relevance for the real world.
Yours in Science,
Alan
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