Today, December 31, 2021, marks the official dissolution of the Nutrition Science Initiative (NuSI.org).
Founded in 2011 with support from the Laura and John Arnold Foundation, the Nutrition Science Initiative funded four projects — three in full and one in part — on the relationship between nutrition, obesity and metabolic diseases. Three of these studies were randomized clinical trials; the fourth was a non-randomized pilot trial. All four resulted in primary publications in top-tier journals (two in JAMA and one each in AJCN and BMJ), all with significant media attention. Three of these papers are now designated “highly cited papers” by the Clarivate Web of Science. These four trials also spawned two dozen ancillary studies, secondary analyses and commentaries, and those, too, generated a fair share of attention from the media. The latest of these — on the effect of dietary sugar on hepatic de novo lipogenesis in pediatric non-alcoholic fatty liver disease – was published just two weeks ago in The Journal of Clinical Investigation.
We’d like to think that NuSI’s research, funding, and general pot-stirring helped move the needle, not just on nutrition research in obesity and metabolic disease but on the thinking about etiology and dietary means of treatment and prevention.
We’ll leave it to the historians to determine whether and to what degree that’s the case.
For those interested in the four NuSI studies, references and summaries are below, listed in order of the very first publication date.
I. Energy Balance Consortium Pilot Study
Principal Investigators: Kevin Hall (National Institutes of Health, NIDDK), Rudolph Leibel (Columbia University Medical College), Eric Ravussin (Pennington Biomedical Research Center), Marc Reitman (National Institutes of Health, NIDDK), Michael Rosenbaum (Columbia University Medical College), Steven Smith (Translational Research Institute for Metabolism and Diabetes)
Hall, K. D., Chen, K. Y., Guo, J., Lam, Y. Y., Leibel, R. L., Mayer, L. E., Reitman, M. L., Rosenbaum, M., Smith, S. R., Walsh, B. T., & Ravussin, E. (2016). Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men. The American Journal of Clinical Nutrition, 104(2), 324–333. https://doi.org/10.3945/ajcn.116.133561
Studies in free-living individuals are crucial to determine the effectiveness of dietary strategies to prevent or treat obesity and related metabolic conditions under real-world conditions. Such studies can provide tests of hypotheses about the cause of these disorders; however rigorous testing of these hypotheses requires greater control over the diets of study subjects than free-living studies permit. In practical terms, this means housing study participants in a facility where their diet is precisely defined, their food intake measured accurately, and their physical activity better controlled and monitored.
As a first step toward a rigorous test of the energy balance hypothesis of obesity – that foods influence fat accumulation only through the amount, but not type, of calories consumed – NuSI organized and funded a consortium of investigators to conduct a small preliminary or “pilot” study using participants confined to metabolic wards. The consortium researchers deemed it unlikely that they could reliably detect meaningful changes in body weight or fat content in an 8-week trial and instead chose to use energy expenditure as the primary outcome of the study.
To test the question of whether the amount or type of calories consumed is critical, participants were fed an equal number of calories from diets differing dramatically in fat and carbohydrate content. In addition to generating useful preliminary data that might address the hypothesis and help determine the number of subjects required for a full-scale study, the goals of this pilot study were operational and methodological: optimize the logistics required for a multi-site study, including, importantly, the assessment and fine-tuning of the precision and sensitivity of techniques for measuring energy expenditure.
A total of 17 male participants, overweight or obese, were housed in metabolic wards at four study sites. For 4 weeks they were fed a basal diet based on a standard American diet (50% carbohydrate, 35% fat, and 15% protein by calories) providing a number of calories intended to maintain them in energy balance as reflected by a stable body weight. Participants were then switched to a “ketogenic” diet of identical caloric content, but radically different macronutrient composition (5% carbohydrate, 80% fat, and 15% protein by calories). Energy expenditure was measured two ways: (i) by respirometry in which participants were housed in small room-sized metabolic chambers for two consecutive days each week throughout the study, and (ii) over the last 2 weeks of each diet period, by a technique known as doubly labeled water that does not require chamber confinement.
