Anti-obesity and metabolic benefits of metformin: Comparison of different delivery routes.

Obesity is a severe public health problem. Healthy lifestyle interventions are commonly recommended for fighting obesity. But they are hard to follow and have low efficacy. Pharmacotherapy and surgery are of high efficacy but are beset with side effects. Browning subcutaneous white adipose tissue (WAT) is a practical and efficient approach for combating obesity. Metformin, a commonly used FDA-approved antidiabetic drug, is potent to induce browning of WAT through phosphorylation and activation of AMP-activated protein kinase. However, oral administration of metformin has low oral bioavailability, fast renal clearance, and low target specificity that limit metformin's application in browning WAT. Local and transdermal delivery of metformin directly to subcutaneous WAT using injection or microneedle (MN) in combination with iontophoresis (INT) may solve these problems. In this paper, we administered metformin to C57BL/6J obese mice using the following three routes: transdermal delivery (MN and INT), local injection into inguinal WAT (IgWAT, a type of subcutaneous WAT in mice), and oral gavage. The anti-obesity and metabolic effects of metformin via these delivery routes were determined and compared. As compared to local IgWAT injection and oral gavage delivery, transdermal delivery of metformin using MN and INT resulted in 9% lower body weight and 7% decrease in body fat% accompanied by improved energy metabolism and decreased inflammation through browning IgWAT in obese C57BL/6J mice. Transdermal delivery of metformin using MN and INT is an effective approach in browning subcutaneous WAT for combating obesity and improving metabolic health.

Effects of a Theory-Based, Multicomponent eHealth Intervention for Obesity Prevention in Young Children from Low-Income Families: A Pilot Randomized Controlled Study.

The purpose of this study was to evaluate a theory-based, multicomponent eHealth intervention aimed at improving child health behaviors and parental psychosocial attributes and feeding practices. A pilot randomized controlled trial was conducted among 73 parents with children (1-3 years). Intervention group participants (IG, n = 37) received theory-based educational videos, cooking tutorials, and text messages with key information for a total of 8 weeks. Control group participants (CG, n = 36) received a booklet about general nutrition recommendations for children. A parent-administered questionnaire was used for data collection at baseline and post-intervention. Linear models were performed using R version 4.1.1. for data analysis. Children in the IG significantly increased their daily intake of fruit (ΔΔ = 0.89 servings, p = 0.00057) and vegetables (ΔΔ = 0.60 servings, p = 0.0037) and decreased use of screen time (ΔΔ = -33.87 min, p = 0.026), compared to the CG. Parents in the IG improved significantly more than the CG in self-efficacy (p = 0.0068) and comprehensive feeding practices (p = 0.0069). There were no significant differences between the study groups for changes in child outcomes, such as physical activity and sedentary behaviors, and parental nutrition knowledge and attitudes.

A Culturally Sensitive and Theory-Based Intervention on Prevention and Management of Diabetes: A Cluster Randomized Control Trial.

Type 2 diabetes is an emerging concern in Kenya. This clustered-randomized trial of peri-urban communities included a theory-based and culturally sensitive intervention to improve diabetes knowledge, health beliefs, dietary intake, physical activity, and weight status among Kenyan adults. Those in the intervention group (IG) received a culturally sensitive diabetes education intervention which applied the Health Belief Model in changing knowledge, health beliefs and behavior. Participants attended daily education sessions for 5 days, each lasting 3 h and received mobile phone messages for an additional 4 weeks. The control group (CG) received standard education on COVID-19. Data was collected at baseline, post-intervention (1 week), and follow-up assessment (5 weeks). Linear mixed effect analysis was performed to assess within and across group differences. Compared to the control, IG significantly increased diabetes knowledge (p < 0.001), health beliefs including perceived susceptibility (p = 0.05), perceived benefits (p = 0.04) and self-efficacy (p = 0.02). IG decreased consumption of oils (p = 0.03), refined grains (p = 0.01), and increased intake of fruits (p = 0.01). Perceived barriers, physical activity, and weight status were not significantly different between both groups. The findings demonstrate the potential of diabetes education in improving diabetes knowledge, health beliefs, and in changing dietary intake of among adults in Kenya.

