The Personalized Nutrition Study (POINTS): evaluation of a genetically informed weight loss approach, a Randomized Clinical Trial.

Weight loss (WL) differences between isocaloric high-carbohydrate and high-fat diets are generally small; however, individual WL varies within diet groups. Genotype patterns may modify diet effects, with carbohydrate-responsive genotypes losing more weight on high-carbohydrate diets (and vice versa for fat-responsive genotypes). We investigated whether 12-week WL (kg, primary outcome) differs between genotype-concordant and genotype-discordant diets. In this 12-week single-center WL trial, 145 participants with overweight/obesity were identified a priori as fat-responders or carbohydrate-responders based on their combined genotypes at ten genetic variants and randomized to a high-fat (n = 73) or high-carbohydrate diet (n = 72), yielding 4 groups: (1) fat-responders receiving high-fat diet, (2) fat-responders receiving high-carbohydrate diet, (3) carbohydrate-responders receiving high-fat diet, (4) carbohydrate-responders receiving high-carbohydrate diet. Dietitians delivered the WL intervention via 12 weekly diet-specific small group sessions. Outcome assessors were blind to diet assignment and genotype patterns. We included 122 participants (54.4 [SD:13.2] years, BMI 34.9 [SD:5.1] kg/m2, 84% women) in the analyses. Twelve-week WL did not differ between the genotype-concordant (-5.3 kg [SD:1.0]) and genotype-discordant diets (-4.8 kg [SD:1.1]; adjusted difference: -0.6 kg [95% CI: -2.1,0.9], p = 0.50). With the current ability to genotype participants as fat- or carbohydrate-responders, evidence does not support greater WL on genotype-concordant diets. ClinicalTrials identifier: NCT04145466.

Physiologic hormone administration improves HbA1C in Native Americans with type 2 diabetes: A retrospective study and review of insulin secretion and action.

Insulin is secreted in pulses from pancreatic beta-cells, and these oscillations maintain fasting plasma glucose levels within a narrow normal range. Within islets, beta-cells exhibit tight synchronization of regular oscillations. This control circuit is disrupted in type 2 diabetes, and irregularities in pulse frequency and amplitude occur. The prevalence of type 2 diabetes is three times higher in American Indian and Native Alaskans compared to Whites, and their genetic ancestry is associated with low beta-cell function. Obesity in this population compounds their vulnerability to adverse outcomes. The purpose of this article is to review insulin secretion and action and its interaction with race. We also present the results from a 6-month retrospective chart review of metabolic outcomes following intravenous physiologic hormone administration to 10 Native Americans. We found reductions in hemoglobin A1C (baseline: 9.03% ± 2.08%, 6 months: 7.03% ± 0.73%, p = 0.008), fasting glucose (baseline: 176.0 ± 42.85 mg/dL, 6 months: 137.11 ± 17.05 mg/dL, p = 0.02), homeostatic model assessment of insulin resistance (baseline: 10.39 ± 4.66, 6 months: 7.74 ± 4.22, p = 0.008), and triglycerides (baseline: 212.20 ± 101.44, 6 months: 165.50 ± 76.48 mg/dL, p = 0.02). Physiologic hormone administration may improve components of the metabolic syndrome. The therapy warrants investigation in randomized controlled trials.

Naringenin and ß-carotene convert human white adipocytes to a beige phenotype and elevate hormone- stimulated lipolysis.

