On 2017 Feb 05, Kevin Hall commented:

The theoretical basis of the carbohydrate-insulin model (CIM) relies on generally accepted physiology about endocrine regulation of adipose tissue– data that were all collected on short time scales. Ludwig appears to suggest that this long debate has been about a “straw man” short-term version of the CIM. This apparently explains why the purported metabolic advantages have been elusive when assessed by inpatient controlled feeding studies that were simply too short to unveil the metabolic advantages of the CIM. Indeed, Ludwig believes he has scored a win in this debate by acknowledging that these metabolic advantages of low carbohydrate diets on energy expenditure and body fat predicted by the CIM must operate on longer time scales, conveniently where no inpatient data have been generated either supporting or negating those predictions. This was accurately described in my review as an ad hoc modification of the CIM – a possibility currently unsupported by data but obviously supported by sincere belief.

On 2017 Feb 05, DAVID LUDWIG commented:

With Hall’s comment of 4 Feb 2017, this long debate nears resolution. He acknowledges it’s “possible” that the very short metabolic studies do not reflect the long-term effects of macronutrients on body weight. We disagree on how likely that possibility is, and now must await further research to resolve the scientific uncertainties.

Finally, on an issue of academic interest only, Hall creates a straw man in claiming to have “falsified” the Carbohydrate-Insulin Model (CIM). Versions of CIM were originally proposed more than a century ago, as detailed by Taubes G, 2013, before short term studies of substrate oxidation would have been possible. Furthermore, in the second paragraph of his review, Hall cites an article I coauthored Ludwig DS, 2014 and three by others Lustig RH, 2006, Taubes G, 2013, Wells JC, 2011 as recent iterations of CIM. Each of these articles focuses on long-term effects, and none asserts that 1 week should be adequate to prove or falsify CIM. In view of the failure of conventional approaches to address the massive public health challenge of obesity, let’s now refocus our energies into the design and execution of more definitive research.

On 2017 Feb 05, Kevin Hall commented:

Ludwig suggests that demonstration of any metabolic adaptations occurring on a time scale of > 1 week after introduction of an isocaloric low carbohydrate diet somehow invalidates all of the inpatient controlled feeding studies with results that violate carbohydrate-insulin model (CIM) predictions. This presents a false dilemma and is a red herring.

There are indeed metabolic adaptations that take place on longer time scales, but many of these changes actually support the conclusion that the purported metabolic advantages for body fat loss predicted by the CIM are inconsistent with the data. For example, as evidence for a prolonged period of fat adaptation, Ludwig notes modest additional increases in blood and urine ketones observed after 1 week of either starvation Owen OE, 1983 or consuming a hypocaloric ketogenic diet Yang MU, 1976. The implication is that daily fat and ketone oxidation presumably increase along with their blood concentrations over extended time periods to eventually result in an acceleration of body fat loss with low carbohydrate high fat diets as predicted by the CIM. But since acceleration of fat loss during prolonged starvation would be counterproductive to survival, might there be data supporting a more physiological interpretation the prolonged increase in blood and urine ketones?

Both adipose lipolysis Bortz WM, 1972 and hepatic ketone production Balasse EO, 1989 reach a maximum within 1 week as demonstrated by isotopic tracer data. Therefore, rising blood ketone concentrations after 1 week must be explained by a reduced rate of removal from the blood. Indeed, muscle ketone oxidation decreases after 1 week of starvation and, along with decreased overall energy expenditure, the reduction in ketone oxidation results in rising blood concentrations and increased urinary excretion (page 144-152 of Burstztein S, et al. ‘Energy Metabolism, Indirect Calorimetry, and Nutrition.’ Williams & Wilkins 1989). Therefore, rather than being indicative of progressive mobilization of body fat to increase oxidation and accelerate fat loss, rising concentrations of blood ketones and fatty acids occurring after 1 week arise from reductions in ketone and fat oxidation concomitant with decreased energy expenditure.

The deleterious effects of a 600 kcal/d low carbohydrate ketogenic diet on body protein and lean mass were demonstrated in Vasquez JA, 1992 and were found to last about 1 month. Since weight loss was not significantly different compared to an isocaloric higher carbohydrate diet, body fat loss was likely attenuated during the ketogenic diet and therefore in direct opposition to the CIM predictions. Subsequent normalization of nitrogen balance would tend to result in an equivalent rate of body fat loss between the isocaloric diets over longer time periods. In Hall KD, 2016, urinary nitrogen excretion increased for 11 days after introducing a 2700 kcal/d ketogenic diet and coincided with attenuated body fat loss measured during the first 2 weeks of the diet. The rate of body fat loss appeared to normalize in the final 2 weeks, but did not exceed the fat loss observed during the isocaloric high carbohydrate run-in diet. Mere normalization of body fat and lean tissue loss over long time periods cannot compensate for early deficiencies. Therefore, these data run against CIM predictions of augmented fat loss with lower carbohydrate diets.

While I believe that outpatient weight loss trials demonstrate that low carbohydrate diets often outperform low fat diets over the short-term, there are little body weight differences over the long-term Freedhoff Y, 2016. However, outpatient studies cannot ensure or adequately measure diet adherence and therefore it is unclear whether greater short-term weight losses with low carbohydrate diets were due to reduced diet calories or the purported “metabolic advantages” of increased energy expenditure and augmented fat loss predicted by the CIM. The inpatient controlled feeding studies demonstrate that the observed short-term energy expenditure and body fat changes often violate CIM predictions.

Ludwig conveniently suggests that all existing inpatient controlled feeding studies have been too short and that longer duration studies might produce results more favorable to the CIM. But even this were true, the current data demonstrating repeated violations of CIM model predictions constitute experimental falsifications of the CIM requiring an ad hoc modification of the model such that the metabolic advantages only begin after a time lag lasting many weeks. This is possible, but unlikely.

On 2017 Feb 04, DAVID LUDWIG commented:

Boiling down his comment of 3 Feb 2017, Hall disputes that the metabolic process of adapting to a high-fat/low-carbohydrate diet confounds interpretation of his and other short term feeding studies. If we can provide evidence that this process could take ≥ 1 week, the last leg of his attack on the Carbohydrate-Insulin Model collapses. Well, a picture is worth a thousand words, and here are 4:

For convenience, these figures can be viewed at this link:

Owen OE, 1983 Figure 1. Ketones are, of course, the hallmark of adaptation to a low-carbohydrate ketogenic diet. Generally speaking, the most potent stimulus of ketosis is fasting, since the consumption of all gluconeogenic precursors (carbohydrate and protein) is zero. As this figure shows, the blood levels of each of the three ketone species (BOHB, AcAc and acetone) continues to rise for ≥3 weeks. Indeed, the prolonged nature of adaptation to complete fasting has been known since the classic starvation studies of Cahill GF Jr, 1971. It stands to reason that this process might take even longer on standard low-carbohydrate diets, which inevitably provide ≥ 20 g carbohydrate/d and substantial protein.

Yang MU, 1976 Figure 3A. Among men with obesity on an 800 kcal/d ketogenic diet (10 g/d carbohydrate, 50 g/d protein), urinary ketones continued to rise for 10 days through the end of the experiment, and by that point had achieved levels equivalent only to those on day 4 of complete fasting. Presumably, this process would be even slower with a non-calorie restricted ketogenic diet (because of inevitably higher carbohydrate and protein content).

