Brain dopamine responses to ultra-processed milkshakes are highly variable and not significantly related to adiposity in humans.

Ultra-processed foods high in fat and sugar may be addictive, in part, due to their purported ability to induce an exaggerated postingestive brain dopamine response akin to drugs of abuse. Using standard [11C]raclopride positron emission tomography (PET) displacement methods used to measure brain dopamine responses to addictive drugs, we measured postingestive striatal dopamine responses to an ultra-processed milkshake high in fat and sugar in 50 young, healthy adults over a wide body mass index range (BMI 20-45 kg/m2). Surprisingly, milkshake consumption did not result in significant postingestive dopamine response in the striatum (p=0.62) nor any striatal subregion (p>0.33) and the highly variable interindividual responses were not significantly related to adiposity (BMI: r=0.076, p=0.51; %body fat: r=0.16, p=0.28). Thus, postingestive striatal dopamine responses to an ultra-processed milkshake were likely substantially smaller than many addictive drugs and below the limits of detection using standard PET methods.

On the pathogenesis of obesity: causal models and missing pieces of the puzzle.

Application of the physical laws of energy and mass conservation at the whole-body level is not necessarily informative about causal mechanisms of weight gain and the development of obesity. The energy balance model (EBM) and the carbohydrate-insulin model (CIM) are two plausible theories, among several others, attempting to explain why obesity develops within an overall common physiological framework of regulation of human energy metabolism. These models have been used to explain the pathogenesis of obesity in individuals as well as the dramatic increases in the prevalence of obesity worldwide over the past half century. Here, we summarize outcomes of a recent workshop in Copenhagen that brought together obesity experts from around the world to discuss causal models of obesity pathogenesis. These discussions helped to operationally define commonly used terms; delineate the structure of each model, particularly focussing on areas of overlap and divergence; challenge ideas about the importance of purported causal factors for weight gain; and brainstorm on the key scientific questions that need to be answered. We hope that more experimental research in nutrition and other related fields, and more testing of the models and their predictions will pave the way and provide more answers about the pathogenesis of obesity than those currently available.

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.

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.

EMPOWER: Enacting Materials to Promote Ownership, Engagement, and Relevance.

Fostering locally relevant and community-centered forms of science learning that develop students' critical science agency problematizes a "one-size-fits-all" model of teacher learning; teachers must examine how community needs and resources, local inequities and justice issues, and curriculum materials can converge to design novel learning opportunities for science learners. This paper presents the core commitments of EMPOWER, a cross-institutional effort that aims to support teachers' sensemaking and adaptations of curriculum materials to promote student ownership, engagement, and relevance at multiple sites across the U.S.

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.

Addressing Bioethical Implications of Implementing Diversion Programs in Resource-Constrained Service Environments.

The opioid epidemic demands the development, implementation, and evaluation of innovative, research-informed practices such as diversion programs. Aritürk et al. have articulated important bioethical considerations for implementing diversion programs in resource-constrained service environments. In this commentary, we expand and advance Aritürk et al.'s discussion by discussing existing resources that can be utilized to implement diversion programs that prevent or otherwise minimize the issues of autonomy, non-maleficence, beneficence, and justice identified by Aritürk et al.

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.

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.

UPDATE trial: investigating the effects of ultra-processed versus minimally processed diets following UK dietary guidance on health outcomes: a protocol for an 8-week community-based cross-over randomised controlled trial in people with overweight or obesity, followed by a 6-month behavioural intervention.

INTRODUCTION: Obesity increases the risk of morbidity and mortality. A major driver has been the increased availability of ultra-processed food (UPF), now the main UK dietary energy source. The UK Eatwell Guide (EWG) provides public guidance for a healthy balanced diet but offers no UPF guidance. Whether a healthy diet can largely consist of UPFs is unclear. No study has assessed whether the health impact of adhering to dietary guidelines depends on food processing. Furthermore, our study will assess the impact of a 6-month behavioural support programme aimed at reducing UPF intake in people with overweight/obesity and high UPF intakes. METHODS AND ANALYSIS: UPDATE is a 2×2 cross-over randomised controlled trial with a 6-month behavioural intervention. Fifty-five adults aged ≥18, with overweight/obesity (≥25 to <40 kg/m2), and ≥50% of habitual energy intake from UPFs will receive an 8-week UPF diet and an 8-week minimally processed food (MPF) diet delivered to their home, both following EWG recommendations, in a random order, with a 4-week washout period. All food/drink will be provided. Participants will then receive 6 months of behavioural support to reduce UPF intake. The primary outcome is the difference in weight change between UPF and MPF diets from baseline to week 8. Secondary outcomes include changes in diet, waist circumference, body composition, heart rate, blood pressure, cardiometabolic risk factors, appetite regulation, sleep quality, physical activity levels, physical function/strength, well-being and aspects of behaviour change/eating behaviour at 8 weeks between UPF/MPF diets, and at 6-month follow-up. Quantitative assessment of changes in brain MRI functional resting-state connectivity between UPF/MPF diets, and qualitative analysis of the behavioural intervention for feasibility and acceptability will be undertaken. ETHICS AND DISSEMINATION: Sheffield Research Ethics Committee approved the trial (22/YH/0281). Peer-reviewed journals, conferences, PhD thesis and lay media will report results. TRIAL REGISTRATION NUMBER: NCT05627570.