Introduction: Naringenin, a peroxisome proliferator-activated receptor (PPAR) activator found in citrus fruits, upregulates markers of thermogenesis and insulin sensitivity in human adipose tissue. Our pharmacokinetics clinical trial demonstrated that naringenin is safe and bioavailable, and our case report showed that naringenin causes weight loss and improves insulin sensitivity. PPARs form heterodimers with retinoic-X-receptors (RXRs) at promoter elements of target genes. Retinoic acid is an RXR ligand metabolized from dietary carotenoids. The carotenoid ß-carotene reduces adiposity and insulin resistance in clinical trials. Our goal was to examine if carotenoids strengthen the beneficial effects of naringenin on human adipocyte metabolism. Methods: Human preadipocytes from donors with obesity were differentiated in culture and treated with 8µM naringenin + 2µM ß-carotene (NRBC) for seven days. Candidate genes involved in thermogenesis and glucose metabolism were measured as well as hormone-stimulated lipolysis. Results: We found that ß-carotene acts synergistically with naringenin to boost UCP1 and glucose metabolism genes including GLUT4 and adiponectin, compared to naringenin alone. Protein levels of PPARα, PPARγ and PPARγ-coactivator-1α, key modulators of thermogenesis and insulin sensitivity, were also upregulated after treatment with NRBC. Transcriptome sequencing was conducted and the bioinformatics analyses of the data revealed that NRBC induced enzymes for several non-UCP1 pathways for energy expenditure including triglyceride cycling, creatine kinases, and Peptidase M20 Domain Containing 1 (PM20D1). A comprehensive analysis of changes in receptor expression showed that NRBC upregulated eight receptors that have been linked to lipolysis or thermogenesis including the ß1-adrenergic receptor and the parathyroid hormone receptor. NRBC increased levels of triglyceride lipases and agonist-stimulated lipolysis in adipocytes. We observed that expression of RXRγ, an isoform of unknown function, was induced ten-fold after treatment with NRBC. We show that RXRγ is a coactivator bound to the immunoprecipitated PPARγ protein complex from white and beige human adipocytes. Discussion: There is a need for obesity treatments that can be administered long-term without side effects. NRBC increases the abundance and lipolytic response of multiple receptors for hormones released after exercise and cold exposure. Lipolysis provides the fuel for thermogenesis, and these observations suggest that NRBC has therapeutic potential.

Orlistat mouth rinse: Using the tongue to deliver antiobesity medication in a double-blind randomized crossover pilot trial.

AIM: To investigate the effects of an orlistat mouth rinse on the intake of a high-fat meal. METHODS: A double-blind, balanced order, crossover study was conducted in participants (n = 10, body mass index 25-30 kg/m2 ) assigned to receive placebo or orlistat (24 mg/mL) prior to a high-fat meal. Participants were divided into low- or high-fat consumers based on calories consumed from fat following placebo administration. RESULTS: The orlistat mouth rinse decreased total and fat calories consumed during the high-fat meal in high-fat consumers, and did not alter calories consumed in low-fat consumers (P < 0.05). CONCLUSIONS: Orlistat decreases long-chain fatty acid (LCFA) absorption by inhibiting lipases that breakdown triglycerides. Orlistat mouth rinse decreased fat intake in high-fat consumers, suggesting that orlistat inhibited the detection of LCFAs from the high-fat test meal. Lingual delivery of orlistat is predicted to eliminate the risk of oil incontinence and promote weight loss in individuals who prefer fat.

A scalable, virtual weight management program tailored for adults with type 2 diabetes: effects on glycemic control.

BACKGROUND: The objective was to test the efficacy of a scalable, virtually delivered, diabetes-tailored weight management program on glycemic control in adults with type 2 diabetes (T2D). METHODS: This was a single arm, three-site clinical trial. Participants had baseline HbA1c between 7-11% and BMI between 27-50 kg/m2. Primary outcome was change in HbA1c at 24 weeks. Secondary outcomes were changes in body weight, waist circumference, the Diabetes Distress Scale (DDS), quality of life (IWQOL-L), and hunger (VAS). Generalized linear effects models were used for statistical analysis. RESULTS: Participants (n = 136) were 56.8 ± 0.8 y (Mean ± SEM), 36.9 ± 0.5 kg/m2, 80.2% female, 62.2% non-Hispanic white. Baseline HbA1c, weight, and total DDS score were 8.0 ± 0.09%, 101.10 ± 1.47 kg, and 2.35 ± 0.08, respectively. At week 24, HbA1c, body weight, and total DDS decreased by 0.75 ± 0.11%, 5.74 ± 0.50%, 0.33 ± 0.10 units, respectively (all p < 0.001). Also, at week 24, quality of life increased by 9.0 ± 1.2 units and hunger decreased by 14.3 ± 2.4 units, (both p < 0.0001). CONCLUSIONS: The scalable, virtually delivered T2D-tailored weight management program had favorable and clinically meaningful effects on glycemic control, body weight, and psychosocial outcomes.

