Ketogenic Diets Alter the Gut Microbiome Resulting in Decreased Intestinal Th17 Cells.

Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.

Metabolomic Profiling of an Ultraprocessed Dietary Pattern in a Domiciled Randomized Controlled Crossover Feeding Trial.

BACKGROUND: Objective markers of ultraprocessed foods (UPF) may improve the assessment of UPF intake and provide insight into how UPF influences health. OBJECTIVES: To identify metabolites that differed between dietary patterns (DPs) high in or void of UPF according to Nova classification. METHODS: In a randomized, crossover, controlled-feeding trial (clinicaltrials.govNCT03407053), 20 domiciled healthy participants (mean ± standard deviation: age 31 ± 7 y, body mass index [kg/m2] 22 ± 11.6) consumed ad libitum a UPF-DP (80% UPF) and an unprocessed DP (UN-DP; 0% UPF) for 2 wk each. Metabolites were measured using liquid chromatography with tandem mass spectrometry in ethylenediaminetetraacetic acid plasma, collected at week 2 and 24-h, and spot urine, collected at weeks 1 and 2, of each DP. Linear mixed models, adjusted for energy intake, were used to identify metabolites that differed between DPs. RESULTS: After multiple comparisons correction, 257 out of 993 plasma and 606 out of 1279 24-h urine metabolites differed between UPF-DP and UN-DP. Overall, 21 known and 9 unknown metabolites differed between DPs across all time points and biospecimen types. Six metabolites were higher (4-hydroxy-L-glutamic acid, N-acetylaminooctanoic acid, 2-methoxyhydroquinone sulfate, 4-ethylphenylsulfate, 4-vinylphenol sulfate, and acesulfame) and 14 were lower following the UPF-DP; pimelic acid, was lower in plasma but higher in urine following the UPF-DP. CONCLUSIONS: Consuming a DP high in, compared with 1 void of, UPF has a measurable impact on the short-term human metabolome. Observed differential metabolites could serve as candidate biomarkers of UPF intake or metabolic response in larger samples with varying UPF-DPs. This trial was registered at clinicaltrials.gov as NCT03407053 and NCT03878108.

No significant salt or sweet taste preference or sensitivity differences following ad libitum consumption of ultra-processed and unprocessed diets: a randomized controlled pilot study.

Ultra-processed food consumption has increased worldwide, yet little is known about the potential links with taste preference and sensitivity. This exploratory study aimed to (i) compare sweet and salty taste detection thresholds and preferences following consumption of ultra-processed and unprocessed diets, (ii) investigate whether sweet and salty taste sensitivity and preference were associated with taste substrates (i.e. sodium and sugar) and ad libitum nutrient intake, and (iii) examine associations of taste detection thresholds and preferences with blood pressure (BP) and anthropometric measures following consumption of ultra-processed and unprocessed diets. In a randomized crossover study, participants (N = 20) received ultra-processed or unprocessed foods for 2 weeks, followed by the alternate diet. Baseline food intake data were collected prior to admission. Taste detection thresholds and preferences were measured at the end of each diet arm. Taste-substrate/nutrient intake, body mass index (BMI), and body weight (BW) were measured daily. No significant differences were observed in participant salt and sweet detection thresholds or preferences after 2 weeks on ultra-processed or unprocessed diets. There was no significant association between salt and sweet taste detection thresholds, preferences, and nutrient intakes on either diet arm. A positive correlation was observed between salt taste preference and systolic BP (r = 0.59; P = 0.01), BW (r = 0.47, P = 0.04), and BMI (r = 0.50; P = 0.03) following consumption of the ultra-processed diet. Thus, a 2-week consumption of an ultra-processed diet does not appear to acutely impact sweet or salty taste sensitivity or preference. Trial Registration: ClinicalTrials.gov Identifier NCT03407053.

Exceptional Reported Effects and Data Anomalies Merit Explanation from "A randomized controlled trial of coordination exercise on cognitive function in obese adolescents" by.

We read the recent article in Psychology of Sport and Exercise by Liu et al. ("A randomized controlled trial of coordination exercise on cognitive function in obese adolescents") with great interest. Our interest in the article stemmed from the extraordinary differences in obesity-related outcomes reported in response to a rope-jumping intervention. We requested the raw data from the authors to confirm the results and, after the journal editors reinforced our request, the authors graciously provided us with their data. We share our evaluation of the original data herein, which includes concerns that weight and BMI loss by the intervention appears extraordinary in both magnitude and aspects of the distributions. We request that the authors address our findings by providing explanations of the extraordinary data or correcting any errors that may have occurred in the original report, as appropriate.

Is Weight Loss-Induced Muscle Mass Loss Clinically Relevant?