Greater protein quality of an egg breakfast may be inadequate to induce satiety during weight loss, compared with a cereal breakfast of equal protein quantity.

We compared the effects of consuming egg-breakfast of superior protein quality to cereal-breakfast of similar energy density and protein quantity, but lower protein quality. Two, two-week randomised crossover clinical trials included 30 otherwise healthy women with overweight or obesity. Subjects received counselling to follow a reduced-calorie diet. Under supervision, participants consumed either breakfast for one-week then crossed over to the opposite breakfast. Experiment-1 outcome variables included post-breakfast appetite hormones, glucose and insulin, subjective markers of satiety and energy intake at lunch and dinner. In Experiment-2, an appealing food (brownies) was included in lunch. Following the breakfasts, Experiment-1 showed no significant differences in outcome variables. In Experiment-2, the egg-breakfast increased fullness (p = 0.038), but lunch-time energy intake was not different. If these findings apply to other breakfasts, it suggests that in comparing two breakfasts with similar protein quantity, the greater protein quality of a breakfast may not be adequate to induce satiety.

Transdermal Delivery of Metformin Using Dissolving Microneedles and Iontophoresis Patches for Browning Subcutaneous Adipose Tissue.

Obesity is a serious public health problem that is strongly associated with increased multiple comorbidities such as diabetes, cardiovascular disease, and some types of cancer. While current anti-obesity treatments have various issues, locally transforming energy-storing white adipose tissue (WAT) into energy-burning brown-like/beige adipose tissue, the so-called browning of WAT, has been suggested to enhance obesity treatment efficiency with minimized side effects. Metformin is a first-line antidiabetes drug and a potent activator of AMP-activated protein kinase. Emerging evidence has suggested that metformin might enhance energy expenditure via the browning of WAT and hence reduce body weight. Subcutaneous WAT is easier to access and has a stronger browning potential than other WAT depots. In this study, we used dissolvable poly (lactic-co-glycolic acid) microneedles (MN) to deliver metformin to the subcutaneous WAT in obese C57BL/6J mice with the assistance of iontophoresis (INT), and then investigated metformin-induced WAT browning and its subsequent thermogenesis effects. Compared with MN alone or INT alone, MN + INT had better anti-obesity activity, as indicated by decreasing body weight and fat gain, increased energy expenditure, decreased fat pad size, and improved energy metabolism through the browning of WAT. Browning subcutaneous WAT by delivering metformin and other browning agents using this MN + INT approach might combat obesity in an effective, easy, and safe regimen.

Egg and saturated fat containing breakfasts have no acute effect on acute glycemic control in healthy adults: a randomized partial crossover trial.

BACKGROUND/OBJECTIVES: High egg consumption is associated with poor glycemic control. Considering the widespread consumption of eggs, it is crucial to determine causality in this association. We tested if egg consumption acutely alters glucose disposal in the absence or presence of saturated fat, which is frequently consumed with eggs. SUBJECTS/METHODS: In a randomized partial crossover clinical trial, 48 subjects (consuming ≥ 1 egg/week) received two of four isocaloric, macronutrient-matched breakfasts. The groups were defined based on the main ingredient of the breakfasts offered: eggs (EB); saturated fat (SB); eggs and saturated fat (ES); and control, which included a cereal based breakfast (CB). The breakfasts were offered in two testing sessions spaced seven days apart. Six blood samples (pre breakfast (fasting); 30, 60, 90, 120, and 180 minutes post breakfast) were collected to measure glucose and insulin levels. Area under the curves (AUC) were analyzed controlling for the baseline concentrations using mixed-effects models accounting for within-subject dependencies to compare these across breakfast assignments. RESULTS: Forty-eight patients (46% males, age 25.8 ± 7.7 years, BMI 25.7 ± 4.6 kg/m2) were included. Neither EB, SB nor ES was associated with a significant difference in AUC of glucose or insulin compared to CB (p > 0.1). CONCLUSIONS: Acutely, consumption of egg breakfast with or without accompanying saturated fat does not adversely affect glucose disposal in healthy adults. While this is reassuring for continued egg consumption, a long-term evaluation of egg intake with or without saturated fat would be the next step.

Errors in the implementation, analysis, and reporting of randomization within obesity and nutrition research: a guide to their avoidance.