Safety and Tolerability of Whole Soybean Products: A Dose-Escalating Clinical Trial in Older Adults with Obesity.

Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70-85 years) with obesity. Whole green soybean pods grown under controlled conditions were processed to flour (WGS) at the United States Department of Agriculture using common cooking techniques such as slicing and heat treatment. WGS incorporated into food products was consumed at 10 g, 20 g, and 30 g/day for one week at each dose. The gastrointestinal outcomes, clinical biomarkers, and adverse events were evaluated. We explored the stimulation of phytoalexin (glyceollin) production in live viable soybean seeds (LSS-G). We compared the compositions of WGS and LSS-G with commercial soybean flour and its fermented and enzymatically hydrolyzed forms. We found that although 30 g WSG was well-tolerated, and it made participants feel full. Our processing produced glyceollins (267 µg/g) in LSS-G. Processing soybean flour decreased the iron content, but reduced the oligosaccharides, which could attenuate flatulence. Providing soybean flour at <30 g/day may be prudent for overall health and to prevent the exclusion of other food groups and nutrients in older adults with obesity.

Bioelectrical impedance phase angle is associated with physical performance before but not after simulated multi-stressor military operations.

Physical performance decrements observed during multi-stressor military operations may be attributed, in part, to cellular membrane dysfunction, which is quantifiable using phase angle (PhA) derived from bioelectrical impedance analysis (BIA). Positive relationships between PhA and performance have been previously reported in cross-sectional studies and following longitudinal exercise training programs, but whether changes in PhA are indicative of acute decrements in performance during military operations is unknown. Data from the Optimizing Performance for Soldiers II study, a clinical trial examining the effects of exogenous testosterone administration on body composition and performance during military stress, was used to evaluate changes in PhA and their associations with physical performance. Recreationally active, healthy males (n = 34; 26.6 ± 4.3 years; 77.9 ± 12.4 kg) were randomized to receive testosterone undecanoate or placebo before a 20-day simulated military operation, which was followed by a 23-day recovery period. PhA of the whole-body (Whole) and legs (Legs) and physical performance were measured before (PRE) and after (POST) the simulated military operation as well as in recovery (REC). Independent of treatment, PhAWhole and PhALegs decreased from PRE to POST (p < 0.001), and PhALegs , but not PhAWhole , remained lower at REC than PRE. PhAWhole at PRE and REC were associated with vertical jump height and Wingate peak power (p < 0.001-0.050), and PhAWhole at PRE was also associated with 3-RM deadlift mass (p = 0.006). However, PhA at POST and changes in PhA from PRE to POST were not correlated with any performance measure (p > 0.05). Additionally, PhA was not associated with aerobic performance at any timepoint. In conclusion, reduced PhA from PRE to POST provides indirect evidence of cellular membrane disruption. Associations between PhA and strength and power were only evident at PRE and REC, suggesting PhA may be a useful indicator of strength and power, but not aerobic capacity, in non-stressed conditions, and not a reliable indicator of physical performance during severe physiological stress.

