The thermoneutral zone in women takes an "arctic" shift compared to men.

Conventionally, women are perceived to feel colder than men, but controlled comparisons are sparse. We measured the response of healthy, lean, young women and men to a range of ambient temperatures typical of the daily environment (17 to 31 °C). The Scholander model of thermoregulation defines the lower critical temperature as threshold of the thermoneutral zone, below which additional heat production is required to defend core body temperature. This parameter can be used to characterize the thermoregulatory phenotypes of endotherms on a spectrum from "arctic" to "tropical." We found that women had a cooler lower critical temperature (mean ± SD: 21.9 ± 1.3 °C vs. 22.9 ± 1.2 °C, P = 0.047), resembling an "arctic" shift compared to men. The more arctic profile of women was predominantly driven by higher insulation associated with more body fat compared to men, countering the lower basal metabolic rate associated with their smaller body size, which typically favors a "tropical" shift. We did not detect sex-based differences in secondary measures of thermoregulation including brown adipose tissue glucose uptake, muscle electrical activity, skin temperatures, cold-induced thermogenesis, or self-reported thermal comfort. In conclusion, the principal contributors to individual differences in human thermoregulation are physical attributes, including body size and composition, which may be partly mediated by sex.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD). OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

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 .

Glycemia and Gluconeogenesis With Metformin and Liraglutide: A Randomized Trial in Youth-onset Type 2 Diabetes.

OBJECTIVE: Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and ß-cell function after therapy in AA Y-T2D. METHODS: In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. ß-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test. RESULTS: At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI. CONCLUSION: Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance ß-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.

Dietary linoleic acid lowering alone does not lower arachidonic acid or endocannabinoids among women with overweight and obesity: A randomized, controlled trial.

The linoleic acid (LA)-arachidonic acid (ARA)-inflammatory axis suggests dietary LA lowering benefits health because it lowers ARA and ARA-derived endocannabinoids (ECB). Dietary LA reduction increases concentrations of omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DHA derived ECB. The aim of this study was to examine targeted reduction of dietary LA, with and without EPA and DHA, on plasma EPA and DHA and ECB (2-arachidonoyl glycerol [2-AG], anandamide [AEA], and docosahexaenoyl ethanolamide [DHA-EA]). Healthy, pre-menopausal women (n = 62, BMI 30 ± 3 kg/m2 , age 35 ± 7 years; mean ± SD) were randomized to three 12-week controlled diets: (1) high LA, low omega-3 EPA and DHA (H6L3); (2) low LA, low omega-3 EPA and DHA (L6L3); or (3) low LA, high omega-3 EPA and DHA (L6H3). Baseline plasma fatty acids and ECB were similar between diets. Starting at 4 weeks, L6L3 and L6H3 lowered plasma LA compared to H6L3 (p < 0.001). While plasma ARA changed from baseline by 8% in L6L3 and -8% in L6H3, there were no group differences. After 4 weeks, plasma EPA and DHA increased from baseline in women on the L6H3 diet (ps < 0.001) and were different than the H6L3 and L6L3 diets. No differences were found between diets for AEA or 2-AG, however, in L6L3 and L6H3, AEA increased by 14% (ps < 0.02). L6H3 resulted in 35% higher DHA-EA (p = 0.013) whereas no changes were seen with the other diets. Lowering dietary LA did not result in the expected changes in fatty acids associated with the LA-ARA inflammatory axis in women with overweight and obesity.

Risk Assessment of Maladaptive Behaviors in Adolescents: Nutrition, Screen Time, Prenatal Exposure, Childhood Adversities - Adolescent Brain Cognitive Development Study.