If, according to the energy balance hypothesis, fat accumulation depended only on the amount of available energy in the foods consumed – if a calorie of carbohydrate is equally fattening as a calorie of fat – no difference would be expected in energy expenditure under the two diet conditions. However, because the very low-carbohydrate ketogenic diet would minimize secretion of insulin, a hormone that promotes the synthesis and storage of fat, an alternative hypothesis (known as the carbohydrate-insulin model or the hormonal/regulatory model of obesity) predicts that energy expenditure will increase during the ketogenic diet period as stored fat is mobilized from stored body fat and burned for fuel along with fat from the diet.
The results showed that energy expenditure measured in the metabolic chambers increased transiently during the first two weeks after the switch to the ketogenic diet by 60 to 100 kcal/day, depending on how expenditures were calculated relative to body weight or composition. As measured by doubly labeled water, energy expenditure increased during the last two weeks of the ketogenic diet period by 150 kcal/day, an observation that is difficult to reconcile with the energy balance, calorie-is-a-calorie perspective.
Interpretation of the results is confounded by limitations of this small pilot study:
- Because the order in which diets were fed to participants were not randomized, no causal inference can be made about the role of diet composition as a cause of any change in energy expenditure. Strictly speaking, the results can be interpreted only in terms of before and after the diet switch and not necessarily because of the switch.
- Although the study plan was to have subjects in energy balance during the end of the four-week basal diet period, this was not achieved. The subjects lost weight throughout the study. This unintentional weight loss complicates interpretation of the magnitude of the increase in energy expenditure because weight loss is typically associated with reduced expenditures, which could mitigate any increase caused by the diet switch.
Despite these limitations, the results suggest that a well-controlled, full-scale study using appropriate methodologies is warranted to definitively address the question of whether fat accumulation is influenced by the macronutrient composition of the diet or only by the available energy content of the foods consumed.
Secondary analyses and ancillary studies
Hall, K. D., Guo, J., Chen, K. Y., Leibel, R. L., Reitman, M. L., Rosenbaum, M., Smith, S. R., & Ravussin, E. (2019). Methodologic considerations for measuring energy expenditure differences between diets varying in carbohydrate using the doubly labeled water method. The American Journal of Clinical Nutrition, 109(5), 1328–1334. https://doi.org/10.1093/ajcn/nqy390
Friedman, M. I., & Appel, S. (2019). Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men: A secondary analysis of energy expenditure and physical activity. PLOS ONE, 14(12), e0222971. https://doi.org/10.1371/journal.pone.0222971
Hall, K. D. (2019). Mystery or method? Evaluating claims of increased energy expenditure during a ketogenic diet. PLOS ONE, 14(12), e0225944. https://doi.org/10.1371/journal.pone.0225944
Friedman M.I. (2019). Effect of a ketogenic diet on energy expenditure: What conclusions can be drawn from a problematic pilot study? PLOS ONE. https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/faa4a7a2-f0e5-486f-8e0f-a72136f90c20
Rosenbaum, M., Hall, K. D., Guo, J., Ravussin, E., Mayer, L. S., Reitman, M. L., Smith, S. R., Walsh, B. T., & Leibel, R. L. (2019). Glucose and Lipid Homeostasis and Inflammation in Humans Following an Isocaloric Ketogenic Diet. Obesity, 27(6), 971–981. https://doi.org/10.1002/oby.22468
Ang, Q. Y., Alexander, M., Newman, J. C., Tian, Y., Cai, J., Upadhyay, V., Turnbaugh, J. A., Verdin, E., Hall, K. D., Leibel, R. L., Ravussin, E., Rosenbaum, M., Patterson, A. D., & Turnbaugh, P. J. (2020). Ketogenic Diets Alter the Gut Microbiome Resulting in Decreased Intestinal Th17 Cells. Cell, 181(6), 1263-1275.e16. https://doi.org/10.1016/j.cell.2020.04.027
II. DIETFITS Trial
Principal Investigator: Christopher Gardner (Stanford University)
Gardner, C. D., Trepanowski, J. F., Del Gobbo, L. C., Hauser, M. E., Rigdon, J., Ioannidis, J. P. A., Desai, M., & King, A. C. (2018). Effect of Low-Fat vs Low-Carbohydrate Diet on 12-Month Weight Loss in Overweight Adults and the Association with Genotype Pattern or Insulin Secretion: The DIETFITS Randomized Clinical Trial. JAMA, 319(7), 667. https://doi.org/10.1001/jama.2018.0245
This trial was prompted by an earlier studyled by Christopher Gardner (“The A to Z Study”), which compared four diets varying in macronutrient (fat and carbohydrate) content and found that participants assigned the diet that resulted in the lowest carbohydrate and highest fat intake lost the most weight.
