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.

Pre- and Post-surgical Prevalence of Thiamine Deficiency in Patients Undergoing Bariatric Surgery: a Systematic Review and Meta-analysis.

Thiamine deficiency is a life-threatening nutritional abnormality observed in the patients with obesity and following bariatric surgery. The aim of the present study is to determine the prevalence of thiamine deficiency prior to and after bariatric procedures. PubMed, Web of Science, Google scholar, CENTRAL, ProQuest, and Scopus were searched to retrieve relevant studies containing data on thiamine deficiency in patients with obesity who underwent bariatric surgery. A proportional meta-analysis approach was used to pool the prevalence of thiamine deficiency prior and after surgery. Our comprehensive literature search retrieved 41 studies with relevant data. The pooled prevalence of thiamine deficiency was 7% (95% CI: 4-12%) at baseline. We observed that 19% (95% CI: 0-68%), 9% (95% CI: 3-17%), and 6% (95% CI: 3-9%) of patients had developed thiamine deficiency at 3 months, 6 months, and 1 year after surgery, respectively. We also report that the prevalence of thiamine deficiency in pregnant women who had history of bariatric surgery. The rate was highest in the first trimester (12%) compared to that in the second (8%) and third (10%) trimesters. The baseline prevalence is 7% for thiamine deficiency in bariatric surgery candidates. The prevalence rate of thiamin deficiency increased to 19% and 9% 3 and 6 months after surgery; however, the rate decreased to 6% 1 year after surgery. Due to the higher prevalence of thiamine deficiency in the early post-operative phase, close monitoring during this period is recommended. A similar strategy should be implemented for pregnant women with history of bariatric surgery in their first trimester.

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.

Anthropometric and Biochemical Measures in Bariatric Surgery Candidates: What Is the Role of Inflammatory Potential of Diet?

BACKGROUND: The present study aimed to assess dietary total antioxidant capacity (TAC), dietary phytochemical intake (PI), and dietary inflammatory index (DII) in patients with morbid obesity who are candidates of bariatric surgery and their association with anthropometric and biochemical parameters. METHODS AND MATERIALS: One hundred seventy patients with morbid obesity who were referred to surgery clinic of Firoozgar Hospital were enrolled in the study. Ideal body weight and adjusted ideal body weight were calculated. The dietary data were collected using a food frequency questionnaire. Anthropometrics and biochemical parameters were assessed. A p-value of <0.05 was considered significant. RESULTS: The strongest correlations of DII with dietary intakes and anthropometric and biochemical biomarkers were found for iron (p<0.0001). Significant association was also observed for ferritin (p=0.02) and transferrin (p=0.02). In terms of PI, The strongest associations were also found for iron (p<0.0001). Additionally, the value of body mass index (BMI) showed significant correlation with PI (p=0.04). The correlations of dietary total antioxidant indices with dietary intakes and anthropometric and biochemical biomarkers were assessed. Non-significant correlation was found between fasting blood sugar (FBS), hemoglobin A1C (HbA1C), vitamin B12, and vitamin D3 with ORAC index. Significant strong correlation showed for the value of iron in both ferric reducing ability of plasma (FRAP) and Oxygen Radical Absorbance Capacity (ORAC) indices (p<0.0001). CONCLUSION: We find statistical significance correlation for dietary PI and BMI. The inflammatory and antioxidant properties of diet were not related to biochemical markers associated with obesity. Graphical abstract.

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.

Recent Advances in Nanoencapsulation of Phytochemicals to Combat Obesity and Its Comorbidities.