Effect of exercise training on insulin-stimulated glucose disposal: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: The effect of exercise training on whole-body insulin sensitivity has not been systematically summarized. We aimed to summarize the data from randomized controlled trials evaluating the effect of exercise training on insulin action, in adults. SUBJECTS: MEDLINE, EMBASE, and CENTRAL databases were searched until January 2021. Randomized controlled trials lasting ≥4 weeks, including adults, and evaluating the effect of exercise on insulin-stimulated glucose disposal measured using the hyperinsulinemic euglycemic clamp, were included. METHODS: Three reviewers extracted summary data from published trials. The primary outcome was insulin-stimulated glucose disposal. Standardized weighted mean differences (SMD) in glucose disposal between intervention and control were compared. The PEDro scale was used to assess risk of bias. RESULTS: We included 25 trials (36 interventions, N = 851). Exercise increased insulin-stimulated glucose disposal relative to control, SMD = 0.52 (95% confidence interval [CI]: 0.39, 0.65; p < 0.001; I2 = 47%) without significantly suppressing hepatic glucose production. In trials without isotopic tracers, exercise increased glucose disposal (SMD = 0.63; 95% CI: 0.48, 0.77; p < 0.001, I2 = 55%). In trials with isotopic tracers, exercise increased glucose disposal only when tracers were added to the exogenous glucose used for clamping (SMD = 0.34; 95% CI: 0.03, 0.66, p = 0.034. I2 = 0%). In a meta-regression model including aerobic exercise, weight change, and tracer technique, only percent weight change explained between trial heterogeneity (ß = 0.069; 95% CI: 0.005, 0.013). The PEDro rating indicated relatively low risk of bias (5.8 ± 0.22). CONCLUSIONS: Exercise training for at least four weeks significantly increases insulin-stimulated glucose disposal. Weight loss maximizes the effect and may be needed to improve hepatic insulin sensitivity. Differences in tracer methodology contribute to divergent outcomes and should be considered when assessing conclusions from research examining the effect of exercise on insulin action. REGISTRATION: PROSPERO (CRD42019124381).

Low-Energy Dense Potato- and Bean-Based Diets Reduce Body Weight and Insulin Resistance: A Randomized, Feeding, Equivalence Trial.

We evaluated the effect of diets low in energy density (1 kcal/g) and high in either potatoes (Potato) or pulses (Bean) on blood glucose control in participants with insulin resistance. We hypothesized that the Potato and Bean diets would have equivalent effects. This was an 8-week randomized, parallel design, controlled feeding study comparing Potato and Bean diets (50-55% carbohydrate, 30-35% fat, 15-20% protein). Equivalence was prespecified as the mean change in the blood glucose concentration for Potato that was within ±20% of the Bean diet. Thirty-six participants (age: 18-60 years, body mass index: 25-40 kg/m2) with insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] >2) were enrolled. Body weight was measured, and subjects underwent a mixed meal tolerance test at baseline and after 8 weeks. Intent-to-treat (ITT) and completer analyses were conducted. Equivalence between the two diets in the area under the curve for serum glucose was attained within ±10%, but the reduction from baseline was not statistically significant. For the Bean diet, insulin (area under the response curve: -2136.3 ± 955.5 mg/[dL∙min], P = .03) and HOMA-IR (-1.4 ± 0.6, P = .02) were lower compared with baseline. ITT and completer analyses were similar, except that HOMA-IR was also reduced by the Potato diet (-1.3 ± 0.6, P < .05). Compliance with the diets was 87-88%, and body weight was reduced in both diets (Potato: -5.6% ± 0.6%; Bean: -4.1% ± 0.6%, P < .001) with no significant difference between the two diets. Potato and Bean diets low in energy density were equally effective in reducing insulin resistance and promoting weight loss in individuals with impaired blood glucose control. Clinical Trial: The trial was registered with ClinicalTrials.gov Identifier: NCT04203238.

Testosterone undecanoate administration prevents declines in fat-free mass but not physical performance during simulated multi-stressor military operations.