Randomization is an important tool used to establish causal inferences in studies designed to further our understanding of questions related to obesity and nutrition. To take advantage of the inferences afforded by randomization, scientific standards must be upheld during the planning, execution, analysis, and reporting of such studies. We discuss ten errors in randomized experiments from real-world examples from the literature and outline best practices for their avoidance. These ten errors include: representing nonrandom allocation as random, failing to adequately conceal allocation, not accounting for changing allocation ratios, replacing subjects in nonrandom ways, failing to account for non-independence, drawing inferences by comparing statistical significance from within-group comparisons instead of between-groups, pooling data and breaking the randomized design, failing to account for missing data, failing to report sufficient information to understand study methods, and failing to frame the causal question as testing the randomized assignment per se. We hope that these examples will aid researchers, reviewers, journal editors, and other readers to endeavor to a high standard of scientific rigor in randomized experiments within obesity and nutrition research.

Browning white adipose tissue using adipose stromal cell-targeted resveratrol-loaded nanoparticles for combating obesity.

Enhancing thermogenic energy expenditure via promoting the browning of white adipose tissue (WAT) is a potential therapeutic strategy to manage energy imbalance and the consequent comorbidities associated with excess body weight. Adverse effects and toxicities of currently available methods to induce browning of WAT have retarded exploration of this promising therapeutic approach. Targeted delivery of browning agents to adipose stromal cells (ASCs) in subcutaneous WAT to induce differentiation into beige adipocytes may overcome these barriers. Herein, we report for the first time, ASC-targeted delivery of trans-resveratrol (R), a representative agent, using ligand-coated R-encapsulated nanoparticles (L-Rnano) that selectively bind to glycanation site-deficient decorin receptors on ASCs. After biweekly intravenous administration of L-Rnano to obese C57BL/6 J mice for 5 weeks targeted R delivery significantly induced ASCs differentiation into beige adipocytes, which subsequently resulted in 40% decrease in fat mass, accompanied by improved glucose homeostasis and decreased inflammation. Our results suggest that the ASC-targeted nanoparticle delivery of browning agents could be a transformative technology in combating obesity and its comorbidities with high efficacy and low toxicity.

Persistent confusion in nutrition and obesity research about the validity of classic nonparametric tests in the presence of heteroscedasticity: evidence of the problem and valid alternatives.

The use of classic nonparametric tests (cNPTs), such as the Kruskal-Wallis and Mann-Whitney U tests, in the presence of unequal variance for between-group comparisons of means and medians may lead to marked increases in the rate of falsely rejecting null hypotheses and decreases in statistical power. Yet, this practice remains prevalent in the scientific literature, including nutrition and obesity literature. Some nutrition and obesity studies use a cNPT in the presence of unequal variance (i.e., heteroscedasticity), sometimes because of the mistaken rationale that the test corrects for heteroscedasticity. Herein, we discuss misconceptions of using cNPTs in the presence of heteroscedasticity. We then discuss assumptions, purposes, and limitations of 3 common tests used to test for mean differences between multiple groups, including 2 parametric tests: Fisher's ANOVA and Welch's ANOVA; and 1 cNPT: the Kruskal-Wallis test. To document the impact of heteroscedasticity on the validity of these tests under conditions similar to those used in nutrition and obesity research, we conducted simple simulations and assessed type I error rates (i.e., false positives, defined as incorrectly rejecting the null hypothesis). We demonstrate that type I error rates for Fisher's ANOVA, which does not account for heteroscedasticity, and Kruskal-Wallis, which tests for differences in distributions rather than means, deviated from the expected significance level. Greater deviation from the expected type I error rate was observed as the heterogeneity increased, especially in the presence of an imbalanced sample size. We provide brief tutorial guidance for authors, editors, and reviewers to identify appropriate statistical tests when test assumptions are violated, with a particular focus on cNPTs.

A short, attribution theory-based video intervention does not reduce weight bias in a nationally representative sample of registered dietitians: a randomized trial.