PURPOSE: We aimed to identify significant contributing factors to the risk of maladaptive behaviors, such as alcohol use disorder or obesity, in children. To achieve this, we utilized the extensive adolescent brain cognitive development data set, which encompasses a wide range of environmental, social, and nutritional factors. METHODS: We divided our sample into equal sets (test, validation; n = 3,415 each). On exploratory factor analysis, six factor domains were identified as most significant (fat/sugar intake, screen time, and prenatal alcohol exposure, parental aggressiveness, hyperactivity, family violence, parental education, and family income) and used to stratify the children into low- (n = 975), medium- (n = 967), high- (n = 977) risk groups. Regression models were used to analyze the relationship between identified risk groups, and differences in reward sensitivity, and behavioral problems at 2-year follow-up. RESULTS: The functional magnetic resonance imaging analyses showed reduced activation in several brain regions during reward or loss anticipation in high/medium-risk (vs. low-risk) children on a monetary incentive delay task. High-risk children exhibited heightened middle frontal cortex activity when receiving large rewards. They also displayed increased impulsive and motivated reward-seeking behaviors, along with behavioral problems. These findings replicated in our validation set, and a negative correlation between middle frontal cortexthickness and impulsivity behavior was observed in high-risk children. DISCUSSION: Our findings show altered reward function and increased impulsiveness in high-risk adolescents. This study has implications for early risk identification and the development of prevention strategies for maladaptive behaviors in children, particularly those at high risk.

Striatal dopamine tone is positively associated with body mass index in humans as determined by PET using dual dopamine type-2 receptor antagonist tracers.

The relationship between adiposity and dopamine type-2 receptor binding potential (D2BP) in the human brain has been repeatedly studied for >20 years with highly discrepant results, likely due to variable methodologies and differing study populations. We conducted a controlled inpatient feeding study to measure D2BP in the striatum using positron emission tomography with both [18F]fallypride and [11C]raclopride in pseudo-random order in 54 young adults with a wide range of body mass index (BMI 20-44 kg/m2). Within-subject D2BP measurements using the two tracers were moderately correlated (r=0.47, p<0.001). D2BP was negatively correlated with BMI as measured by [11C]raclopride (r= -0.51; p<0.0001) but not [18F]fallypride (r=-0.01; p=0.92) and these correlation coefficients were significantly different from each other (p<0.001). Given that [18F]fallypride has greater binding affinity to dopamine type-2 receptors than [11C]raclopride, which is more easily displaced by endogenous dopamine, our results suggest that adiposity is positively associated with increased striatal dopamine tone.

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.

Dietary fat restriction affects brain reward regions in a randomized crossover trial.

BACKGROUNDWeight-loss diets often target dietary fat or carbohydrates, macronutrients that are sensed via distinct gut-brain pathways and differentially affect peripheral hormones and metabolism. However, the effects of such diet changes on the human brain are unclear. METHODSWe investigated whether selective isocaloric reductions in dietary fat or carbohydrates altered dopamine D2/3 receptor binding potential (D2BP) and neural activity in brain-reward regions in response to visual food cues in 17 inpatient adults with obesity as compared with a eucaloric baseline diet using a randomized crossover design. RESULTSOn the fifth day of dietary fat restriction, but not carbohydrate restriction, both D2BP and neural activity to food cues were decreased in brain-reward regions. After the reduced-fat diet, ad libitum intake shifted toward foods high in both fat and carbohydrates. CONCLUSIONThese results suggest that dietary fat restriction increases tonic dopamine in brain-reward regions and affects food choice in ways that may hamper diet adherence. TRIAL REGISTRATIONClinicalTrials.gov NCT00846040 FUNDING. NIDDK 1ZIADK013037.

Ad libitum meal energy intake is positively influenced by energy density, eating rate and hyper-palatable food across four dietary patterns.

Diets for the prevention and treatment of obesity are often informed by theories about food characteristics believed to support spontaneous reductions in ad libitum energy intake without inducing hunger. Here we estimated how energy density, hyper-palatability, protein content and eating rate affected ad libitum energy intake of 2,733 meals from four dietary patterns. Energy density, eating rate and hyper-palatable foods were consistently positively related to meal energy intake across all diets. Protein content was positively related to meal energy intake during ultraprocessed and unprocessed diets but was not significantly related to energy intake of minimally processed low-fat or low-carbohydrate meals.