An increasing epidemic of obesity has become a serious public health concern primarily because it contributes to pathogenesis of many chronic diseases including type 2 diabetes, cardiovascular disease, hepatobiliary disease, obstructive sleep apnea, kidney disease, some types of cancer, among others. Consumption of a variety of phytochemicals has emerged as a promising potential for combating obesity and its comorbidities. However, the generally low aqueous solubility, stability, bioavailability, and target specificity of phytochemicals, along with their side-effects and toxicity seen when used at high doses, have restricted their clinical applications. As a solution, phytochemicals can be encapsulated into nanoparticles to increase their stability and solubility, enhance their bioavailability, protect them from premature degradation in the body, prolong their circulation time, and thus enhance their antiobesity activity. In this perspective, we summarize the problems and limitations of the prominent phytochemicals (epigallocatechin gallate, trans-resveratrol, curcumin, and quercetin), the major biocompatible and biodegradable nanoparticles, and the efficacy of nanoencapsulated forms of these phytochemicals in combating obesity and its comorbidities.

Effects of Quercetin Supplementation on Hematological Parameters in Non-Alcoholic Fatty Liver Disease: a Randomized, Double-Blind, Placebo-Controlled Pilot Study.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease which has become a public health concern. Since oxidative stress plays a crucial role in the pathogenesis of NAFLD, subsequent hematological disorders are expected. Therefore, antioxidant compounds such as quercetin could ameliorate the related side-effect of oxidative stress. The aim of the current study was to assess the effect of quercetin on hematological parameters in NAFLD patients. A randomized, double-blind, placebo-controlled trial was conducted as a pilot study. In this study 90 patients with NAFLD were supplemented with either a quercetin or a placebo capsule twice daily (500 mg) for 12 weeks. Blood sample was obtained for laboratory parameters at baseline and the end of week 12. End of trial values for red blood cell (RBC; p = 0.002), mean corpuscular hemoglobin concentration (p = 0.029), and mean platelet volume (p = 0.017), significantly increased and the levels of mean corpuscular volume (MCV; p = 0.023), RBC distribution width-coefficient of variation (p = 0.005), platelet distribution width (p = 0.015), and ferritin (p = 0.002) significantly decreased compared to the baseline in group receiving quercetin. Between group analysis revealed that RBC significantly increased (p = 0.025) but, mean corpuscular volume (p = 0.004), mean corpuscular hemoglobin (MCH; p = 0.002), and ferritin (p = 0.013) significantly decreased compared to placebo group. In this work quercetin showed significant effect on RBC, ferritin, MCV, and MCH in intervention group. TRIAL REGISTRATION: Iranian Center for Clinical Trials Identifier: IRCT2016060628299N1.

Beneficial Metabolic Effects of Mirabegron In Vitro and in High-Fat Diet-Induced Obese Mice.

Mirabegron, a ß3-adrenergic receptor agonist, has been shown to stimulate the activity of brown fat and increase the resting metabolic rate in humans. However, it is unknown whether mirabegron can reduce body weight and improve metabolic health. We investigated the antiobesity effects of mirabegron using both in vitro and in vivo models. Mouse brown preadipocytes and 3T3-L1 cells were treated with different concentrations of mirabegron (0.03-3 µg/ml), and the expression of brown fat-related genes was measured by quantitative real-time polymerase chain reaction. Furthermore, male C57BL/6J mice were fed a high-fat diet for 10 weeks, and mirabegron (2 mg/kg body weight) or a vehicle control was delivered to the interscapular brown adipose tissue (iBAT) using ALZET osmotic pumps from week 7 to 10. The metabolic parameters and tissues were analyzed. In both mouse brown preadipocytes and 3T3-L1 cells, mirabegron stimulated uncoupling protein 1 (UCP1) expression. In animal studies, mirabegron-treated mice had a lower body weight and adiposity. Lipid droplets in the iBAT of mirabegron-treated mice were fewer and smaller in size compared with those from vehicle-treated mice. H&E staining and immunohistochemistry indicated that mirabegron increased the abundance of beige cells in inguinal white adipose tissue (iWAT). Compared with vehicle-treated mice, mirabegron-treated mice had a higher gene expression of UCP1 (14-fold) and cell death-inducing DNA fragmentation factor alpha-like effector A (CIDEA) (4-fold) in iWAT. Furthermore, mirabegron-treated mice had improved glucose tolerance and insulin sensitivity. Taken together, mirabegron enhances UCP1 expression and promotes browning of iWAT, which are accompanied by improved glucose tolerance and insulin sensitivity and prevention from high-fat diet-induced obesity.

