On 2017 Feb 09, Kevin Hall commented:

The theoretical basis of the carbohydrate-insulin model (CIM) relies on generally accepted physiology about the endocrine regulation of adipose tissue based on short-term experiments lasting days and weeks. While there are indeed metabolic adaptations that take place on longer time scales, 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.

Ludwig uses linear extrapolation to claim that our data “would imply a 13 kg greater body fat loss versus the higher-fat diet over a year”. However, the same computational model that correctly predicted the difference in short-term body fat loss projected only small differences in long-term body fat between the diets. Based on these model simulations we concluded that “the body acts to minimize body fat differences with prolonged isocaloric diets varying in carbohydrate and fat.”

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 demonstrate repeated violations of CIM model predictions and constitute experimental falsifications of the CIM. This possibility was accurately described in my review Hall KD, 2017 and requires an ad hoc modification of the CIM such that the metabolic advantages of isocaloric lower carbohydrate diets only begin after a time lag lasting many weeks – a possibility currently unsupported by data but obviously supported by sincere belief.

On 2017 Feb 07, DAVID LUDWIG commented:

In his comment of 31 January 2017, Hall continues to insist that the results of his 6-day study and other very short feeding studies of substrate oxidation inform understanding of the long-term relationship between diet and body composition. This contention can be simply dismissed, with recognition that the 36 g/d advantage in fat oxidation on Hall’s low-fat diet would imply a 13 kg greater body fat loss versus the higher-fat diet over a year. There is simply no precedent for such an effect, and if anything the long-term clinical trials suggest the opposite Tobias DK, 2015 Mansoor N, 2016 Mancini JG, 2016 Sackner-Bernstein J, 2015 Bueno NB, 2013.

The reason short term studies of high-fat diets are misleading is that the process of adapting to reduced carbohydrate intake can take several weeks. We can clearly observe this phenomenon in 4 published graphs involving very-low-carbohydrate diets.

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 very-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 process 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. Another study by Hall 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, Hall KD, 2016 Miyashita Y, 2004 Ebbeling CB, 2012. Any meaningful conclusions about the long-term effects of macronutrients must await longer studies.

On 2017 Jan 31, Kevin Hall commented:

My recent review of the carbohydrate-insulin model Hall KD, 2017 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 carbohydrate-insulin model.

Ludwig comments that the diets used in Hall KD, 2015 were either too low in fat or insufficiently low in carbohydrate. However, while these considerations may be clinically important for sustainability of the diets, they are irrelevant to whether the diets resulted in a valid test of the carbohydrate-insulin model predictions. We 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 carbohydrate-insulin model 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.

While the DXA methodology was not sufficiently precise to detect significant differences in body fat loss 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 carbohydrate-insulin model 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 described in the report and our observations clearly falsified important aspects of the carbohydrate-insulin model.

Ludwig argues that “it can take the body weeks to fully adapt to a high fat diet”, However, daily fat oxidation has been observed to plateau within the first week when added dietary fat is accompanied by an isocaloric reduction in carbohydrate 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 violations of model predictions on time scales of 1 month or less are somehow reversed.

Ludwig is correct that it takes the body a long time to equilibrate to added dietary fat 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 run counter to carbohydrate-insulin model 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.

Of course, differences in long term ad libitum food intake between diets varying in macronutrient composition could either obviate or amplify any predicted body fat differences based solely on fat oxidation or energy expenditure considerations. Such mechanisms warrant further investigation and will inform improved models of obesity. Nevertheless, it is clear that several important aspects of the carbohydrate-insulin model have been experimentally falsified by a variety of studies, including Hall KD, 2015.

On 2017 Jan 17, DAVID LUDWIG commented:

In a recent review, the first author of this Cell Metabolism article (Kevin Hall) cites this 6-day study as a basis for having “falsified” the Carbohydrate-Insulin Model of obesity. That argument disregards some key limitations of this study, which warrant elucidation.

In the discussion section of this study, 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). Beyond short duration and confounding by transient biological adaptations, the study: 1) did not find a difference in actual fat mass by DXA (p=0.78); 2) used an exceptionally low fat content for the low-fat diet (< 8% of total energy), arguably without precedent in any population consuming natural diets; 3) used a relatively mild restriction of carbohydrate (30% of total energy), well short of typical very-low-carbohydrate diets; 4) had protocol errors and post-randomization data exclusions that could confound findings; and 5) failed to verify biologically available energy of the diet (e.g., by analysis of the diets and stools for energy content). Regarding this last point, 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.

Thus, this study should not be interpreted as providing a definitive test of the Carbohydrate-Insulin Model.