The Diet Intervention Examining the Factors Interacting with Treatment Success (DIETFITS) trial extended this work by comparing the effects of low-carbohydrate and low-fat diets on body weight when both diets restrict processed foods and sugars. By supplementing a major grant from the National Institutes of Health, NuSI funding for the DIETFITS trial substantially increased the number of study participants and helped support ancillary studies using study participants and secondary analyses based on trial data.
Understanding the role of diet composition in human health and disease over periods of time longer than a few months requires that participants be “free-living;” that they select and eat their own food, live in their own homes, and go about their lives as usual. The longer the study lasts and the greater the number of participants, the more researchers can learn about the health risks and effectiveness of a diet in the “real world,” but the less control they retain over what and how much the participants actually eat.
Participants in the DIETFITS trial were free-living. Consequently, the researchers implemented an intensive program of counseling and monitoring to optimize participant retention and adherence to assigned diets throughout the year-long trial. Nearly 80% of those enrolled completed the 12-month trial, which is notable for a long-term study in free-living participants.
Over a 2-year period, 609 participants in five cohorts were enrolled in the trial and were randomized to one of the two diets. Participants were given no explicit instructions to reduce calorie intake, but were instructed to eat “healthy” diets, which, among other features, maximized vegetable intake, minimized intake of added sugars and refined flours, and focused on minimally processed foods that were prepared at home. The two groups prescribed the “healthy low-fat“or “healthy low-carbohydrate” diets showed significant differences in their carbohydrate and fat intakes. However, despite these differences, the low-carbohydrate and low-fat diet groups lost similar amounts of body weight during the trial.
This result of the DIETFITS trial differed from that of the A to Z Study in which participants eating the low-carbohydrate diet lost more than twice the weight as those consuming the low-fat diet, a discrepancy that may be attributed to differences in the composition of the diets in the two studies. The differences between total carbohydrate and fat intake were much greater in the A to Z Study than they were in the DIETFITS trial perhaps because in the DIETFITS trial, unlike the A to Z Study, subjects in both groups were counseled to avoid added sugar and refined flour. Participants consuming the low-carbohydrate and low-fat diets in both studies reduced calorie intake to the same extent. Additional research is needed to determine whether there is a threshold of dietary carbohydrate and/or fat content that results in weight loss greater than would be predicted from a reduction in calorie intake alone.