BACKGROUND/OBJECTIVES: Weight bias among registered dietitians (RDs) is a concern and effective interventions to reduce weight bias are sparse. Our objective was to determine if a short, attribution theory-based online video intervention would reduce weight bias in RDs. SUBJECTS/METHODS: Dietitians from a nationally representative sample were recruited for a randomized, parallel-arm study with online surveys at pre-, post-intervention and 1-month follow-up. One hundred and forty-seven RDs who watched one of three videos embedded in an online survey from June to August 2019 were considered for the analysis. RDs were randomized to watch either the intervention, positive control, or negative control video. The primary outcome was the change in the "blame" component of the Anti-Fat Attitude Test (AFAT) from pre-to immediate post-intervention. Differences in changes in AFAT and Implicit Association Test (IAT) scores across treatment groups were assessed via linear models; multiple imputation were performed for missing data. RESULTS: Baseline demographics, AFAT and IAT scores of the 147 participants who watched a video were not significantly different between the study groups (p > 0.05). The intervention group's AFAT-blame score reduced by an average of 0.05 between pre- and immediate post-intervention but was not statistically significant (p = 0.76, confidence intervals (CI) = -0.40, 0.30). Furthermore, there were no significant changes for AFAT-social, AFAT-physical subscores, and IAT within or between groups between pre- and immediate post-intervention (p > 0.05). Due to high attrition rates, the changes at 1-month follow-up are not reported. CONCLUSIONS: This study was the first to explore the effectiveness of an online video intervention to reduce weight bias in RDs. This study was unable to detect a significant impact of a short, attribution theory-based video intervention on weight bias in practicing RDs and future larger studies are needed to confirm our findings.

No association between consumption of eggs with energy or macronutrient intake: Objective evidence from the remote food photography method.

BACKGROUND AND AIMS: Greater egg consumption is associated with poor glycemic control. However, greater egg intake could simply be a marker for other dietary indiscretions such as greater intake of energy or saturated fat, which may influence glycemic control. We examined the association between egg consumption and total energy intake and saturated fat intake, measured using the remote food photography method. METHODS: An observational study was conducted with 48 healthy adults consuming ≥1 eggs/week. Photographs of all meals consumed for seven days were captured via a smartphone application called SmartIntake® and analyzed for nutrient intake. Fasting blood samples were collected. Linear correlations between egg consumption and nutrient intake or measures of glycemic control were determined. RESULTS: Daily egg intake was significantly associated with cholesterol intake, but not with the daily energy and saturated fat intake or measures of glycemic control. CONCLUSIONS: Higher consumption of eggs in free-living conditions was not associated with undesirable profiles of macronutrient intake, total EI, or an impaired glycemic profile in this study population. Thus, the assertion that eggs are linked with impaired glycemic control because of the accompanying intake of greater energy and saturated fat, does not appear valid. TRIAL REGISTRATION: NCT03404700.

Assessing Biota Accumulation Due to Contamination of Sediments by Storm Water Heavy Metals.

Evaluating sediment recontamination due to storm water discharges is important when evaluating the long-term effectiveness of sediment remediation efforts at reducing biological impacts. The bioaccumulation of the heavy metals zinc, nickel, copper, cadmium, mercury, and lead and the metalloid arsenic in a clam (Macoma nasuta) was studied in surficial sediments before and after storm water inputs from Paleta Creek, California, USA, during wet seasons in 2015 to 2016 and 2016 to 2017. The bioaccumulation was compared with bulk sediment concentrations and porewater concentrations measured by diffusion gradient in thin film devices. Significant reductions in biota accumulation and porewater concentrations were observed in samples collected after storm seasons compared with before storm seasons despite bulk sediment concentrations remaining the same or increasing. This was apparently the result of the deposition of storm water contaminants in low bioavailable forms. The bioaccumulation of all the measured contaminants showed a positive significant correlation with porewater concentrations (p < 0.1, α = 0.1) and weak or no correlations with bulk sediment concentration. In conclusion, observed bulk sediment recontamination due to storm water should not be assumed to lead directly to greater biota accumulation without bioavailability assessment. Environ Toxicol Chem 2020;39:2475-2484. © 2020 SETAC.

Assessing sediment recontamination from metals in stormwater.