Male military personnel conducting strenuous operations experience reduced testosterone concentrations, muscle mass, and physical performance. Pharmacological restoration of normal testosterone concentrations may attenuate performance decrements by mitigating muscle mass loss. Previously, administering testosterone enanthate (200 mg/wk) during 28 days of energy deficit prompted supraphysiological testosterone concentrations and lean mass gain without preventing isokinetic/isometric deterioration. Whether administering a practical dose of testosterone protects muscle and performance during strenuous operations is undetermined. The objective of this study was to test the effects of a single dose of testosterone undecanoate on body composition and military-relevant physical performance during a simulated operation. After a 7-day baseline phase (P1), 32 males (means ± SD; 77.1 ± 12.3 kg, 26.5 ± 4.4 yr) received a single dose of either testosterone undecanoate (750 mg; TEST) or placebo (PLA) before a 20-day simulated military operation (P2), followed by a 23-day recovery (P3). Assessments included body composition and physical performance at the end of each phase and circulating endocrine biomarkers throughout the study. Total and free testosterone concentrations in TEST were greater than PLA throughout most of P2 (P < 0.05), but returned to P1 values during P3. Fat-free mass (FFM) was maintained from P1 to P2 in TEST (means ± SE; 0.41 ± 0.65 kg, P = 0.53), but decreased in PLA (-1.85 ± 0.69 kg, P = 0.01) and recovered in P3. Regardless of treatment, total body mass and fat mass decreased from P1 to P2 (P < 0.05), but did not fully recover by P3. Physical performance decreased during P2 (P < 0.05) and recovered by P3, regardless of treatment. In conclusion, administering testosterone undecanoate before a simulated military operation protected FFM but did not prevent decrements in physical performance.NEW & NOTEWORTHY This study demonstrated that a single intramuscular dose of testosterone undecanoate (750 mg) administered to physically active males before a 20-day simulated, multi-stressor military operation increased circulating total and free testosterone concentrations within normal physiological ranges and spared FFM. However, testosterone administration did not attenuate decrements in physical performance across multiple measures of power, strength, anaerobic or aerobic capacity.

Technical report: an online international weight control registry to inform precision approaches to healthy weight management.

BACKGROUND: Personalizing approaches to prevention and treatment of obesity will be a crucial aspect of precision health initiatives. However, in considering individual susceptibility to obesity, much remains to be learned about how to support healthy weight management in different population subgroups, environments and geographical locations. SUBJECTS/METHODS: The International Weight Control Registry (IWCR) has been launched to facilitate a deeper and broader understanding of the spectrum of factors contributing to success and challenges in weight loss and weight loss maintenance in individuals and across population groups. The IWCR registry aims to recruit, enroll and follow a diverse cohort of adults with varying rates of success in weight management. Data collection methods include questionnaires of demographic variables, weight history, and behavioral, cultural, economic, psychological, and environmental domains. A subset of participants will provide objective measures of physical activity, weight, and body composition along with detailed reports of dietary intake. Lastly, participants will be able to provide qualitative information in an unstructured format on additional topics they feel are relevant, and environmental data will be obtained from public sources based on participant zip code. CONCLUSIONS: The IWCR will be a resource for researchers to inform improvements in interventions for weight loss and weight loss maintenance in different countries, and to examine environmental and policy-level factors that affect weight management in different population groups. This large scale, multi-level approach aims to inform efforts to reduce the prevalence of obesity worldwide and its associated comorbidities and economic impacts. TRIAL REGISTRATION: NCT04907396 (clinicaltrials.gov) sponsor SB Roberts; Tufts University IRB #13075.

Effects of acute arginine supplementation on neuroendocrine, metabolic, cardiovascular, and mood outcomes in younger men: A double-blind, placebo-controlled trial.

OBJECTIVES: Arginine is an amino-acid supplement and precursor for nitric-oxide synthesis, which affects various biologic processes. The objective of this study was to determine the effects of arginine supplementation on growth hormone (GH) and metabolic parameters. METHODS: Thirty physically active, healthy men (age 18-39 y; body mass index: 18.5-25 kg/m2) were randomized in a double-blind, placebo-controlled, crossover trial. Arginine (10 g) and placebo (0 g) beverages were consumed after an overnight fast. Blood samples were collected at baseline and 1.5, 3.0, and 24 h after supplementation. The primary outcomes were serum GH and metabolomics. Also, amino acids, glucose, insulin, triacylglycerols, thyroid hormones, testosterone, cortisol, dehydroepiandrosterone, and mood state were assessed. Individuals with detectable increases in GH were analyzed separately (responders: n = 16; < 0.05 ng/mL at 1.5 h). Repeated-measure analyses of variance estimated the treatment effects at each timepoint. RESULTS: Arginine levels increased at 1.5 h (146%) and 3.0 h (95%; P ≤ 0.001) and GH (193%) and thyroid-stimulating hormone (TSH; 10%) levels at 24 h (P < 0.05) after arginine versus placebo consumption. Arginine versus placebo increased glucose levels at 1.5 h (5%) and 3.0 h (3%; P ≤ 0.001). Arginine versus placebo did not affect other dependent measures, including mood state (P > 0.05), but changes in the urea, glutamate, and citric-acid pathways were observed. Among responders, arginine versus placebo increased GH at 1.5 h (37%), glucose at 1.5 h (4%) and 3.0 h (4%), and TSH at 24 h (9%; P < 0.05). Responders had higher levels of benzoate metabolites at baseline and 1.5 h, and an unknown compound (X-16124) at baseline, 1.5 h, and 24 h that corresponds to a class of gut microbes (P < 0.05). CONCLUSIONS: Arginine supplementation modestly increased GH, glucose, and TSH levels in younger men. Responders had higher benzoate metabolites and an unknown analyte attributed to the gut microbiome. Future studies should examine whether the increased prevalence of these gut microorganisms corresponds with GH response after arginine supplementation.