The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes.

Disclosure summary: Dr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose. Background: Metformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin's side effects by shifting microbiota composition and activity. Objective: The aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity. Methods: In a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase. Results: Six Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m2), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria, Enterobacteriaceae, and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month. Conclusion: Administration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04209075.

The Complex Effects of Light on Metabolism in Humans.

Light is an essential part of many life forms. The natural light-dark cycle has been the dominant stimulus for circadian rhythms throughout human evolution. Artificial light has restructured human activity and provided opportunities to extend the day without reliance on natural day-night cycles. The increase in light exposure at unwanted times or a reduced dynamic range of light between the daytime and nighttime has introduced negative consequences for human health. Light exposure is closely linked to sleep-wake regulation, activity and eating patterns, body temperature, and energy metabolism. Disruptions to these areas due to light are linked to metabolic abnormalities such as an increased risk of obesity and diabetes. Research has revealed that various properties of light influence metabolism. This review will highlight the complex role of light in human physiology, with a specific emphasis on metabolic regulation from the perspective of four main properties of light (intensity, duration, timing of exposure, and wavelength). We also discuss the potential influence of the key circadian hormone melatonin on sleep and metabolic physiology. We explore the relationship between light and metabolism through circadian physiology in various populations to understand the optimal use of light to mitigate short and long-term health consequences.

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.

Prenatal Caffeine Exposure Is Linked to Elevated Sugar Intake and BMI, Altered Reward Sensitivity, and Aberrant Insular Thickness in Adolescents: An ABCD Investigation.

Prenatal caffeine exposure (PCE) has been positively associated with elevated body mass index (BMI) in children. Why this association occurs is unclear, but it is possible that PCE alters the in utero development of brain structures associated with food preference, leading to more total sugar intake (TSI, grams) later in childhood. To test this hypothesis, we investigated if PCE (daily/weekly/ 0.01) of excessive PCE (vs. no exposure) with elevated BMI (daily/weekly/daily limit; consistent in boys and girls), increased TSI (daily) and insular thickness (daily/weekly), as well as low middle frontal cortex (MFC) activation (daily). Our sub-analysis revealed an association of daily/weekly PCE (vs. no exposure) with increased gram sugar intake from soft drinks. We also identified a positive relationship of excessive PCE with elevated TSI and increased insular thickness (a key gustatory region), while in a Sobel test, reward sensitivity (reduced brain reactivity to reward anticipation in MFC; tracks reward outcomes) mediated (Test statistic = 2.23; p = 0.02) the PCE-linked BMI changes in adolescents. Our findings suggest that excessive PCE might be detrimental to frontal lobe development and altered reward sensitivity to food, thereby increasing risk for elevated TSI and obesity. Our results support recommendations to limit caffeine intake during pregnancy.

Effects of interrupting daily sedentary behavior on children's glucose metabolism: A 6-day randomized controlled trial.

BACKGROUND: Metabolic disease risk in youth is influenced by sedentary behaviors. Acute in-lab studies show that, during a single day, interrupting a sedentary period with short bouts of physical activity improves glucometabolic outcomes. OBJECTIVE: To determine if acutely improved glucose metabolism persists after multi-day interruptions of sitting with walking brief bouts. We hypothesized that children who underwent interrupting sitting on multiple days would demonstrate lower insulin area under the curve during an oral glucose tolerance test compared to uninterrupted sitting. METHODS: Healthy, normoglycemic children (N = 109) ages 7-11 years were randomized to one of two conditions: Control (3 h of daily Uninterrupted Sitting) or Interrupted Sitting (3-min of moderate-intensity walking every 30 min for 3 h daily); with dietary intake controlled through provision of foodstuffs for the entire experiment. Participants attended six consecutive daily visits at a research ambulatory unit. The primary outcome was insulin area under the curve during the oral glucose tolerance test on day 6 during interrupted or uninterrupted sitting; secondary outcomes included glucose and c-peptide area under the curve, energy intake at a buffet meal on day 6, and free-living activity. RESULTS: Among 93 children (42 uninterrupted sitting, 51 interrupted sitting), daily interrupted sitting resulted in 21% lower insulin (ß = 0.102 CI:0.032-0.172, p = 0.005) and a 10% lower C-peptide (ß = 0.043, CI:0.001-0.084, p = 0.045) area under the curve. Matsuda and Glucose Effectiveness Indices were also improved (p's < 0.05). There were no group differences in energy intake or expenditure. CONCLUSIONS: Sustained behavioral change by interrupting sedentary behaviors is a promising intervention strategy for improving metabolic risk in children.