This Viewpoint explores the effects of weight loss achieved through GLP-1­based antiobesity medications on weight regain, fat-free mass, and skeletal muscle mass in people with obesity.

Obesity Energetics: Body Weight Regulation and the Effects of Diet Composition.

Weight changes are accompanied by imbalances between calorie intake and expenditure. This fact is often misinterpreted to suggest that obesity is caused by gluttony and sloth and can be treated by simply advising people to eat less and move more. Rather various components of energy balance are dynamically interrelated and weight loss is resisted by counterbalancing physiological processes. While low-carbohydrate diets have been suggested to partially subvert these processes by increasing energy expenditure and promoting fat loss, our meta-analysis of 32 controlled feeding studies with isocaloric substitution of carbohydrate for fat found that both energy expenditure (26 kcal/d; P <.0001) and fat loss (16 g/d; P <.0001) were greater with lower fat diets. We review the components of energy balance and the mechanisms acting to resist weight loss in the context of static, settling point, and set-point models of body weight regulation, with the set-point model being most commensurate with current data.

Low-carbohydrate diets for the treatment of obesity and type 2 diabetes.

PURPOSE OF REVIEW: Summarize the physiological effects of low-carbohydrate diets as they relate to weight loss, glycemic control, and metabolic health. RECENT FINDINGS: Low-carbohydrate diets are at least as effective for weight loss as other diets, but claims about increased energy expenditure and preferential loss of body fat are unsubstantiated. Glycemic control and hyperinsulinemia are improved by low-carbohydrate diets, but insulin sensitivity and glucose-stimulated insulin secretion may be impaired, especially in the absence of weight loss. Fasting lipid parameters are generally improved, but such improvements may depend on the quality of dietary fat and the carbohydrates they replaced. Postprandial hyperlipemia is a potential concern given the high fat content typical of low-carbohydrate diets. SUMMARY: Low-carbohydrate diets have several potential benefits for treatment of obesity and type 2 diabetes, but more research is required to better understand their long-term consequences as well as the variable effects on the endocrine control of glucose, lipids, and metabolism.

Child and adolescent obesity: part of a bigger picture.

The prevalence of childhood overweight and obesity has risen substantially worldwide in less than one generation. In the USA, the average weight of a child has risen by more than 5 kg within three decades, to a point where a third of the country's children are overweight or obese. Some low-income and middle-income countries have reported similar or more rapid rises in child obesity, despite continuing high levels of undernutrition. Nutrition policies to tackle child obesity need to promote healthy growth and household nutrition security and protect children from inducements to be inactive or to overconsume foods of poor nutritional quality. The promotion of energy-rich and nutrient-poor products will encourage rapid weight gain in early childhood and exacerbate risk factors for chronic disease in all children, especially those showing poor linear growth. Whereas much public health effort has been expended to restrict the adverse marketing of breastmilk substitutes, similar effort now needs to be expanded and strengthened to protect older children from increasingly sophisticated marketing of sedentary activities and energy-dense, nutrient-poor foods and beverages. To meet this challenge, the governance of food supply and food markets should be improved and commercial activities subordinated to protect and promote children's health.

Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders.

Nutritional management of acute metabolic decompensation in amino acid inborn errors of metabolism (AA IEM) aims to restore nitrogen balance. While nutritional recommendations have been published, they have never been rigorously evaluated. Furthermore, despite these recommendations, there is a wide variation in the nutritional strategies employed amongst providers, particularly regarding the inclusion of parenteral lipids for protein-free caloric support. Since randomized clinical trials during acute metabolic decompensation are difficult and potentially dangerous, mathematical modeling of metabolism can serve as a surrogate for the preclinical evaluation of nutritional interventions aimed at restoring nitrogen balance during acute decompensation in AA IEM. A validated computational model of human macronutrient metabolism was adapted to predict nitrogen balance in response to various nutritional interventions in a simulated patient with a urea cycle disorder (UCD) during acute metabolic decompensation due to dietary non-adherence or infection. The nutritional interventions were constructed from published recommendations as well as clinical anecdotes. Overall, dextrose alone (DEX) was predicted to be better at restoring nitrogen balance and limiting nitrogen excretion during dietary non-adherence and infection scenarios, suggesting that the published recommended nutritional strategy involving dextrose and parenteral lipids (ISO) may be suboptimal. The implications for patients with AA IEM are that the medical course during acute metabolic decompensation may be influenced by the choice of protein-free caloric support. These results are also applicable to intensive care patients undergoing catabolism (postoperative phase or sepsis), where parenteral nutritional support aimed at restoring nitrogen balance may be more tailored regarding metabolic fuel selection.

Increased food energy supply as a major driver of the obesity epidemic: a global analysis.