Trial design, ancillary studies and secondary analyses
Stanton, M. V., Robinson, J. L., Kirkpatrick, S. M., Farzinkhou, S., Avery, E. C., Rigdon, J., Offringa, L. C., Trepanowski, J. F., Hauser, M. E., Hartle, J. C., Cherin, R. J., King, A. C., Ioannidis, J. P. A., Desai, M., & Gardner, C. D. (2017). DIETFITS study (diet intervention examining the factors interacting with treatment success) – Study design and methods. Contemporary Clinical Trials, 53, 151–161. https://doi.org/10.1016/j.cct.2016.12.021
Shih, C. W., Hauser, M. E., Aronica, L., Rigdon, J., & Gardner, C. D. (2019). Changes in blood lipid concentrations associated with changes in intake of dietary saturated fat in the context of a healthy low-carbohydrate weight-loss diet: A secondary analysis of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) trial. The American Journal of Clinical Nutrition, 109(2), 433–441. https://doi.org/10.1093/ajcn/nqy305
Guo, J., Robinson, J. L., Gardner, C. D., & Hall, K. D. (2019). Objective versus Self-Reported Energy Intake Changes During Low-Carbohydrate and Low-Fat Diets: Intake Changes During Low-Carbohydrate vs. Low-Fat Diets. Obesity, 27(3), 420–426. https://doi.org/10.1002/oby.22389
Fielding‐Singh, P., Patel, M. L., King, A. C., & Gardner, C. D. (2019). Baseline Psychosocial and Demographic Factors Associated with Study Attrition and 12‐Month Weight Gain in the DIETFITS Trial. Obesity, 27(12), 1997–2004. https://doi.org/10.1002/oby.22650
Grembi, J. A., Nguyen, L. H., Haggerty, T. D., Gardner, C. D., Holmes, S. P., & Parsonnet, J. (2020). Gut microbiota plasticity is correlated with sustained weight loss on a low-carb or low-fat dietary intervention. Scientific Reports, 10(1), 1405. https://doi.org/10.1038/s41598-020-58000-y
Fragiadakis, G. K., Wastyk, H. C., Robinson, J. L., Sonnenburg, E. D., Sonnenburg, J. L., & Gardner, C. D. (2020). Long-term dietary intervention reveals resilience of the gut microbiota despite changes in diet and weight. The American Journal of Clinical Nutrition, 111(6), 1127-1136. https://doi.org/10.1093/ajcn/nqaa046
Figarska, S. M., Rigdon, J., Ganna, A., Elmståhl, S., Lind, L., Gardner, C. D., & Ingelsson, E. (2020). Proteomic profiles before and during weight loss: Results from randomized trial of dietary intervention. Scientific Reports, 10(1), 7913. https://doi.org/10.1038/s41598-020-64636-7
Aronica, L., Rigdon, J., Offringa, L. C., Stefanick, M. L., & Gardner, C. D. (2021). Examining differences between overweight women and men in 12-month weight loss study comparing healthy low-carbohydrate vs. Low-fat diets. International Journal of Obesity, 45(1), 225–234. https://doi.org/10.1038/s41366-020-00708-y
Vergara, M., Hauser, M. E., Aronica, L., Rigdon, J., Fielding-Singh, P., Shih, C. W., & Gardner, C. D. (2021). Associations of Changes in Blood Lipid Concentrations with Changes in Dietary Cholesterol Intake in the Context of a Healthy Low-Carbohydrate Weight Loss Diet: A Secondary Analysis of the DIETFITS Trial. Nutrients, 13(6), 1935. https://doi.org/10.3390/nu13061935
III. Framingham State Food Study
Principal Investigators: David Ludwig and Cara Ebbeling (Boston Children’s Hospital; Harvard Medical School)
Ebbeling, C. B., Feldman, H. A., Klein, G. L., Wong, J. M. W., Bielak, L., Steltz, S. K., Luoto, P. K., Wolfe, R. R., Wong, W. W., & Ludwig, D. S. (2018). Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: Randomized trial. BMJ, k4583. https://doi.org/10.1136/bmj.k4583
Weight loss is the first challenge in treating obesity. The second challenge is maintaining that loss. Only sustained weight reduction can prevent the negative health consequences associated with obesity. However, maintaining significant weight loss indefinitely is notoriously difficult, making the development of strategies that facilitate maintenance of a reduced body weight critical for the effective long-term treatment of obesity.