Time to revisit the passive overconsumption hypothesis? Humans show sensitivity to calories in energy-rich meals.

BACKGROUND: A possible driver of obesity is insensitivity (passive overconsumption) to food energy density (ED, kcal/g); however, it is unclear whether this insensitivity applies to all meals. OBJECTIVES: We assessed the influence of ED on energy intake (kcal) across a broad and continuous range of EDs comprised of noncovertly manipulated, real-world meals. We also allowed for the possibility that the association between energy intake and ED is nonlinear. METHODS: We completed a secondary analysis of 1519 meals which occurred in a controlled environment as part of a study conducted by Hall and colleagues to assess the effects of food ultra-processing on energy intake. To establish the generalizability of the findings, the analyses were repeated in 32,162 meals collected from free-living humans using data from the UK National Diet and Nutrition Survey (NDNS). Segmented regressions were performed to establish ED "breakpoints" at which the association between consumed meal ED and mean centered meal caloric intake (kcal) changed. RESULTS: Significant breakpoints were found in both the Hall et al. data set (1.41 kcal/g) and the NDNS data set (1.75 and 2.94 kcal/g). Centered meal caloric intake did not increase linearly with consumed meal ED, and this pattern was captured by a 2-component ("volume" and "calorie content" [biologically derived from the sensing of fat, carbohydrate, and protein]) model of physical meal size (g), in which volume is the dominant signal with lower energy-dense foods and calorie content is the dominant signal with higher energy-dense foods. CONCLUSIONS: These analyses reveal that, on some level, humans are sensitive to the energy content of meals and adjust meal size to minimize the acute aversive effects of overconsumption. Future research should consider the relative importance of volume and calorie-content signals, and how individual differences impact everyday dietary behavior and energy balance.

Effect of a plant-based, low-fat diet versus an animal-based, ketogenic diet on ad libitum energy intake.

The carbohydrate-insulin model of obesity posits that high-carbohydrate diets lead to excess insulin secretion, thereby promoting fat accumulation and increasing energy intake. Thus, low-carbohydrate diets are predicted to reduce ad libitum energy intake as compared to low-fat, high-carbohydrate diets. To test this hypothesis, 20 adults aged 29.9 ± 1.4 (mean ± s.e.m.) years with body mass index of 27.8 ± 1.3 kg m-2 were admitted as inpatients to the National Institutes of Health Clinical Center and randomized to consume ad libitum either a minimally processed, plant-based, low-fat diet (10.3% fat, 75.2% carbohydrate) with high glycemic load (85 g 1,000 kcal-1) or a minimally processed, animal-based, ketogenic, low-carbohydrate diet (75.8% fat, 10.0% carbohydrate) with low glycemic load (6 g 1,000 kcal-1) for 2 weeks followed immediately by the alternate diet for 2 weeks. One participant withdrew due to hypoglycemia during the low-carbohydrate diet. The primary outcomes compared mean daily ad libitum energy intake between each 2-week diet period as well as between the final week of each diet. We found that the low-fat diet led to 689 ± 73 kcal d-1 less energy intake than the low-carbohydrate diet over 2 weeks (P < 0.0001) and 544 ± 68 kcal d-1 less over the final week (P < 0.0001). Therefore, the predictions of the carbohydrate-insulin model were inconsistent with our observations. This study was registered on ClinicalTrials.gov as NCT03878108 .