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 .

A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines.

Decentralized manufacture of thermostable mRNA vaccines in a microneedle patch (MNP) format could enhance vaccine access in low-resource communities by eliminating the need for a cold chain and trained healthcare personnel. Here we describe an automated process for printing MNP Coronavirus Disease 2019 (COVID-19) mRNA vaccines in a standalone device. The vaccine ink is composed of lipid nanoparticles loaded with mRNA and a dissolvable polymer blend that was optimized for high bioactivity by screening formulations in vitro. We demonstrate that the resulting MNPs are shelf stable for at least 6 months at room temperature when assessed using a model mRNA construct. Vaccine loading efficiency and microneedle dissolution suggest that efficacious, microgram-scale doses of mRNA encapsulated in lipid nanoparticles could be delivered with a single patch. Immunizations in mice using manually produced MNPs with mRNA encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain stimulate long-term immune responses similar to those of intramuscular administration.

Physiology of the Weight Loss Plateau after Calorie Restriction, GLP-1 Receptor Agonism, and Bariatric Surgery.

Objective: 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 balance and body composition dynamics was used to simulate mean weight loss trajectories in response to intensive calorie restriction, semaglutide 2.4 mg, tirzepatide 10 mg, and Roux en-Y gastric bypass (RYGB) surgery interventions. Each intervention was simulated by varying two model parameters affecting energy intake to fit the observed mean weight loss data. One parameter represented the persistent magnitude of the intervention to shift 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 4-fold greater than calorie restriction and about double that of tirzepatide and semaglutide. All interventions except calorie 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 GLP-1 receptor agonism and RYGB surgery interventions act to weaken the appetite feedback control circuit regulating body weight and induce greater persistent effects to shift the body weight equilibrium as compared to intensive calorie restriction.

Hypoxia and HIF-1α promote lytic de novo KSHV infection.

IMPORTANCE: The current view is that the default pathway of Kaposi's sarcoma-associated herpesvirus (KSHV) infection is the establishment of latency, which is a prerequisite for lifelong infection and viral oncogenesis. This view about KSHV infection is supported by the observations that KSHV latently infects most of the cell lines cultured in vitro in the absence of any environmental stresses that may occur in vivo. The goal of this study was to determine the effect of hypoxia, a natural stress stimulus, on primary KSHV infection. Our data indicate that hypoxia promotes euchromatin formation on the KSHV genome following infection and supports lytic de novo KSHV infection. We also discovered that hypoxia-inducible factor-1α is required and sufficient for allowing lytic KSHV infection. Based on our results, we propose that hypoxia promotes lytic de novo infection in cells that otherwise support latent infection under normoxia; that is, the environmental conditions can determine the outcome of KSHV primary infection.

Diet order affects energy balance in randomized crossover feeding studies that vary in macronutrients but not ultra-processing.

BACKGROUND: Crossover studies can induce order effects, especially when they lack a wash-out period. OBJECTIVE: To explore diet order effects on energy balance and food intake between randomized diet order groups in two inpatient crossover studies originally designed to compare within-subject differences in ad libitum energy intake between either minimally processed low carbohydrate (LC) versus low fat (LF) diets or macronutrient-matched diets composed of mostly minimally processed food (MPF) or ultra-processed food (UPF). METHODS: Diet order group comparisons of changes in body weight, body composition, and differences in energy expenditure, and food intake were assessed over four weeks in 20 adults randomized to either the LC followed immediately by the LF diet (LC→LF) or the opposite order (LF→LC) as well as 20 adults randomized to either the MPF followed by UPF (MPF→UPF) diets or the opposite order (UPF→MPF). RESULTS: Subjects randomized 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 922 ± 304 kcal/d less than the LF→LC group (p = 0.0024). Reduced energy intake in LC→LF vs LF→LC was driven by the last two weeks (-1610 ± 306 kcal/d; p<0.00001) perhaps due to carryover effects of gut adaptations over the first two weeks arising from large differences in the mass of food (1295 ± 209 g/d; p<0.00001) and fiber intake (58 ± 5 g/d; p<0.00001). There were no diet order effects on ad libitum energy intake, body weight, or body composition change between UPF→MPF versus MPF→UPF groups. CONCLUSIONS: Diet order influences daily ad libitum energy intake, body weight change, and fat change within the context of a 4-week crossover inpatient diet study varying in macronutrients, but not varying in extent and purpose of processing. Funding sources: Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Clinical Trial Registration: NCT03407053 and NCT03878108.

New insights in the mechanisms of weight-loss maintenance: Summary from a Pennington symposium.

Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long-term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight-loss maintenance, and systems-level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight-reduced state.