An earlier study, led by Drs. David Ludwig and Cara Ebbeling, of 24 subjects suggested that eating a low-carbohydrate, high-fat diet over a 30-day period increased energy expenditure after weight loss more than did eating a high-carbohydrate, low-fat diet. This finding challenged the conventional thinking that obesity is an energy balance disorder in which the amount of available calories in the foods consumed, independent of the source of those calories (i.e., carbohydrates and fat), is the critical factor in fat accumulation.
NuSI funded the Framingham State Food Study, or (FS)2, a larger, longer, and more robust trial, to more rigorously address the question of whether the amount or type of calories eaten is the determining factor for preventing fat accumulation after weight reduction.
(FS)2 was a “feeding study,” meaning that the researchers supplied participants with all of their food throughout the study in order to control the amount and composition of food eaten and monitor the amount consumed. In the first phase of the trial, the total food intake (carbohydrates, fats, and protein) of these overweight and obese participants was restricted to produce, on average, a 12% loss in body weight. At the start of the second phase of the study, the 164 participants who achieved this weight loss goal were randomly assigned to either a low-, moderate-, or high-carbohydrate diet containing (by calories) 20% protein and, respectively, either 20% carbohydrate and 60% fat, 40% carbohydrate and 40% fat, or 60% carbohydrate and 20% fat. For the next 20 weeks, the number of calories of each diet provided to each participant was adjusted to maintain their reduced body weight.
Total daily energy expenditure, the primary outcome for the trial, was measured before and after participants were randomly assigned to the different diets. If only the amount of calories consumed was important for weight maintenance, then energy expenditure should be the same for all three groups. This was not the case. Instead, energy expenditure increased to a greater extent in participants eating the low- or moderate-carbohydrate diets compared with those consuming the high-carbohydrate diet. Those eating the low-carbohydrate diet showed the largest increase.
Limiting calorie intake and increasing expenditure through physical activity is the standard prescription for both losing weight and preventing weight gain. However, weight loss due to restriction of calorie intake typically results in a decrease in total bodily energy expenditure. This drop in expenditure restrains continuing weight loss and may contribute to weight regain unless calorie intake is even further restricted. Maintaining energy expenditure during weight loss, or increasing it after weight reduction, as observed in the (FS)2 trial in association with the lower-carbohydrate, higher-fat diets, would therefore be expected to facilitate further weight loss and prevent weight regain.
The results also suggest that the type or mix of calories (i.e., carbohydrate or fat) is a critical factor for maintaining a healthy body weight. These findings, while not supportive of an energy balance model of obesity, are consistent with an alternative hypothesis that emphasizes the different effects of carbohydrates and fats on the hormonal regulation of fat accumulation (known as the carbohydrate-insulin model or the hormonal/regulatory model of obesity).
Trial design, ancillary studies, commentaries and secondary analyses
Ebbeling, C. B., Klein, G. L., Luoto, P. K., Wong, J. M. W., Bielak, L., Eddy, R. G., Steltz, S. K., Devlin, C., Sandman, M., Hron, B., Shimy, K., Heymsfield, S. B., Wolfe, R. R., Wong, W. W., Feldman, H. A., & Ludwig, D. S. (2018). A randomized study of dietary composition during weight-loss maintenance: Rationale, study design, intervention, and assessment. Contemporary Clinical Trials, 65, 76–86. https://doi.org/10.1016/j.cct.2017.12.004