Vazquez JA, 1992 Figure 5B. On a conventional high-carbohydrate diet, the brain is critically dependent on glucose. With acute restriction of dietary carbohydrate (by fasting or a ketogenic diet), the body obtains gluconeogenic precursors by breaking down muscle. However, with rising ketone concentrations, the brain becomes adapted, sparing glucose. In this way, the body shifts away from protein to fat metabolism, sparing lean tissue. This phenomenon is clearly depicted among women with obesity given a calorie-restricted ketogenic diet (10 g carbohydrate/d) vs a nonketogenic diet (76 g carbohydrate/d), both with protein 50 g protein/d. For 3 weeks, nitrogen balance was strongly negative on the ketogenic diet compared to the non-ketogenic diet, but this difference was completely abolished by week 4. What would subsequently happen? We simply can’t know from the short-term studies.

Hall KD, 2016 Figure 2B. Hall’s own study shows that the transient decrease in rate of fat loss upon initiation of the ketogenic diet accelerates after 2 weeks.

The existence of this prolonged adaptive process explains why metabolic advantages for low-fat diet are consistently seen in very short metabolic studies. But after 2 to 4 weeks, advantages for low-carbohydrate diets begin to emerge, as summarized in my comment of 3 Feb 2017, below.

Fat adaptation on low-carbohydrate diets has admittedly not been thoroughly studied, and its duration may differ among individuals and between experimental conditions. Nevertheless, there is strong reason to think that short feeding studies (i.e., < 3 to 4 weeks) have no relevance to the long-term effects of macronutrients on metabolism and body composition.

On 2017 Feb 04, Kevin Hall commented:

Is it really an “extreme argument” to conclude that important aspects of the carbohydrate-insulin model (CIM) have been falsified based on data from 20 highly controlled inpatient human feeding studies that failed to support key CIM model predictions? While previously ignoring this conforming body of data from other research groups, Ludwig now conveniently concludes that all of these studies were flawed in some way and are therefore irrelevant and incapable of testing any aspect of the carbohydrate-insulin model.

To Ludwig, more relevant for assessing the energy expenditure and body fat predictions of the CIM are rodent studies and outpatient human studies where diet adherence cannot be adequately controlled or assessed Winkler JT, 2005. One such study Ludwig uses to bolster the CIM Ebbeling CB, 2012 did not measure body fat during the test diets and showed no significant energy expenditure differences between diets with the same amount of protein but varying in carbohydrate vs. fat. Ludwig claims that the study supports the CIM because energy expenditure was observed to increase with a very low carbohydrate diet. But the concomitant 50% increase in protein vs. the comparator diets makes it impossible to definitively conclude that any observed effect was due to carbohydrate reduction alone. Ludwig’s arguments about the possibly minimal effects of dietary protein changes on energy expenditure cannot eliminate this important confound.

Ludwig argues that “adaptation to a higher-fat diet can take at least a week and perhaps considerably longer”. One of Ludwig’s citations in this regard describes the role of diet composition on fuel utilization and exercise performance Hawley JA, 2011. This review paper reported that adaptation to a high fat diet for <1 week was sufficient to alter fuel utilization, but 4-7 days of fat adaptation was required to maintain subsequent exercise performance. Interestingly, longer periods of fat adaptation during training (7 weeks) were concluded to limit exercise capacity and impair exercise performance. The other two studies Ludwig cited to support the necessity for long term fat adaptation fail to support the CIM. An inpatient controlled feeding study Vasquez JA, 1992 showed that a very low carbohydrate, high fat diet led to significantly greater loss of body protein and lean tissue mass despite no significant difference in weight loss compared to an isocaloric higher carbohydrate, lower fat diet. The second study was an outpatient feeding trial Velum VL, 2017 that failed to demonstrate a significant difference in body weight or fat loss despite prescribing diets substantially varying in carbohydrate vs. fat for 3 months.

I agree with Ludwig that it likely takes a long time to equilibrate to added dietary fat without simultaneously reducing carbohydrate because, unlike carbohydrate and protein, dietary fat does not directly promote its own oxidation and does not significantly increase daily energy expenditure Schutz Y, 1989 and Horton TJ, 1995. Unfortunately, these observations also run counter to CIM predictions because they imply that added dietary fat results in a particularly efficient means to accumulate body fat compared to added carbohydrate or protein Bray GA, 2012. If such an added fat diet is sustained, adipose tissue will continue to expand until lipolysis is increased to sufficiently elevate circulating fatty acids and thereby increase daily fat oxidation to reestablish balance with fat intake Flatt JP, 1988.

In contrast, when added fat is accompanied by an isocaloric reduction in carbohydrate, daily fat oxidation plateaus within the first week as indicated by the rapid and sustained drop in daily respiratory quotient in Hall KD, 2016 and Schrauwen P, 1997. Similarly, Hall KD, 2015 observed a decrease and plateau in daily respiratory quotient with the reduced carbohydrate diet, whereas the reduced fat diet resulted in no significant changes indicating that daily fat oxidation was unaffected. As further evidence that adaptations to carbohydrate restriction occur relatively quickly, adipose tissue lipolysis is known to reach a maximum within the first week of a prolonged fast Bortz WM, 1972 as does hepatic ketone production Balasse EO, 1989.

While there is no evidence that carbohydrate restricted diets lead to an acceleration of daily fat oxidation on time scales longer than 1 week, and there is no known physiological mechanism for such an effect, this possibility cannot be ruled out. Such speculative long term effects constitute an ad hoc modification of the carbohydrate-insulin model whereby repeated violations of model predictions on time scales of 1 month or less are somehow reversed.

As I have repeatedly acknowledged, prescribing lower carbohydrate diets in free-living subjects generally leads to greater loss of weight and body fat over the short-term when people are likely adhering most closely to the diet prescriptions. The CIM suggests that such diets offer a “metabolic advantage” that substantially increases energy expenditure and body fat loss even if diet calories are equal. However, inpatient controlled feeding studies do not support this contention as they have repeatedly failed to show significant differences in energy expenditure and body fat. Furthermore, such studies have occasionally measured significant differences in diametrically opposite directions than were predicted on the basis of carbohydrate intake and insulin secretion. These apparent falsifications of the CIM do not imply that dietary carbohydrates and insulin are unimportant for energy expenditure and body fat regulation. Rather, their role is more complicated than the CIM suggests and the model requires thoughtful modification.

On 2017 Feb 03, DAVID LUDWIG commented:

In his comment of January 31, 2017, Hall presses an extreme argument, that he successfully "falsified" major aspects of the Carbohydrate-Insulin Model (CIM) of obesity, and complains that opponents won't embrace their error. His argument boils down to 3 points:

First, Hall’s small 6-day study and his small, “observational,” “pilot” study are fundamentally correct. Regarding the 6-day study Hall KD, 2015, he continues to insist that results of a very short intervention have relevance to understanding the long-term effects of macronutrients on body composition, despite evidence that adaptation to a higher-fat diet can take at least a week and perhaps considerably longer Hawley JA, 2011 Vazquez JA, 1992 Veum VL, 2017. (We need look no further than his observational study Hall KD, 2016, to see in Figure 2B that the transient decrease in rate of fat loss upon initiation of the low-carbohydrate diet accelerates after 2 weeks.) Of note, the 36 g/d greater predicted body fat loss on his low-fat diet would, if persistent, translate into a massive advantage in adiposity after just one year. If anything, the meta-analyses of long-term clinical trials suggest the opposite Tobias DK, 2015 Mansoor N, 2016 Mancini JG, 2016 Sackner-Bernstein J, 2015 Bueno NB, 2013. Furthermore, Hall’s two studies are mutually inconsistent: The 6-day study implies a major increase in energy expenditure from fat oxidation on the low-fat diet, whereas the observational study shows an increase in energy expenditure after 2 weeks (by doubly-labeled water) on the low-carbohydrate diet. Other limitations of his observational study have been considered elsewhere.