Recontamination of sediments by stormwater is a major concern when evaluating the potential effectiveness of sediment remediation. Stormwater and sediment sampling were conducted in a mixed-use watershed at Paleta Creek in San Diego, CA to evaluate methods for assessing sediment recontamination by metals. Size-segregated stormwater contaminant loads with simultaneous receiving water and sediment measurements were used to identify dominant sources and contaminants with respect to their impact on sediment recontamination. Most of the stormwater contaminant loads of Cd, Cu, Pb, and Zn were associated with residential and highway sources from the upstream portions of the watershed and As, Ni and Hg were more significantly influenced by the downstream area of the watershed. Cd was strongly associated with large particles (>63 µm) and observed to settle in near shore areas with some attenuation due to mixing and dilution. Cu, in contrast, was associated more with the filtered fraction (<0.45 µm) and clay fraction (0.45-5 µm), resulting in less near shore sediment recontamination. Depositing sediment and other metals, particularly Cu and Hg, exhibited greater accumulation in settling traps than could be attributed to stormwater loads indicating the importance of other sources or resuspension of bay sediments on surficial sediment concentrations. Pb, Zn, Ni, and As showed influences of both stormwater and other sources. The study showed that measurement of size-segregated stormwater contaminant mass and concentrations combined with simultaneous measurements of deposition in sediment traps could differentiate between recontamination by stormwater and that of other sources.

Psychological and weight history variables as predictors of short-term weight and body fat mass loss.

OBJECTIVE: Identifying predictors of early weight loss may have value in predicting longer-term success in weight loss programmes. This study examined if weight history variables (ie, weight cycling history [WCH], age of onset of obesity [AOO]), and preintervention Three-Factor Eating Questionnaire (TFEQ) and Power of Food Scale (PFS) scores predicted weight loss (WL) and fat mass loss (FML) following a 3-week calorie restriction intervention. METHODS: Thirty-two participants (19-60 y; body mass index [BMI] 30-39.9 kg/m2) participated in a 3-week calorie restriction intervention (1120 kcal/d) as part of a larger clinical trial with 28 completers included in the current analyses. Preintervention WCH, AOO, TFEQ, and PFS subscale scores were collected, and WL and FML were measured. Multiple linear regression analyses were performed to predict WL and FML for relevant covariates in this study. RESULTS: WCH, AOO, preintervention TFEQ subscale scores, and PFS subscale scores did not predict WL (all Ps > .08) or FML (Ps > .06) except, PFS-food tasted scores significantly predicted WL (r = -0.40, P = .03). CONCLUSION: Although these variables were not robust predictors, results for at least the PFS suggest there may be value in further exploring this measure using larger sample sizes.

Both Dietary Ratio of n-6 to n-3 Fatty Acids and Total Dietary Lipid Are Positively Associated with Adiposity and Reproductive Health in Zebrafish.

BACKGROUND: Controversial findings have been reported in human and animal studies regarding the influence of n-6 (ω-6) to n-3 (ω-3) fatty acid ratios on obesity and health. Two confounding factors may be related to interactions with other dietary lipid components or sex-specific differences in fatty acid metabolism. OBJECTIVE: This study investigated main and interactive effects of total dietary lipid, ratio of n-6 to n-3 fatty acids, and sex on growth, adiposity, and reproductive health in wild-type zebrafish. METHODS: Male and female zebrafish (3 wk old) were fed 9 diets consisting of 3 ratios of n-6 to n-3 fatty acids (1.4:1, 5:1, and 9.5:1) varied within 3 total lipid amounts (80, 110, and 140 g/kg) for 16 wk. Data were then collected on growth, body composition (determined by chemical carcass analysis), and female reproductive success (n = 32 breeding events/diet over 4 wk). Main and interactive effects of dietary lipid and sex were evaluated with regression methods. Significant differences within each dietary lipid component were relative to the intercept/reference group (80 g/kg and 1.4:1 ratio). RESULTS: Dietary lipid and sex interacted in their effects on body weight (P = 0.015), total body length (P = 0.003), and total lipid mass (P = 0.029); thus, these analyses were stratified by sex. Female spawning success decreased as dietary total lipid and fatty acid ratio increased (P = 0.030 and P = 0.026, respectively). While total egg production was not associated with either dietary lipid component, females fed the 5:1 ratio produced higher proportions of viable embryos compared with the 1.4:1 ratio [median (95% CI): 0.915 (0.863, 0.956) vs 0.819 (0.716, 0.876); P < 0.001]. CONCLUSIONS: Further characterization of dietary lipid requirements will help define healthy balances of dietary lipid, while the sex-specific responses to dietary lipid identified in this study may partially explain sex disparities in the development of obesity and its comorbidities.