Hall, K. D., Guo, J., & Speakman, J. R. (2019). Do low-carbohydrate diets increase energy expenditure? International Journal of Obesity, 43(12), 2350–2354. https://doi.org/10.1038/s41366-019-0456-3
Ludwig, D. S., Lakin, P. R., Wong, W. W., & Ebbeling, C. B. (2019). Scientific discourse in the era of open science: A response to Hall et al. regarding the Carbohydrate-Insulin Model. International Journal of Obesity, 43(12), 2355–2360. https://doi.org/10.1038/s41366-019-0466-1
Ludwig, D. S., Greco, K. F., Ma, C., & Ebbeling, C. B. (2020). Testing the carbohydrate-insulin model of obesity in a 5-month feeding study: The perils of post-hoc participant exclusions. European Journal of Clinical Nutrition, 74(7), 1109–1112. https://doi.org/10.1038/s41430-020-0658-8
Ebbeling, C. B., Bielak, L., Lakin, P. R., Klein, G. L., Wong, J. M. W., Luoto, P. K., Wong, W. W., & Ludwig, D. S. (2020). Energy Requirement Is Higher During Weight-Loss Maintenance in Adults Consuming a Low- Compared with High-Carbohydrate Diet. The Journal of Nutrition, 150(8), 2009–2015. https://doi.org/10.1093/jn/nxaa150
Shimy, K. J., Feldman, H. A., Klein, G. L., Bielak, L., Ebbeling, C. B., & Ludwig, D. S. (2020). Effects of Dietary Carbohydrate Content on Circulating Metabolic Fuel Availability in the Postprandial State. Journal of the Endocrine Society, 4(7), bvaa062. https://doi.org/10.1210/jendso/bvaa062
Ebbeling, C. B., Knapp, A., Johnson, A., Wong, J. M. W., Greco, K. F., Ma, C., Mora, S., & Ludwig, D. S. (2021). Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia—A randomized controlled feeding trial. The American Journal of Clinical Nutrition, nqab287. https://doi.org/10.1093/ajcn/nqab287
Holsen, L. M., Hoge, W. S., Lennerz, B. S., Cerit, H., Hye, T., Moondra, P., Goldstein, J. M., Ebbeling, C. B., & Ludwig, D. S. (2021). Diets Varying in Carbohydrate Content Differentially Alter Brain Activity in Homeostatic and Reward Regions in Adults. The Journal of Nutrition, 151(8), 2465–2476. https://doi.org/10.1093/jn/nxab090
Wong, J. M. W., Yu, S., Ma, C., Mehta, T., Dickinson, S. L., Allison, D. B., Heymsfield, S. B., Ebbeling, C. B., & Ludwig, D. S. (2021). Stimulated Insulin Secretion Predicts Changes in Body Composition Following Weight Loss in Adults with High BMI. The Journal of Nutrition, nxab315. https://doi.org/10.1093/jn/nxab315
IV. Pediatric Nonalcoholic Fatty Liver Disease Study
Principal Investigators: Jeffrey Schwimmer (University of California, San Diego) and Miriam Vos (Emory University)
Schwimmer, J. B., Ugalde-Nicalo, P., Welsh, J. A., Angeles, J. E., Cordero, M., Harlow, K. E., Alazraki, A., Durelle, J., Knight-Scott, J., Newton, K. P., Cleeton, R., Knott, C., Konomi, J., Middleton, M. S., Travers, C., Sirlin, C. B., Hernandez, A., Sekkarie, A., McCracken, C., & Vos, M. B. (2019). Effect of a Low Free Sugar Diet vs Usual Diet on Nonalcoholic Fatty Liver Disease in Adolescent Boys: A Randomized Clinical Trial. JAMA, 321(3), 256-265. https://doi.org/10.1001/jama.2018.20579
Nonalcoholic fatty liver disease (NAFLD), characterized by an excess of fat in the liver, is the most common form of liver disease. NAFLD can progress to a more serious inflammatory condition, nonalcoholic steatohepatitis (NASH), which can lead to liver cirrhosis, end-stage liver disease, and death. NAFLD also increases the risk for type 2 diabetes, liver cancer, and cardiovascular disease. NAFLD is typically associated with obesity, but also develops in lean individuals, who appear to have a poorer prognosis than those who are obese.
NAFLD is a global problem, affecting about 20% of the world’s population. In the US, 64 million people have NAFLD according to recent estimates. This includes about 7 million children, which is particularly troubling as the likelihood that NAFLD will progress to NASH increases with time.