Second, our randomized 3-arm cross-over study Ebbeling CB, 2012 is fundamentally wrong. I’ve addressed Hall’s concerns elsewhere. Here, he reiterates that the 10% difference in protein content (intended by design to reflect the Atkins diet) could account for our observed 325 kcal/d difference in energy expenditure. However, there is no basis in the literature for this belief. Among 10 studies published at the time of our feeding trial in which protein intake was compared within the physiological range (10 to 35% of total energy), energy expenditure on the higher vs. lower protein diets ranged from +95 kcal/d to -97 kcal/d, with the mean difference of near zero Dulloo AG, 1999 Hochstenbach-Waelen A, 2009 Lejeune MP, 2006 Luscombe ND, 2003 Mikkelsen PB, 2000 Veldhorst MA, 2009 Veldhorst MA, 2010 Westerterp KR, 1999 Westerterp-Plantenga MS, 2009 Whitehead JM, 1996. Though these studies have methodological limitations themselves, the finding is consistent with thermodynamic considerations that indicate a very minor increment in the "thermic effect of food" from a 10% increase in protein.

Third, 18 other studies provide definitive support his position. This facile contention disregards that these studies are riddled with the same inherent limitations as his studies, including a combination of short duration, highly limited power, indirect measurements of body composition, reliance on metabolic chambers (which have been shown to underestimate adaptive thermogenesis compared to doubly-labeled water Rosenbaum M, 1996), quality control concerns and other issues. Of the cited studies, six were 1 to 4 days Astrup A, 1994 Dirlewanger M, 2000 Davy KP, 2001 Smith SR, 2000 Thearle MS, 2013 Yerboeket-van de Venne WP, 1996, seven were 7 to 15 days Horton TJ, 1995 Shepard TY, 2001 Eckel RH, 2006 Hill JO, 1991 Schrauwen P, 1997 Treuth MS, 2003 Yang MU, 1976, and just five were 4 to 6 weeks. One of these longer studies was based on recovered data from about 30 years prior to publication, with no direct measurements of body composition or energy expenditure Leibel RL, 1992. The other four longer studies employed severe calorie restriction, which would plausibly obscure macronutrient effects over this short duration. Two of these studies had just 4 subjects per diet group Rumpler WV, 1991 Bogardus C, 1981. The remaining two showed either a non-significant (2 kg lower total body fat) Golay A, 1996 or significant (30 cc lower visceral fat) Miyashita Y, 2004 advantage for the lower-carbohydrate diet. We’ve been down this road before, with the launch of the 40-year low-fat diet era based on over-interpretation of methodologically limited research. Let’s not make the same mistake again.

Even as he over-interprets the short-term feeding studies, Hall disregards extensive animal research, high quality observational studies, mechanistic studies, and clinical trials in support of CIM, as summarized here and elsewhere Ludwig DS, 2014 Lucan SC, 2015 Templeman NM, 2017.

Finally, Hall claims that I misunderstand the notion of “energy gap.” As both Hall and I Katan MB, 2010 have considered elsewhere, a decrease in energy intake produces a compensatory decrease in energy expenditure, resulting in less weight loss than would be predicted from the simple observation that a pound of fat contains 3500 kcal. However, here we consider the opposite phenomenon – an increase in energy expenditure resulting from changing dietary quality, not quantity. There is no reason to believe that compensatory increases in energy intake would occur as a result of faster metabolic rate over a similar time frame as that observed with compensatory changes to energy restriction. (Indeed, Hall himself acknowledges the possibility that low-carbohydrate diets might also lower energy intake.) Of course, progressive weight loss regardless of cause would eventually reduce energy expenditure, but we cannot infer from current data when that energy gap would reach zero. Even with conventional assumptions, NIDDK’s Body Weight Planner indicates the 150 kcal/d change in energy balance Hall found on the low-carbohydrate diet by doubly-labeled water would produce more than a 15 lb weight loss for a typical individual over several years – amounting to half the mean change in weight that occurred during the obesity epidemic in the U.S. Why would we dismiss findings with such major potential public health significance?

Hall's premature claims of (at least partial) victory and calls for curtailment of funding for more research Freedhoff Y, 2016 do not do justice to a complicated scientific question. In view of the failure of conventional obesity treatment and the massive public health challenges, all participants in this debate would do well to acknowledge the limitations of existing evidence and join in the design of more definitive research.

On 2017 Jan 31, Kevin Hall commented:

Science progresses through an iterative process of formulating models to explain our observations and subjecting those models to experimental interrogation. A single valid experimental result that runs counter to a model prediction falsifies the model and thereby requires its reformulation. Alternatively, refutation of an apparent model falsification requires demonstrating that the experimental observation was invalid.

My review of the carbohydrate-insulin model (CIM) presented a synthesis of the evidence from 20 inpatient controlled feeding studies strongly suggesting that at least some important aspects of the model are in need of modification. In particular, our recent studies Hall KD, 2015, Hall KD, 2016 employing carefully controlled inpatient isocaloric diets with constant protein, but differing in carbohydrate and fat, resulted in statistically significant differences between the diets regarding body fat and energy expenditure that were in directions opposite to predictions of the CIM.

Rather than using our experimental results as the basis for clarifying and reformulating the CIM, Ludwig challenges their validity and simply ignores the 18 other inpatient controlled feeding studies with their conforming body of results failing to support the energy expenditure or body fat predictions of the CIM.

Ludwig’s comments on the diets used in Hall KD, 2015 are irrelevant to whether they resulted in a valid test of the CIM predictions. We fed people diets that selectively reduced 30% of baseline calories solely by restricting either carbohydrate or fat. These diets achieved substantial differences in daily insulin secretion as measured by ~20% lower 24hr urinary C-peptide excretion with the reduced carbohydrate diet as compared with the reduced fat diet (p= 0.001) which was unchanged from baseline. Whereas the reduced fat diet resulted in no significant energy expenditure changes from baseline, carbohydrate restriction resulted in a ~100 kcal/d decrease in both daily energy expenditure and sleeping metabolic rate. These results were in direct opposition to the CIM predictions, but in accord with the previous studies described in the review as well as a subsequent study demonstrating that lower insulin secretion was associated with a greater reduction of metabolic rate during weight loss Muller MJ, 2015.

Ludwig erroneously claims that the study suffered from an “inability to directly document change in fat mass by DXA”, but DXA measurements indicated statistically significant reductions in body fat with both diets. While DXA was not sufficiently precise to detect significant differences between the diets, even this null result runs counter to the predicted greater body fat loss with the reduced carbohydrate diet. Importantly, the highly sensitive fat balance technique demonstrated small but statistically significant differences in cumulative body fat loss (p<0.0001) in the direction opposite to the CIM predictions. Ludwig claims that our results are invalid because “rates of fat oxidation, the primary endpoint, are exquisitely sensitive to energy balance. A miscalculation of available energy for each diet of 5% in opposite directions could explain the study’s findings.” However, it is highly implausible that small uncertainties in the metabolizable energy content of the diet amounting to <100 kcal/d could explain the >400 kcal/d (p<0.0001) measured difference in daily fat oxidation rate. Furthermore, our results were robust to the study errors and exclusions fully reported in Hall KD, 2015 and clearly falsified important aspects of the CIM.