On 2017 Jan 17, DAVID LUDWIG commented:

In a recent review, the first author of this Cell Metabolism article (Kevin Hall) cites this 6-day study as a basis for having “falsified” the Carbohydrate-Insulin Model of obesity. That argument disregards some key limitations of this study, which warrant elucidation.

In the discussion section of this study, 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). Beyond short duration and confounding by transient biological adaptations, the study: 1) did not find a difference in actual fat mass by DXA (p=0.78); 2) used an exceptionally low fat content for the low-fat diet (< 8% of total energy), arguably without precedent in any population consuming natural diets; 3) used a relatively mild restriction of carbohydrate (30% of total energy), well short of typical very-low-carbohydrate diets; 4) had protocol errors and post-randomization data exclusions that could confound findings; and 5) failed to verify biologically available energy of the diet (e.g., by analysis of the diets and stools for energy content). Regarding this last point, 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.

Thus, this study should not be interpreted as providing a definitive test of the Carbohydrate-Insulin Model.

On 2017 Jan 31, Kevin Hall commented:

My recent review of the carbohydrate-insulin model Hall KD, 2017 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 carbohydrate-insulin model.

Ludwig comments that the diets used in Hall KD, 2015 were either too low in fat or insufficiently low in carbohydrate. However, while these considerations may be clinically important for sustainability of the diets, they are irrelevant to whether the diets resulted in a valid test of the carbohydrate-insulin model predictions. We 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 carbohydrate-insulin model 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.

While the DXA methodology was not sufficiently precise to detect significant differences in body fat loss 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 carbohydrate-insulin model 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 described in the report and our observations clearly falsified important aspects of the carbohydrate-insulin model.

Ludwig argues that “it can take the body weeks to fully adapt to a high fat diet”, However, daily fat oxidation has been observed to plateau within the first week when added dietary fat is accompanied by an isocaloric reduction in carbohydrate 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 violations of model predictions on time scales of 1 month or less are somehow reversed.

Ludwig is correct that it takes the body a long time to equilibrate to added dietary fat 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 run counter to carbohydrate-insulin model 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.

Of course, differences in long term ad libitum food intake between diets varying in macronutrient composition could either obviate or amplify any predicted body fat differences based solely on fat oxidation or energy expenditure considerations. Such mechanisms warrant further investigation and will inform improved models of obesity. Nevertheless, it is clear that several important aspects of the carbohydrate-insulin model have been experimentally falsified by a variety of studies, including Hall KD, 2015.

On 2017 Feb 07, DAVID LUDWIG commented:

In his comment of 31 January 2017, Hall continues to insist that the results of his 6-day study and other very short feeding studies of substrate oxidation inform understanding of the long-term relationship between diet and body composition. This contention can be simply dismissed, with recognition that the 36 g/d advantage in fat oxidation on Hall’s low-fat diet would imply a 13 kg greater body fat loss versus the higher-fat diet over a year. There is simply no precedent for such an effect, and if anything the long-term clinical trials suggest the opposite Tobias DK, 2015 Mansoor N, 2016 Mancini JG, 2016 Sackner-Bernstein J, 2015 Bueno NB, 2013.

The reason short term studies of high-fat diets are misleading is that the process of adapting to reduced carbohydrate intake can take several weeks. We can clearly observe this phenomenon in 4 published graphs involving very-low-carbohydrate diets.

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 very-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 process 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. Another study by Hall 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, Hall KD, 2016 Miyashita Y, 2004 Ebbeling CB, 2012. Any meaningful conclusions about the long-term effects of macronutrients must await longer studies.

On 2017 Feb 09, Kevin Hall commented:

The theoretical basis of the carbohydrate-insulin model (CIM) relies on generally accepted physiology about the endocrine regulation of adipose tissue based on short-term experiments lasting days and weeks. While there are indeed metabolic adaptations that take place on longer time scales, 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.

Ludwig uses linear extrapolation to claim that our data “would imply a 13 kg greater body fat loss versus the higher-fat diet over a year”. However, the same computational model that correctly predicted the difference in short-term body fat loss projected only small differences in long-term body fat between the diets. Based on these model simulations we concluded that “the body acts to minimize body fat differences with prolonged isocaloric diets varying in carbohydrate and fat.”

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 demonstrate repeated violations of CIM model predictions and constitute experimental falsifications of the CIM. This possibility was accurately described in my review Hall KD, 2017 and requires an ad hoc modification of the CIM such that the metabolic advantages of isocaloric lower carbohydrate diets only begin after a time lag lasting many weeks – a possibility currently unsupported by data but obviously supported by sincere belief.