Sympathomimetic increases resting energy expenditure following bariatric surgery: A randomized controlled clinical trial.

OBJECTIVE: The aim of this study was to test the hypothesis that ephedrine + caffeine (EC) reduces the fall in resting energy expenditure (REE) following bariatric surgery. METHODS: This 32-week, randomized, double-blinded, placebo-controlled trial included 142 patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery. Participants were randomized to either EC or placebo for 27 weeks, beginning 5 weeks post surgery. The primary end points were change in REE (measured), percentage of predicted REE ([measured REE/Harris-Benedict equation-predicted REE] × 100), and body composition. Secondary outcomes included change in percentage of weight. Adverse events (AEs) were recorded. RESULTS: The reduction in REE was smaller in the EC versus the placebo group, but it was not significant. Percentage of predicted REE was increased in the EC versus the placebo group (difference, mean [SE]: 5.82 [2.29], p = 0.013). Percentage of weight (difference: -3.83 [1.39], p = 0.007) was reduced in the EC versus the placebo group. Percentage of predicted REE was increased and body weight decreased in the EC-treated participants who underwent SG compared with those who underwent SG and were treated with placebo (difference in percentage of predicted REE = 8.06 [2.83], p = 0.006; difference in weight percentage = -4.37 [1.92], p = 0.025). Percentage of fat-free mass was increased in the SG participants treated with EC versus placebo (difference: 1.31 [0.63], p = 0.042). The most common AEs were anxiety, dizziness, insomnia, and tremors. Most AEs were not different from placebo by Week 32. CONCLUSIONS: EC enhances weight loss and reduces the fall in REE following bariatric surgery. Adrenergic symptoms mostly resolve over time.

Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial.

Importance: Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. Objective: To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity. Design, Setting, and Participants: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338). Interventions: Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85). Main Outcomes and Measures: The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points. Results: Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide. Conclusions and Relevance: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04074161.

Exercise as a Moderator of Persistent Neuroendocrine Symptoms of COVID-19.

Precipitated by chronic psychological stress, immune system dysregulation, and a hyperinflammatory state, the sequelae of postacute COVID-19 (long COVID) include depression and new-onset diabetes. We hypothesize that exercise counters the neuropsychiatric and endocrine sequelae of long COVID by inducing the release of circulating factors that mediate the anti-inflammatory response, support brain homeostasis, and increase insulin sensitivity.

MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect.

A glucose-lowering medication that acts by a different mechanism than metformin, or other approved diabetes medications, can supplement monotherapies when patients fail to meet blood glucose goals. We examined the actions underlying the effects of an insulin sensitizer, tolimidone (MLR-1023) and investigated its effects on body weight. Diet-induced obesity (CD1/ICR) and type 2 diabetes (db/db) mouse models were used to study the effect of MLR-1023 on metabolic outcomes and to explore its synergy with menthol. We also examined the efficacy of MLR-1023 alone in a clinical trial (NCT02317796), as well as in combination with menthol in human adipocytes. MLR-1023 produced weight loss in humans in four weeks, and in mice fed a high-fat diet it reduced weight gain and fat mass without affecting food intake. In human adipocytes from obese donors, the upregulation of Uncoupling Protein 1, Glucose (UCP)1, adiponectin, Glucose Transporter Type 4 (GLUT4), Adipose Triglyceride Lipase (ATGL), Carnitine palmitoyltransferase 1 beta (CPT1ß), and Transient Receptor Potential Melastin (TRPM8) mRNA expression suggested the induction of thermogenesis. The TRPM8 agonist, menthol, potentiated the effect of MLR-1023 on the upregulation of genes for energy expenditure and insulin sensitivity in human adipocytes, and reduced fasting blood glucose in mice. The amplification of the thermogenic program by MLR-1023 and menthol in the absence of adrenergic activation will likely be well-tolerated, and bears investigation in a clinical trial.