We previously responded Hall KD, 2016b to Ludwig’s comments Ludwig DS, 2016 on our ketogenic diet study. Ludwig now argues that we set the bar too high regarding the energy expenditure predictions of the CIM based on “speculative claims by non-scientists like Robert Atkins”. But scientists well-known for promoting low carb diets have claimed that “very low carbohydrate diets, in their early phases, also must supply substantial glucose to the brain from gluconeogenesis…the energy cost, at 4–5 kcal/gram could amount to as much as 400–600 kcal/day” Fine EJ, 2004. Ludwig also sets the energy expenditure bar quite high in his New York Times opinion article, JAMA commentary, and book “Always Hungry” where he claims to have demonstrated a 325 kcal/d increase in expenditure in accordance with the CIM predictions Ebbeling CB, 2012. What Ludwig fails to mention is that such an interpretation is confounded by the low-carbohydrate diet having 50% greater dietary protein which is well-known to increase expenditure. Ludwig also doesn’t mention that his study failed to demonstrate a significant effect on either resting or daily energy expenditure when comparing diets with the same protein content, but varying in carbohydrate and fat.

What was the energy expenditure bar set by our ketogenic diet study Hall KD, 2016? The clinical protocol specified that the primary daily energy expenditure outcome (measured by room calorimetry) must increase by >150 kcal/d to be considered physiologically meaningful. With the agreement of funders at the Nutrition Science Initiative, notable proponents of the CIM, the pre-specified 150 kcal/d threshold was used to calculate number of study subjects required to estimate the energy expenditure effect size in a homogeneous population of men consuming an extremely low carbohydrate diet. If the measured effect size exceeded 150 kcal/d then the results could be reasonably interpreted as a physiologically important increase in energy expenditure worthy of future study in a wider population using a more realistic and sustainable diets. Unfortunately, the primary energy expenditure outcome was substantially less than 150 kcal/d and it would have been unethical to retrospectively “move the goal posts” or emphasize exploratory outcomes that could possibly be interpreted as more favorable to the CIM.

Ludwig sets the bar far too low when he claims that a ~100 kcal/d effect size “would be of major scientific and clinical significance” for treatment of obesity. Ludwig bases this claim on a misunderstanding of the tiny “energy imbalance gap” between calorie intake and expenditure corresponding with the rise of population obesity prevalence Hall KD, 2011. This is especially puzzling since Ludwig himself used the same mathematical model calculations to conclude that development of obesity in adults requires an increased energy intake (or decreased expenditure) amounting to ~400-700 kcal/d Katan MB, 2010.

As described in my review, the carbohydrate-insulin model is clearly in need of reformulation regarding the predicted effects of isocaloric variations in dietary carbohydrate and fat on energy expenditure and body fat. However, other aspects of the model remain to be adequately investigated and reasonable ad hoc modifications of the model have been proposed. Finally, it is important to emphasize that regardless of whether the carbohydrate-insulin model is true or false, dietary carbohydrates and insulin may promote obesity and low carbohydrate diets may offer benefits for weight loss and metabolic health.

On 2017 Jan 17, DAVID LUDWIG commented:

In this review, Hall claims to have “falsified” the Carbohydrate-Insulin Model (CIM) of obesity as iterated by Mark Friedman and me in 2014 Ludwig DS, 2014. Hall describes this achievement as “rare” in nutritional science and analogous to the refutation of the “luminiferous ether” hypothesis of the 19th century. Elsewhere, he argues that the published data are so definitive as to warrant curtailment of further funding for macronutrient-focused obesity research Freedhoff Y, 2016. 

To loosely paraphrase Mark Twain, rumors of CIM’s demise have been greatly exaggerated.

Hall bases his case mainly on his two feeding studies, one small and short (6 days), the other small, non-randomized (i.e., observational) and designated a pilot.

In the discussion section of the 6-day study Hall KD, 2015, Hall and colleagues write: “Our relatively short-term experimental study has obvious limitations in its ability to translate to fat mass changes over prolonged durations” (NB: it can take the body weeks to fully adapt to a high fat diet Hawley JA, 2011 Vazquez JA, 1992 Veum VL, 2017). This appropriately cautious interpretation was evidently abandoned in the current review. Indeed, the study has numerous limitations beyond short duration, as reviewed elsewhere, including: 1) inability to directly document change in fat mass by DXA; 2) use of an exceptionally low fat content for the low-fat diet (< 8% of total energy), arguably without precedent in any population consuming natural diets; 3) use of a relatively mild restriction of carbohydrate (30% of total energy), well short of typical very-low-carbohydrate diets; and 4) experimental errors and exclusions of data that could confound findings. In addition, the investigators failed to verify biologically available energy of the diet (e.g., by analysis of the diets and stools for energy content). Rates of fat oxidation, the primary endpoint, are exquisitely sensitive to energy balance. A miscalculation of available energy for each diet of 5% in opposite directions could explain the study’s findings – and this possibility can’t be ruled out in studies of such short duration.

Hall’s non-randomized pilot Hall KD, 2016 potentially suffers from all the well-recognized limitations of small observational studies, importantly including confounding by any time-varying covariate. One such factor is miscalculation of energy requirements, leading to progressive weight loss that would have introduced bias against the very-low-carbohydrate diet. Other major design and interpretive limitations have been considered elsewhere.

Furthermore, Hall sets the bar for the CIM unrealistically high (i.e., 400 to 600 kcal/d greater total energy expenditure), citing speculative claims by non-scientists like Robert Atkins. In fact, effect estimates of 100 to 300 kcal/day – as demonstrated by Hall himself Hall KD, 2016 and by us Ebbeling CB, 2012 using doubly-labeled water – would be of major scientific and clinical significance if real, and do not represent "ad hoc modifications" to evade "falsification." (For comparison, Hall previously argued that the actual energy imbalance underlying the entire obesity epidemic is < 10 kcal/d Hall KD, 2011.)

To test the CIM, we need high-quality studies of adequate duration to eliminate transient biological processes (ideally ≥ 1 month); using a randomized-controlled design; with definitive measurements of body composition (e.g. DXA or MRI); and including appropriate process measures to assure that the diets are properly controlled for biologically available energy content. No such studies have yet been published. Thus, the CIM is neither proven nor “falsified” by existing data. In view of the complexity of diet, many high-quality studies will likely be needed to provide a complete answer to this question, versions of which have been debated for a century.

The CIM aims to explain a paradox: Body weight is controlled (“defended”) by biological factors affecting fat storage, hunger and energy expenditure Leibel RL, 1995. However, the average defended body weight has increased rapidly throughout the world among genetically stable populations. Lacking a definitive explanation for the ongoing obesity epidemic, or effective non-surgical treatment, we should not casually dismiss CIM, especially in light of many studies suggesting benefits of carbohydrate-modified/higher-fat diets for obesity Tobias DK, 2015 Mansoor N, 2016 Mancini JG, 2016 Sackner-Bernstein J, 2015 Bueno NB, 2013, cardiovascular disease Estruch R, 2013 and possibly longevity Wang DD, 2016.