A randomized cross-over trial to determine the effect of a protein vs. carbohydrate preload on energy balance in ad libitum settings.

BACKGROUND: Although high protein diets have been tested in controlled environments for applications to weight management, it is not understood if adding high protein foods to the diet would impact ad libitum energy balance in the absence of other lifestyle changes. METHODS: This double-blinded randomized crossover trial compared the effects of a protein shake (PS) to a carbohydrate shake (CS), consumed prior to each major meal to equate to 20% of total energy needs over the course of the day, on energy balance over two 5-day treatment periods in healthy adults with BMI 20-30 kg/m2. Tri-axial accelerometers estimated physical activity energy expenditure. Ad libitum energy intake was measured in a laboratory kitchen. RESULTS: Energy balance was positive during both treatment periods but was not different between periods. There were no interactions between treatment and preload caloric dose or treatment and BMI status on energy balance. Satiety ratings did not differ for any pairwise comparisons between treatment and caloric dose. Controlling for gender and basal metabolic rate, thermic effect of food was greater for PS than CS. CONCLUSIONS: Preload periods significantly altered the macronutrient composition of the overall diet. This study found limited evidence that carbohydrate or protein preloads have differential effects on energy balance in short-term ad libitum settings. TRIAL REGISTRATION: This trial was pre-registered on clinicaltrials.gov as NCT02613065 on 11/30/2015.

Childhood obesity intervention studies: A narrative review and guide for investigators, authors, editors, reviewers, journalists, and readers to guard against exaggerated effectiveness claims.

Being able to draw accurate conclusions from childhood obesity trials is important to make advances in reversing the obesity epidemic. However, obesity research sometimes is not conducted or reported to appropriate scientific standards. To constructively draw attention to this issue, we present 10 errors that are commonly committed, illustrate each error with examples from the childhood obesity literature, and follow with suggestions on how to avoid these errors. These errors are as follows: using self-reported outcomes and teaching to the test; foregoing control groups and risking regression to the mean creating differences over time; changing the goal posts; ignoring clustering in studies that randomize groups of children; following the forking paths, subsetting, p-hacking, and data dredging; basing conclusions on tests for significant differences from baseline; equating "no statistically significant difference" with "equally effective"; ignoring intervention study results in favor of observational analyses; using one-sided testing for statistical significance; and stating that effects are clinically significant even though they are not statistically significant. We hope that compiling these errors in one article will serve as the beginning of a checklist to support fidelity in conducting, analyzing, and reporting childhood obesity research.

Obesity, adipocyte hypertrophy, fasting glucose, and resistin are potential contributors to nonalcoholic fatty liver disease in South Asian women.

Purpose: Nonalcoholic fatty liver disease (NAFLD) is often referred to as the hepatic manifestation of the metabolic syndrome. The relationship between body weight, NAFLD, and insulin resistance is not well characterized in humans. Additionally, it is unclear why South Asians develop these complications at lower levels of obesity compared to their Western counterparts. Patients and methods: To address this question, we performed a cross-sectional study using a convenience sample of Sri Lankan adult females (n=34) and collected anthropometric data, adipose tissue specimens (for histology), and fasted serum samples (for metabolic and inflammatory markers). Hepatic steatosis was assessed by ultrasound scanning and used to classify participants as NAFL 0, NAFL 1, and NAFL 2. Results: Waist circumference significantly increased with increasing NAFL grade. Participants with NAFL had significantly higher body mass index, hip circumference, and fasting plasma glucose, as well as a higher mean adipocyte area in both abdominal subcutaneous and visceral areas, indicating a higher degree of adipocyte hypertrophy associated with fatty liver. There were, however, no differences in measures of dyslipidemia. Of the multiple adipokines measured, resistin was the only proinflammatory adipokine significantly elevated in NAFL 2. Conclusion: These findings indicate that measures of adiposity, fasting serum glucose, and resistin may be important indicators of NAFLD in South Asian women.