OBJECTIVE: We investigated associations between changes in national food energy supply and in average population body weight. METHODS: We collected data from 24 high-, 27 middle- and 18 low-income countries on the average measured body weight from global databases, national health and nutrition survey reports and peer-reviewed papers. Changes in average body weight were derived from study pairs that were at least four years apart (various years, 1971-2010). Selected study pairs were considered to be representative of an adolescent or adult population, at national or subnational scale. Food energy supply data were retrieved from the Food and Agriculture Organization of the United Nations food balance sheets. We estimated the population energy requirements at survey time points using Institute of Medicine equations. Finally, we estimated the change in energy intake that could theoretically account for the observed change in average body weight using an experimentally-validated model. FINDINGS: In 56 countries, an increase in food energy supply was associated with an increase in average body weight. In 45 countries, the increase in food energy supply was higher than the model-predicted increase in energy intake. The association between change in food energy supply and change in body weight was statistically significant overall and for high-income countries (P < 0.001). CONCLUSION: The findings suggest that increases in food energy supply are sufficient to explain increases in average population body weight, especially in high-income countries. Policy efforts are needed to improve the healthiness of food systems and environments to reduce global obesity.

Dynamic interplay among homeostatic, hedonic, and cognitive feedback circuits regulating body weight.

Obesity is associated with a prolonged imbalance between energy intake and expenditure, both of which are regulated by multiple feedback processes within and across individuals. These processes constitute 3 hierarchical control systems-homeostatic, hedonic, and cognitive-with extensive interaction among them. Understanding complex eating behavior requires consideration of all 3 systems and their interactions. Existing models of these processes are widely scattered, with relatively few attempts to integrate across mechanisms. We briefly review available empirical evidence and dynamic models, discussing challenges and potential for better integration. We conclude that developing richer models of dynamic interplay among systems should be a priority in the future study of obesity and that systems science modeling offers the potential to aid in this goal.

Physiology of the weight-loss plateau in response to diet restriction, GLP-1 receptor agonism, and bariatric surgery.

OBJECTIVE: The objective of this study was to investigate why different weight-loss interventions result in varying durations of weight loss prior to approaching plateaus. METHODS: A validated mathematical model of energy metabolism and body composition dynamics was used to simulate mean weight- and fat-loss trajectories in response to diet restriction, semaglutide 2.4 mg, tirzepatide 10 mg, and Roux-en-Y gastric bypass (RYGB) surgery interventions. Each intervention was simulated by adjusting two model parameters affecting energy intake to fit the mean weight-loss data. One parameter represented the persistent shift of the system from baseline equilibrium, and the other parameter represented the strength of the feedback control circuit relating weight loss to increased appetite. RESULTS: RYGB surgery resulted in a persistent intervention magnitude more than threefold greater than diet restriction and about double that of tirzepatide and semaglutide. All interventions except diet restriction substantially weakened the appetite feedback control circuit, resulting in an extended period of weight loss prior to the plateau. CONCLUSIONS: These preliminary mathematical modeling results suggest that both glucagon-like peptide 1 (GLP-1) receptor agonism and RYGB surgery interventions act to weaken the appetite feedback control circuit that regulates body weight and induce greater persistent effects to shift the body weight equilibrium compared with diet restriction.

Gut-derived appetite hormones do not explain energy intake differences in humans following low-carbohydrate versus low-fat diets.

OBJECTIVE: The objective of this study was to explore how dietary macronutrient composition influences postprandial appetite hormone responses and subsequent energy intake. METHODS: A total of 20 adults (mean [SEM], age 30 [1] years, BMI 27.8 [1.3] kg/m2, n = 8 with normal weight, n = 6 with overweight, n = 6 with obesity) consumed a low-fat (LF) diet (10% fat, 75% carbohydrate) and a low-carbohydrate (LC) diet (10% carbohydrate, 75% fat) for 2 weeks each in an inpatient randomized crossover design. At the end of each diet, participants consumed isocaloric macronutrient-representative breakfast test meals, and 6-h postprandial responses were measured. Ad libitum energy intake was measured for the rest of the day. RESULTS: The LC meal resulted in greater mean postprandial plasma active glucagon-like peptide-1 (GLP-1; LC: 6.44 [0.78] pg/mL, LF: 2.46 [0.26] pg/mL; p < 0.0001), total glucose-dependent insulinotropic polypeptide (GIP; LC: 578 [60] pg/mL, LF: 319 [37] pg/mL; p = 0.0004), and peptide YY (PYY; LC: 65.6 [5.6] pg/mL, LF: 50.7 [3.8] pg/mL; p = 0.02), whereas total ghrelin (LC: 184 [25] pg/mL, LF: 261 [47] pg/mL; p = 0.0009), active ghrelin (LC: 91 [9] pg/mL, LF: 232 [28] pg/mL; p < 0.0001), and leptin (LC: 26.9 [6.5] ng/mL, LF: 35.2 [7.5] ng/mL; p = 0.01) were lower compared with LF. Participants ate more during LC at lunch (244 [85] kcal; p = 0.01) and dinner (193 [86] kcal; p = 0.04), increasing total subsequent energy intake for the day compared with LF (551 [103] kcal; p < 0.0001). CONCLUSIONS: In the short term, endogenous gut-derived appetite hormones do not necessarily determine ad libitum energy intake.