On 2017 Jan 17, DAVID LUDWIG commented:

In this review, Hall claims to have “falsified” the Carbohydrate-Insulin Model (CIM) of obesity as iterated by Mark Friedman and me in 2014 Ludwig DS, 2014. Hall describes this achievement as “rare” in nutritional science and analogous to the refutation of the “luminiferous ether” hypothesis of the 19th century. Elsewhere, he argues that the published data are so definitive as to warrant curtailment of further funding for macronutrient-focused obesity research Freedhoff Y, 2016. 

To loosely paraphrase Mark Twain, rumors of CIM’s demise have been greatly exaggerated.

Hall bases his case mainly on his two feeding studies, one small and short (6 days), the other small, non-randomized (i.e., observational) and designated a pilot.

In the discussion section of the 6-day study Hall KD, 2015, Hall and colleagues write: “Our relatively short-term experimental study has obvious limitations in its ability to translate to fat mass changes over prolonged durations” (NB: it can take the body weeks to fully adapt to a high fat diet Hawley JA, 2011 Vazquez JA, 1992 Veum VL, 2017). This appropriately cautious interpretation was evidently abandoned in the current review. Indeed, the study has numerous limitations beyond short duration, as reviewed elsewhere, including: 1) inability to directly document change in fat mass by DXA; 2) use of an exceptionally low fat content for the low-fat diet (< 8% of total energy), arguably without precedent in any population consuming natural diets; 3) use of a relatively mild restriction of carbohydrate (30% of total energy), well short of typical very-low-carbohydrate diets; and 4) experimental errors and exclusions of data that could confound findings. In addition, the investigators failed to verify biologically available energy of the diet (e.g., by analysis of the diets and stools for energy content). Rates of fat oxidation, the primary endpoint, are exquisitely sensitive to energy balance. A miscalculation of available energy for each diet of 5% in opposite directions could explain the study’s findings – and this possibility can’t be ruled out in studies of such short duration.

Hall’s non-randomized pilot Hall KD, 2016 potentially suffers from all the well-recognized limitations of small observational studies, importantly including confounding by any time-varying covariate. One such factor is miscalculation of energy requirements, leading to progressive weight loss that would have introduced bias against the very-low-carbohydrate diet. Other major design and interpretive limitations have been considered elsewhere.

Furthermore, Hall sets the bar for the CIM unrealistically high (i.e., 400 to 600 kcal/d greater total energy expenditure), citing speculative claims by non-scientists like Robert Atkins. In fact, effect estimates of 100 to 300 kcal/day – as demonstrated by Hall himself Hall KD, 2016 and by us Ebbeling CB, 2012 using doubly-labeled water – would be of major scientific and clinical significance if real, and do not represent "ad hoc modifications" to evade "falsification." (For comparison, Hall previously argued that the actual energy imbalance underlying the entire obesity epidemic is < 10 kcal/d Hall KD, 2011.)

To test the CIM, we need high-quality studies of adequate duration to eliminate transient biological processes (ideally ≥ 1 month); using a randomized-controlled design; with definitive measurements of body composition (e.g. DXA or MRI); and including appropriate process measures to assure that the diets are properly controlled for biologically available energy content. No such studies have yet been published. Thus, the CIM is neither proven nor “falsified” by existing data. In view of the complexity of diet, many high-quality studies will likely be needed to provide a complete answer to this question, versions of which have been debated for a century.

The CIM aims to explain a paradox: Body weight is controlled (“defended”) by biological factors affecting fat storage, hunger and energy expenditure Leibel RL, 1995. However, the average defended body weight has increased rapidly throughout the world among genetically stable populations. Lacking a definitive explanation for the ongoing obesity epidemic, or effective non-surgical treatment, we should not casually dismiss CIM, especially in light of many studies suggesting benefits of carbohydrate-modified/higher-fat diets for obesity Tobias DK, 2015 Mansoor N, 2016 Mancini JG, 2016 Sackner-Bernstein J, 2015 Bueno NB, 2013, cardiovascular disease Estruch R, 2013 and possibly longevity Wang DD, 2016.

On 2017 Jan 31, Kevin Hall commented:

Science progresses through an iterative process of formulating models to explain our observations and subjecting those models to experimental interrogation. A single valid experimental result that runs counter to a model prediction falsifies the model and thereby requires its reformulation. Alternatively, refutation of an apparent model falsification requires demonstrating that the experimental observation was invalid.

My review of the carbohydrate-insulin model (CIM) presented a synthesis of the evidence from 20 inpatient controlled feeding studies strongly suggesting that at least some important aspects of the model are in need of modification. In particular, our recent studies Hall KD, 2015, Hall KD, 2016 employing carefully controlled inpatient isocaloric diets with constant protein, but differing in carbohydrate and fat, resulted in statistically significant differences between the diets regarding body fat and energy expenditure that were in directions opposite to predictions of the CIM.

Rather than using our experimental results as the basis for clarifying and reformulating the CIM, Ludwig challenges their validity and simply ignores the 18 other inpatient controlled feeding studies with their conforming body of results failing to support the energy expenditure or body fat predictions of the CIM.

Ludwig’s comments on the diets used in Hall KD, 2015 are irrelevant to whether they resulted in a valid test of the CIM predictions. We fed people diets that selectively reduced 30% of baseline calories solely by restricting either carbohydrate or fat. These diets achieved substantial differences in daily insulin secretion as measured by ~20% lower 24hr urinary C-peptide excretion with the reduced carbohydrate diet as compared with the reduced fat diet (p= 0.001) which was unchanged from baseline. Whereas the reduced fat diet resulted in no significant energy expenditure changes from baseline, carbohydrate restriction resulted in a ~100 kcal/d decrease in both daily energy expenditure and sleeping metabolic rate. These results were in direct opposition to the CIM predictions, but in accord with the previous studies described in the review as well as a subsequent study demonstrating that lower insulin secretion was associated with a greater reduction of metabolic rate during weight loss Muller MJ, 2015.

Ludwig erroneously claims that the study suffered from an “inability to directly document change in fat mass by DXA”, but DXA measurements indicated statistically significant reductions in body fat with both diets. While DXA was not sufficiently precise to detect significant differences between the diets, even this null result runs counter to the predicted greater body fat loss with the reduced carbohydrate diet. Importantly, the highly sensitive fat balance technique demonstrated small but statistically significant differences in cumulative body fat loss (p<0.0001) in the direction opposite to the CIM predictions. Ludwig claims that our results are invalid because “rates of fat oxidation, the primary endpoint, are exquisitely sensitive to energy balance. A miscalculation of available energy for each diet of 5% in opposite directions could explain the study’s findings.” However, it is highly implausible that small uncertainties in the metabolizable energy content of the diet amounting to <100 kcal/d could explain the >400 kcal/d (p<0.0001) measured difference in daily fat oxidation rate. Furthermore, our results were robust to the study errors and exclusions fully reported in Hall KD, 2015 and clearly falsified important aspects of the CIM.