There is currently no approved drug treatment for NAFLD. Liver transplant is an option for those with more advanced disease, but with the prevalence and incidence of NAFLD and NASH growing rapidly, the demand for transplantable livers will easily overwhelm the limited supply. In short, NAFLD represents a staggering medical and public health challenge, made worse by the fact that few people have even heard of it.
With no established pharmaceutical solution and the impracticality of liver transplant for such a prevalent disease, treatment guidelines for NAFLD emphasize lifestyle modifications for weight loss, including exercise and diet. However, no consensus exists on what type of diet would be best to prevent or reverse NAFLD.
In this context, NuSI convened two meetings of leading physicians and researchers with interest and expertise in adult and pediatric NAFLD to discuss and design possible studies to identify potential dietary triggers and treatment of the disease. In particular, metabolic and epidemiologic data implicated dietary sugar in the occurrence and progression of NAFLD, but no controlled clinical trial data existed to support an evidence-based recommendation for patients to limit sugar intake.
As a result, with an eye toward impacting clinical practice, the group recommended conducting a preliminary, but well-controlled trial on the effects of reducing sugar intake in children. NuSI responded by funding a study led by Drs. Jeffrey Schwimmer and Miriam Vos that examined the effect of a diet low in free sugars (i.e., low in sugar or high fructose corn syrup, either added to food and beverages or from fruit juices) on liver fat content in children with NAFLD.
A total of 40 boys, 11 – 16 years old, with diagnosed and active NAFLD were randomly assigned to either a low free sugar diet (intervention diet) group or a usual diet group for 8 weeks. Before the intervention diet was instituted, study staff replaced all sugars or sugar-containing products in the intervention group’s households with no or low-sugar substitutes. For the duration of the study, families of the participants in the intervention group were then provided with all their food or food ingredients, tailored to their preferences and the participant’s habitual diet, but containing less than 3% free sugars. In addition to instructing participants in the intervention group to avoid sugar-containing foods and beverages, study staff contacted their families twice-weekly to assess satisfaction with the diet and address dietary issues regarding special events and holidays. Families of participants in the usual diet group were instructed to eat their usual diet and were given a weekly stipend with which to purchase food and beverages of their choice.
Liver fat content of participants was measured using magnetic resonance imaging (MRI) at the beginning and end of the 8-week trial. Liver fat content decreased more and was significantly lower after 8 weeks in the diet intervention group compared with the usual diet group. These effects of the low free-sugar diet were observed after controlling for differences in body weight or body mass index (BMI) between the two groups, suggesting that the reduction in sugar intake, not weight or weight loss, was primarily responsible for the improvement in liver fat content. Blood concentration of ALT (alanine aminotransferase), a marker for liver function indicative of the degree of damage associated with NAFLD and NASH, also improved more in the diet intervention group.
These findings suggest that limiting sugar intake can be beneficial for children with NAFLD and therefore constitute evidence implicating excessive intake of sugars in the etiology of NAFLD. However, additional research is needed to establish a causal role for dietary sugars in NAFLD and to buttress a strategy of limiting intake of sugars in its prevention and treatment. In particular, it will be important to conduct longer duration controlled trials in a larger and more diverse population of patients, including with participants of both genders and a range of ethnicities, and under more realistic conditions in which participants and their families are responsible for selecting their own diets.
Ancillary Study
Cohen, C. C., Li, K. W., Alazraki, A. L., Beysen, C., Carrier, C. A., Cleeton, R. L., Dandan, M., Figueroa, J., Knight-Scott, J., Knott, C. J., Newton, K. P., Nyangau, E. M., Sirlin, C. B., Ugalde-Nicalo, P. A., Welsh, J. A., Hellerstein, M. K., Schwimmer, J. B., & Vos, M. B. (2021). Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease. Journal of Clinical Investigation, 131(24), e150996. https://doi.org/10.1172/JCI150996