Measuring ketone bodies for the monitoring of pathologic and therapeutic ketosis.

BACKGROUND: The ketone bodies ß-hydroxybutyrate (BOHB) and acetone are generated as a byproduct of the fat metabolism process. In healthy individuals, ketone body levels are ∼0.1 mM for BOHB and ∼1 part per million for breath acetone (BrAce). These levels can increase dramatically as a consequence of a disease process or when used therapeutically for disease treatment. For example, increased ketone body concentration during weight loss is an indication of elevated fat metabolism. Ketone body measurement is relatively inexpensive and can provide metabolic insights to help guide disease management and optimize weight loss. METHODS: This review of the literature provides metabolic mechanisms and typical concentration ranges of ketone bodies, which can give new insights into these conditions and rationale for measuring ketone bodies. RESULTS: Diseases such as heart failure and ketoacidosis can affect caloric intake and macronutrient management, which can elevate BOHB 30-fold and BrAce 1000-fold. Other diseases associated with obesity, such as brain dysfunction, cancer, and diabetes, may cause dysfunction because of an inability to use glucose, excessive reliance on glucose, or poor insulin signaling. Elevating ketone body concentrations (e.g., nutritional ketosis) may improve these conditions by forcing utilization of ketone bodies, in place of glucose, for fuel. During weight loss, monitoring ketone body concentration can demonstrate program compliance and can be used to optimize the weight-loss plan. CONCLUSIONS: The role of ketone bodies in states of pathologic and therapeutic ketosis indicates that accurate measurement and monitoring of BOHB or BrAce will likely improve disease management. Bariatric surgery is examined as a case study for monitoring both types of ketosis.

Effects of testosterone undecanoate on performance during multi-stressor military operations: A trial protocol for the Optimizing Performance for Soldiers II study.

BACKGROUND: Previously, young males administered 200 mg/week of testosterone enanthate during 28 days of energy deficit (EDef) gained lean mass and lost less total mass than controls (Optimizing Performance for Soldiers I study, OPS I). Despite that benefit, physical performance deteriorated similarly in both groups. However, some experimental limitations may have precluded detection of performance benefits, as performance measures employed lacked military relevance, and the EDef employed did not elicit the magnitude of stress typically experienced by Soldiers conducting operations. Additionally, the testosterone administered required weekly injections, elicited supra-physiological concentrations, and marked suppression of endogenous testosterone upon cessation. Therefore, this follow-on study will address those limitations and examine testosterone's efficacy for preserving Solder performance during strenuous operations. METHODS: In OPS II, 32 males will participate in a randomized, placebo-controlled, double-blind trial. After baseline testing, participants will be administered either testosterone undecanoate (750 mg) or placebo before completing four consecutive, 5-day cycles simulating a multi-stressor, sustained military operation (SUSOPS). SUSOPS will consist of two low-stress days (1000 kcal/day exercise-induced EDef; 8 h/night sleep), followed by three high-stress days (3000 kcal/day and 4 h/night). A 23-day recovery period will follow SUSOPS. Military relevant physical performance is the primary outcome. Secondary outcomes include 4-comparment body composition, muscle and whole-body protein turnover, intramuscular mechanisms, biochemistries, and cognitive function/mood. CONCLUSIONS: OPS II will determine if testosterone undecanoate safely enhances performance, while attenuating muscle and total mass loss, without impairing cognitive function, during and in recovery from SUSOPS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04120363.