We previously responded Hall KD, 2016b to Ludwig’s comments Ludwig DS, 2016 on our ketogenic diet study. Ludwig now argues that we set the bar too high regarding the energy expenditure predictions of the CIM based on “speculative claims by non-scientists like Robert Atkins”. But scientists well-known for promoting low carb diets have claimed that “very low carbohydrate diets, in their early phases, also must supply substantial glucose to the brain from gluconeogenesis…the energy cost, at 4–5 kcal/gram could amount to as much as 400–600 kcal/day” Fine EJ, 2004. Ludwig also sets the energy expenditure bar quite high in his New York Times opinion article, JAMA commentary, and book “Always Hungry” where he claims to have demonstrated a 325 kcal/d increase in expenditure in accordance with the CIM predictions Ebbeling CB, 2012. What Ludwig fails to mention is that such an interpretation is confounded by the low-carbohydrate diet having 50% greater dietary protein which is well-known to increase expenditure. Ludwig also doesn’t mention that his study failed to demonstrate a significant effect on either resting or daily energy expenditure when comparing diets with the same protein content, but varying in carbohydrate and fat.

What was the energy expenditure bar set by our ketogenic diet study Hall KD, 2016? The clinical protocol specified that the primary daily energy expenditure outcome (measured by room calorimetry) must increase by >150 kcal/d to be considered physiologically meaningful. With the agreement of funders at the Nutrition Science Initiative, notable proponents of the CIM, the pre-specified 150 kcal/d threshold was used to calculate number of study subjects required to estimate the energy expenditure effect size in a homogeneous population of men consuming an extremely low carbohydrate diet. If the measured effect size exceeded 150 kcal/d then the results could be reasonably interpreted as a physiologically important increase in energy expenditure worthy of future study in a wider population using a more realistic and sustainable diets. Unfortunately, the primary energy expenditure outcome was substantially less than 150 kcal/d and it would have been unethical to retrospectively “move the goal posts” or emphasize exploratory outcomes that could possibly be interpreted as more favorable to the CIM.

Ludwig sets the bar far too low when he claims that a ~100 kcal/d effect size “would be of major scientific and clinical significance” for treatment of obesity. Ludwig bases this claim on a misunderstanding of the tiny “energy imbalance gap” between calorie intake and expenditure corresponding with the rise of population obesity prevalence Hall KD, 2011. This is especially puzzling since Ludwig himself used the same mathematical model calculations to conclude that development of obesity in adults requires an increased energy intake (or decreased expenditure) amounting to ~400-700 kcal/d Katan MB, 2010.

As described in my review, the carbohydrate-insulin model is clearly in need of reformulation regarding the predicted effects of isocaloric variations in dietary carbohydrate and fat on energy expenditure and body fat. However, other aspects of the model remain to be adequately investigated and reasonable ad hoc modifications of the model have been proposed. Finally, it is important to emphasize that regardless of whether the carbohydrate-insulin model is true or false, dietary carbohydrates and insulin may promote obesity and low carbohydrate diets may offer benefits for weight loss and metabolic health.

On 2017 Feb 03, DAVID LUDWIG commented:

In his comment of January 31, 2017, Hall presses an extreme argument, that he successfully "falsified" major aspects of the Carbohydrate-Insulin Model (CIM) of obesity, and complains that opponents won't embrace their error. His argument boils down to 3 points:

First, Hall’s small 6-day study and his small, “observational,” “pilot” study are fundamentally correct. Regarding the 6-day study Hall KD, 2015, he continues to insist that results of a very short intervention have relevance to understanding the long-term effects of macronutrients on body composition, despite evidence that adaptation to a higher-fat diet can take at least a week and perhaps considerably longer Hawley JA, 2011 Vazquez JA, 1992 Veum VL, 2017. (We need look no further than his observational study Hall KD, 2016, to see in Figure 2B that the transient decrease in rate of fat loss upon initiation of the low-carbohydrate diet accelerates after 2 weeks.) Of note, the 36 g/d greater predicted body fat loss on his low-fat diet would, if persistent, translate into a massive advantage in adiposity after just one year. If anything, the meta-analyses of long-term clinical trials suggest the opposite Tobias DK, 2015 Mansoor N, 2016 Mancini JG, 2016 Sackner-Bernstein J, 2015 Bueno NB, 2013. Furthermore, Hall’s two studies are mutually inconsistent: The 6-day study implies a major increase in energy expenditure from fat oxidation on the low-fat diet, whereas the observational study shows an increase in energy expenditure after 2 weeks (by doubly-labeled water) on the low-carbohydrate diet. Other limitations of his observational study have been considered elsewhere.

Second, our randomized 3-arm cross-over study Ebbeling CB, 2012 is fundamentally wrong. I’ve addressed Hall’s concerns elsewhere. Here, he reiterates that the 10% difference in protein content (intended by design to reflect the Atkins diet) could account for our observed 325 kcal/d difference in energy expenditure. However, there is no basis in the literature for this belief. Among 10 studies published at the time of our feeding trial in which protein intake was compared within the physiological range (10 to 35% of total energy), energy expenditure on the higher vs. lower protein diets ranged from +95 kcal/d to -97 kcal/d, with the mean difference of near zero Dulloo AG, 1999 Hochstenbach-Waelen A, 2009 Lejeune MP, 2006 Luscombe ND, 2003 Mikkelsen PB, 2000 Veldhorst MA, 2009 Veldhorst MA, 2010 Westerterp KR, 1999 Westerterp-Plantenga MS, 2009 Whitehead JM, 1996. Though these studies have methodological limitations themselves, the finding is consistent with thermodynamic considerations that indicate a very minor increment in the "thermic effect of food" from a 10% increase in protein.

Third, 18 other studies provide definitive support his position. This facile contention disregards that these studies are riddled with the same inherent limitations as his studies, including a combination of short duration, highly limited power, indirect measurements of body composition, reliance on metabolic chambers (which have been shown to underestimate adaptive thermogenesis compared to doubly-labeled water Rosenbaum M, 1996), quality control concerns and other issues. Of the cited studies, six were 1 to 4 days Astrup A, 1994 Dirlewanger M, 2000 Davy KP, 2001 Smith SR, 2000 Thearle MS, 2013 Yerboeket-van de Venne WP, 1996, seven were 7 to 15 days Horton TJ, 1995 Shepard TY, 2001 Eckel RH, 2006 Hill JO, 1991 Schrauwen P, 1997 Treuth MS, 2003 Yang MU, 1976, and just five were 4 to 6 weeks. One of these longer studies was based on recovered data from about 30 years prior to publication, with no direct measurements of body composition or energy expenditure Leibel RL, 1992. The other four longer studies employed severe calorie restriction, which would plausibly obscure macronutrient effects over this short duration. Two of these studies had just 4 subjects per diet group Rumpler WV, 1991 Bogardus C, 1981. The remaining two showed either a non-significant (2 kg lower total body fat) Golay A, 1996 or significant (30 cc lower visceral fat) Miyashita Y, 2004 advantage for the lower-carbohydrate diet. We’ve been down this road before, with the launch of the 40-year low-fat diet era based on over-interpretation of methodologically limited research. Let’s not make the same mistake again.

Even as he over-interprets the short-term feeding studies, Hall disregards extensive animal research, high quality observational studies, mechanistic studies, and clinical trials in support of CIM, as summarized here and elsewhere Ludwig DS, 2014 Lucan SC, 2015 Templeman NM, 2017.