Diet order significantly affects energy balance for diets varying in macronutrients but not ultraprocessing in crossover studies without a washout period.

BACKGROUND: Crossover studies can induce order effects, especially when they lack a washout period. OBJECTIVES: We performed secondary analyses comparing groups of subjects randomly assigned to different diet orders in 2 inpatient crossover studies originally designed to compare within-subject differences in ad libitum energy intake. One study compared minimally processed low-carbohydrate (LC) compared with low-fat (LF) diets, and the other matched macronutrients and compared minimally processed food (MPF) with ultraprocessed food (UPF) diets. METHODS: Diet order group comparisons of changes in body weight and body composition, and differences in energy expenditure and food intake were assessed over 4 wk in 20 adults randomly assigned to either the LC followed immediately by the LF diet (LC → LF) or the opposite order (LF → LC), and 20 adults randomly assigned to either the MPF followed by the UPF (MPF → UPF) diets or the opposite order (UPF → MPF). RESULTS: Subjects randomly assigned to LC → LF lost 2.9 ± 1.1 kg more body weight (P <0.001) and 1.5 ± 0.6 kg more body fat (P = 0.03) than the LF → LC group, likely because the LC → LF group consumed 921 ± 304 kcal/d less than the LF → LC group (P = 0.003). These energy intake differences were driven by the last 2 wk (-1610 ± 312 kcal/d; P < 0.0001), perhaps because of carryover effects of gut adaptations during the first 2 wk arising from large differences in the mass of food (1296 ± 215 g/d; P <0.00001) and fiber consumed (58 ± 6 g/d; P <0.00001). There were no significant diet order effects on energy intake, body weight, or body composition changes between UPF → MPF and MPF → UPF groups. CONCLUSIONS: Diet order significantly affected energy intake, body weight, and body fat in a 4-wk crossover inpatient diet study varying in macronutrients, but not in a similarly structured study varying in ultraprocessed foods. This trial was registered at clinicaltrials.gov as NCT03407053 and NCT03878108.

Beyond day and night: The importance of ultradian rhythms in mouse physiology.

Our circadian world shapes much of metabolic physiology. In mice ∼40% of the light and ∼80% of the dark phase time is characterized by bouts of increased energy expenditure (EE). These ultradian bouts have a higher body temperature (Tb) and thermal conductance and contain virtually all of the physical activity and awake time. Bout status is a better classifier of mouse physiology than photoperiod, with ultradian bouts superimposed on top of the circadian light/dark cycle. We suggest that the primary driver of ultradian bouts is a brain-initiated transition to a higher defended Tb of the active/awake state. Increased energy expenditure from brown adipose tissue, physical activity, and cardiac work combine to raise Tb from the lower defended Tb of the resting/sleeping state. Thus, unlike humans, much of mouse metabolic physiology is episodic with large ultradian increases in EE and Tb that correlate with the active/awake state and are poorly aligned with circadian cycling.

Differential peripheral immune signatures elicited by vegan versus ketogenic diets in humans.

Nutrition has broad impacts on all physiological processes. However, how nutrition affects human immunity remains largely unknown. Here we explored the impact of a dietary intervention on both immunity and the microbiota by performing a post hoc analysis of a clinical trial in which each of the 20 participants sequentially consumed vegan or ketogenic diets for 2 weeks ( NCT03878108 ). Using a multiomics approach including multidimensional flow cytometry, transcriptomic, proteomic, metabolomic and metagenomic datasets, we assessed the impact of each diet, and dietary switch, on host immunity and the microbiota. Our data revealed that overall, a ketogenic diet was associated with a significant upregulation of pathways and enrichment in cells associated with the adaptive immune system. In contrast, a vegan diet had a significant impact on the innate immune system, including upregulation of pathways associated with antiviral immunity. Both diets significantly and differentially impacted the microbiome and host-associated amino acid metabolism, with a strong downregulation of most microbial pathways following ketogenic diet compared with baseline and vegan diet. Despite the diversity of participants, we also observed a tightly connected network between datasets driven by compounds associated with amino acids, lipids and the immune system. Collectively, this work demonstrates that in diverse participants 2 weeks of controlled dietary intervention is sufficient to significantly and divergently impact host immunity, which could have implications for precision nutritional interventions. ClinicalTrials.gov registration: NCT03878108 .