Finally, Hall claims that I misunderstand the notion of “energy gap.” As both Hall and I Katan MB, 2010 have considered elsewhere, a decrease in energy intake produces a compensatory decrease in energy expenditure, resulting in less weight loss than would be predicted from the simple observation that a pound of fat contains 3500 kcal. However, here we consider the opposite phenomenon – an increase in energy expenditure resulting from changing dietary quality, not quantity. There is no reason to believe that compensatory increases in energy intake would occur as a result of faster metabolic rate over a similar time frame as that observed with compensatory changes to energy restriction. (Indeed, Hall himself acknowledges the possibility that low-carbohydrate diets might also lower energy intake.) Of course, progressive weight loss regardless of cause would eventually reduce energy expenditure, but we cannot infer from current data when that energy gap would reach zero. Even with conventional assumptions, NIDDK’s Body Weight Planner indicates the 150 kcal/d change in energy balance Hall found on the low-carbohydrate diet by doubly-labeled water would produce more than a 15 lb weight loss for a typical individual over several years – amounting to half the mean change in weight that occurred during the obesity epidemic in the U.S. Why would we dismiss findings with such major potential public health significance?

Hall's premature claims of (at least partial) victory and calls for curtailment of funding for more research Freedhoff Y, 2016 do not do justice to a complicated scientific question. In view of the failure of conventional obesity treatment and the massive public health challenges, all participants in this debate would do well to acknowledge the limitations of existing evidence and join in the design of more definitive research.

On 2017 Feb 04, Kevin Hall commented:

Is it really an “extreme argument” to conclude that important aspects of the carbohydrate-insulin model (CIM) have been falsified based on data from 20 highly controlled inpatient human feeding studies that failed to support key CIM model predictions? While previously ignoring this conforming body of data from other research groups, Ludwig now conveniently concludes that all of these studies were flawed in some way and are therefore irrelevant and incapable of testing any aspect of the carbohydrate-insulin model.

To Ludwig, more relevant for assessing the energy expenditure and body fat predictions of the CIM are rodent studies and outpatient human studies where diet adherence cannot be adequately controlled or assessed Winkler JT, 2005. One such study Ludwig uses to bolster the CIM Ebbeling CB, 2012 did not measure body fat during the test diets and showed no significant energy expenditure differences between diets with the same amount of protein but varying in carbohydrate vs. fat. Ludwig claims that the study supports the CIM because energy expenditure was observed to increase with a very low carbohydrate diet. But the concomitant 50% increase in protein vs. the comparator diets makes it impossible to definitively conclude that any observed effect was due to carbohydrate reduction alone. Ludwig’s arguments about the possibly minimal effects of dietary protein changes on energy expenditure cannot eliminate this important confound.

Ludwig argues that “adaptation to a higher-fat diet can take at least a week and perhaps considerably longer”. One of Ludwig’s citations in this regard describes the role of diet composition on fuel utilization and exercise performance Hawley JA, 2011. This review paper reported that adaptation to a high fat diet for <1 week was sufficient to alter fuel utilization, but 4-7 days of fat adaptation was required to maintain subsequent exercise performance. Interestingly, longer periods of fat adaptation during training (7 weeks) were concluded to limit exercise capacity and impair exercise performance. The other two studies Ludwig cited to support the necessity for long term fat adaptation fail to support the CIM. An inpatient controlled feeding study Vasquez JA, 1992 showed that a very low carbohydrate, high fat diet led to significantly greater loss of body protein and lean tissue mass despite no significant difference in weight loss compared to an isocaloric higher carbohydrate, lower fat diet. The second study was an outpatient feeding trial Velum VL, 2017 that failed to demonstrate a significant difference in body weight or fat loss despite prescribing diets substantially varying in carbohydrate vs. fat for 3 months.

I agree with Ludwig that it likely takes a long time to equilibrate to added dietary fat without simultaneously reducing carbohydrate because, unlike carbohydrate and protein, dietary fat does not directly promote its own oxidation and does not significantly increase daily energy expenditure Schutz Y, 1989 and Horton TJ, 1995. Unfortunately, these observations also run counter to CIM predictions because they imply that added dietary fat results in a particularly efficient means to accumulate body fat compared to added carbohydrate or protein Bray GA, 2012. If such an added fat diet is sustained, adipose tissue will continue to expand until lipolysis is increased to sufficiently elevate circulating fatty acids and thereby increase daily fat oxidation to reestablish balance with fat intake Flatt JP, 1988.

In contrast, when added fat is accompanied by an isocaloric reduction in carbohydrate, daily fat oxidation plateaus within the first week as indicated by the rapid and sustained drop in daily respiratory quotient in Hall KD, 2016 and Schrauwen P, 1997. Similarly, Hall KD, 2015 observed a decrease and plateau in daily respiratory quotient with the reduced carbohydrate diet, whereas the reduced fat diet resulted in no significant changes indicating that daily fat oxidation was unaffected. As further evidence that adaptations to carbohydrate restriction occur relatively quickly, adipose tissue lipolysis is known to reach a maximum within the first week of a prolonged fast Bortz WM, 1972 as does hepatic ketone production Balasse EO, 1989.

While there is no evidence that carbohydrate restricted diets lead to an acceleration of daily fat oxidation on time scales longer than 1 week, and there is no known physiological mechanism for such an effect, this possibility cannot be ruled out. Such speculative long term effects constitute an ad hoc modification of the carbohydrate-insulin model whereby repeated violations of model predictions on time scales of 1 month or less are somehow reversed.

As I have repeatedly acknowledged, prescribing lower carbohydrate diets in free-living subjects generally leads to greater loss of weight and body fat over the short-term when people are likely adhering most closely to the diet prescriptions. The CIM suggests that such diets offer a “metabolic advantage” that substantially increases energy expenditure and body fat loss even if diet calories are equal. However, inpatient controlled feeding studies do not support this contention as they have repeatedly failed to show significant differences in energy expenditure and body fat. Furthermore, such studies have occasionally measured significant differences in diametrically opposite directions than were predicted on the basis of carbohydrate intake and insulin secretion. These apparent falsifications of the CIM do not imply that dietary carbohydrates and insulin are unimportant for energy expenditure and body fat regulation. Rather, their role is more complicated than the CIM suggests and the model requires thoughtful modification.

On 2017 Feb 04, DAVID LUDWIG commented:

Boiling down his comment of 3 Feb 2017, Hall disputes that the metabolic process of adapting to a high-fat/low-carbohydrate diet confounds interpretation of his and other short term feeding studies. If we can provide evidence that this process could take ≥ 1 week, the last leg of his attack on the Carbohydrate-Insulin Model collapses. Well, a picture is worth a thousand words, and here are 4:

For convenience, these figures can be viewed at this link:

Owen OE, 1983 Figure 1. Ketones are, of course, the hallmark of adaptation to a low-carbohydrate ketogenic diet. Generally speaking, the most potent stimulus of ketosis is fasting, since the consumption of all gluconeogenic precursors (carbohydrate and protein) is zero. As this figure shows, the blood levels of each of the three ketone species (BOHB, AcAc and acetone) continues to rise for ≥3 weeks. Indeed, the prolonged nature of adaptation to complete fasting has been known since the classic starvation studies of Cahill GF Jr, 1971. It stands to reason that this process might take even longer on standard low-carbohydrate diets, which inevitably provide ≥ 20 g carbohydrate/d and substantial protein.

Yang MU, 1976 Figure 3A. Among men with obesity on an 800 kcal/d ketogenic diet (10 g/d carbohydrate, 50 g/d protein), urinary ketones continued to rise for 10 days through the end of the experiment, and by that point had achieved levels equivalent only to those on day 4 of complete fasting. Presumably, this process would be even slower with a non-calorie restricted ketogenic diet (because of inevitably higher carbohydrate and protein content).

Vazquez JA, 1992 Figure 5B. On a conventional high-carbohydrate diet, the brain is critically dependent on glucose. With acute restriction of dietary carbohydrate (by fasting or a ketogenic diet), the body obtains gluconeogenic precursors by breaking down muscle. However, with rising ketone concentrations, the brain becomes adapted, sparing glucose. In this way, the body shifts away from protein to fat metabolism, sparing lean tissue. This phenomenon is clearly depicted among women with obesity given a calorie-restricted ketogenic diet (10 g carbohydrate/d) vs a nonketogenic diet (76 g carbohydrate/d), both with protein 50 g protein/d. For 3 weeks, nitrogen balance was strongly negative on the ketogenic diet compared to the non-ketogenic diet, but this difference was completely abolished by week 4. What would subsequently happen? We simply can’t know from the short-term studies.

Hall KD, 2016 Figure 2B. Hall’s own study shows that the transient decrease in rate of fat loss upon initiation of the ketogenic diet accelerates after 2 weeks.

The existence of this prolonged adaptive process explains why metabolic advantages for low-fat diet are consistently seen in very short metabolic studies. But after 2 to 4 weeks, advantages for low-carbohydrate diets begin to emerge, as summarized in my comment of 3 Feb 2017, below.

Fat adaptation on low-carbohydrate diets has admittedly not been thoroughly studied, and its duration may differ among individuals and between experimental conditions. Nevertheless, there is strong reason to think that short feeding studies (i.e., < 3 to 4 weeks) have no relevance to the long-term effects of macronutrients on metabolism and body composition.

On 2017 Feb 05, Kevin Hall commented:

Ludwig suggests that demonstration of any metabolic adaptations occurring on a time scale of > 1 week after introduction of an isocaloric low carbohydrate diet somehow invalidates all of the inpatient controlled feeding studies with results that violate carbohydrate-insulin model (CIM) predictions. This presents a false dilemma and is a red herring.

There are indeed metabolic adaptations that take place on longer time scales, but many of these changes actually support the conclusion that the purported metabolic advantages for body fat loss predicted by the CIM are inconsistent with the data. For example, as evidence for a prolonged period of fat adaptation, Ludwig notes modest additional increases in blood and urine ketones observed after 1 week of either starvation Owen OE, 1983 or consuming a hypocaloric ketogenic diet Yang MU, 1976. The implication is that daily fat and ketone oxidation presumably increase along with their blood concentrations over extended time periods to eventually result in an acceleration of body fat loss with low carbohydrate high fat diets as predicted by the CIM. But since acceleration of fat loss during prolonged starvation would be counterproductive to survival, might there be data supporting a more physiological interpretation the prolonged increase in blood and urine ketones?

Both adipose lipolysis Bortz WM, 1972 and hepatic ketone production Balasse EO, 1989 reach a maximum within 1 week as demonstrated by isotopic tracer data. Therefore, rising blood ketone concentrations after 1 week must be explained by a reduced rate of removal from the blood. Indeed, muscle ketone oxidation decreases after 1 week of starvation and, along with decreased overall energy expenditure, the reduction in ketone oxidation results in rising blood concentrations and increased urinary excretion (page 144-152 of Burstztein S, et al. ‘Energy Metabolism, Indirect Calorimetry, and Nutrition.’ Williams & Wilkins 1989). Therefore, rather than being indicative of progressive mobilization of body fat to increase oxidation and accelerate fat loss, rising concentrations of blood ketones and fatty acids occurring after 1 week arise from reductions in ketone and fat oxidation concomitant with decreased energy expenditure.

The deleterious effects of a 600 kcal/d low carbohydrate ketogenic diet on body protein and lean mass were demonstrated in Vasquez JA, 1992 and were found to last about 1 month. Since weight loss was not significantly different compared to an isocaloric higher carbohydrate diet, body fat loss was likely attenuated during the ketogenic diet and therefore in direct opposition to the CIM predictions. Subsequent normalization of nitrogen balance would tend to result in an equivalent rate of body fat loss between the isocaloric diets over longer time periods. In Hall KD, 2016, urinary nitrogen excretion increased for 11 days after introducing a 2700 kcal/d ketogenic diet and coincided with attenuated body fat loss measured during the first 2 weeks of the diet. The rate of body fat loss appeared to normalize in the final 2 weeks, but did not exceed the fat loss observed during the isocaloric high carbohydrate run-in diet. Mere normalization of body fat and lean tissue loss over long time periods cannot compensate for early deficiencies. Therefore, these data run against CIM predictions of augmented fat loss with lower carbohydrate diets.

While I believe that outpatient weight loss trials demonstrate that low carbohydrate diets often outperform low fat diets over the short-term, there are little body weight differences over the long-term Freedhoff Y, 2016. However, outpatient studies cannot ensure or adequately measure diet adherence and therefore it is unclear whether greater short-term weight losses with low carbohydrate diets were due to reduced diet calories or the purported “metabolic advantages” of increased energy expenditure and augmented fat loss predicted by the CIM. The inpatient controlled feeding studies demonstrate that the observed short-term energy expenditure and body fat changes often violate CIM predictions.

Ludwig conveniently suggests that all existing inpatient controlled feeding studies have been too short and that longer duration studies might produce results more favorable to the CIM. But even this were true, the current data demonstrating repeated violations of CIM model predictions constitute experimental falsifications of the CIM requiring an ad hoc modification of the model such that the metabolic advantages only begin after a time lag lasting many weeks. This is possible, but unlikely.

On 2017 Feb 05, DAVID LUDWIG commented:

With Hall’s comment of 4 Feb 2017, this long debate nears resolution. He acknowledges it’s “possible” that the very short metabolic studies do not reflect the long-term effects of macronutrients on body weight. We disagree on how likely that possibility is, and now must await further research to resolve the scientific uncertainties.

Finally, on an issue of academic interest only, Hall creates a straw man in claiming to have “falsified” the Carbohydrate-Insulin Model (CIM). Versions of CIM were originally proposed more than a century ago, as detailed by Taubes G, 2013, before short term studies of substrate oxidation would have been possible. Furthermore, in the second paragraph of his review, Hall cites an article I coauthored Ludwig DS, 2014 and three by others Lustig RH, 2006, Taubes G, 2013, Wells JC, 2011 as recent iterations of CIM. Each of these articles focuses on long-term effects, and none asserts that 1 week should be adequate to prove or falsify CIM. In view of the failure of conventional approaches to address the massive public health challenge of obesity, let’s now refocus our energies into the design and execution of more definitive research.

On 2017 Feb 05, Kevin Hall commented:

The theoretical basis of the carbohydrate-insulin model (CIM) relies on generally accepted physiology about endocrine regulation of adipose tissue– data that were all collected on short time scales. Ludwig appears to suggest that this long debate has been about a “straw man” short-term version of the CIM. This apparently explains why the purported metabolic advantages have been elusive when assessed by inpatient controlled feeding studies that were simply too short to unveil the metabolic advantages of the CIM. Indeed, Ludwig believes he has scored a win in this debate by acknowledging that these metabolic advantages of low carbohydrate diets on energy expenditure and body fat predicted by the CIM must operate on longer time scales, conveniently where no inpatient data have been generated either supporting or negating those predictions. This was accurately described in my review as an ad hoc modification of the CIM – a possibility currently unsupported by data but obviously supported by sincere belief.