Anti-atherogenic effects of CD36-targeted epigallocatechin gallate-loaded nanoparticles.

Intimal macrophages play a critical role in atherosclerotic lesion initiation and progression by taking up oxidized low-density lipoprotein (oxLDL) and promoting inflammatory process. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdiA-PC), a major type of oxidized phosphatidylcholines (PC) found on oxLDL, has a high binding affinity to the macrophage scavenger receptor CD36 and participates in CD36-mediated recognition and uptake of oxLDL by intimal macrophages. We successfully synthesized epigallocatechin gallate (EGCG)-loaded nanoparticles (Enano), which were composed of EGCG, PC, (+) alpha-tocopherol acetate, and surfactant. We also incorporated KOdiA-PC on the surface of Enano to make ligand-coated Enano (L-Enano) to target intimal macrophages. The objectives of this study were to determine the anti-atherogenic effects of Enano and L-Enano in LDL receptor null (LDLr-/-) mice. Our in vitro data demonstrated that L-Enano had a higher binding affinity to mouse peritoneal macrophages than Enano. This high binding affinity was diminished by CD36 antibodies or knockdown of the CD36 receptor in mouse peritoneal macrophages, confirming the specific binding of L-Enano to the macrophage CD36 receptor. LDLr-/- mice were randomly divided to six groups and received weekly tail vein injection with PBS, EGCG, void nanoparticles (Vnano), Enano, ligand-coated Vnano (L-Vnano), or L-Enano once per week for 22 weeks. The dose of EGCG was 25 mg per kg body weight. L-Enano at 20 µg/mL significantly decreased production of monocyte chemoattractant protein-1, tumor necrosis factor alpha, and interleukin-6 from mouse macrophages, while having no effect on their plasma levels compared to the PBS control. There were no significant differences in blood lipid profiles among six treatment groups. Mice treated with L-Enano also had significantly smaller lesion surface areas on aortic arches compared to the PBS control. Liver EGCG content was decreased by treatments in the order of EGCG>Enano>L-Enano. Native EGCG had inhibitory effects on liver and body fat accumulation. This molecular target approach signals an important step towards inhibiting atherosclerosis development via targeted delivery of bioactive compounds to intimal macrophages.

Dietary Total Antioxidant Capacity and the Risk of Chronic Kidney Disease in Patients With Type 2 Diabetes: A Nested Case-Control Study in the Tehran Lipid Glucose Study.

OBJECTIVE: Dietary total antioxidant capacity (DTAC) has been hypothesized as being involved in health promotion and disease prevention. However, data about the association of the DTAC (as estimated by ferric reducing antioxidant power) with diabetes chronic complications are scarce. Therefore, the aim of this study was to determine the associations between the DTAC and chronic kidney disease (CKD) risk in subjects with type 2 diabetic. METHODS: The present case-control study consisted of 210 (102 cases and 108 controls) patients with type 2 diabetic who were participants of the phase 5 Tehran Lipid and Glucose Study and were classified based on their CKD status. DTAC was estimated based on the ferric reducing antioxidant power of selected foods. Dietary intake, sociodemographic data, medical history, and anthropometric measurements were collected from participants using a validated questionnaire. RESULTS: The mean DTAC value, as well as total calorie intake, did not show significant differences between cases and controls. CONCLUSION: No significant association was found between DTAC and CKD in patients with type 2 diabetic. Further studies are needed to confirm the effects of DTAC on the risk of CKD.

A 12-week evaluation of annatto tocotrienol supplementation for postmenopausal women: safety, quality of life, body composition, physical activity, and nutrient intake.

BACKGROUND: Evidence suggests that tocotrienols may benefit bone health in osteopenic women. However, their safety in this population has never been investigated. This study was to evaluate the safety of a 12-week supplementation of annato tocotrienol in postmenopausal osteopenic women, along with effects of the supplementation on quality of life, body composition, physical activity, and nutrient intake in this population. METHODS: Eighty nine postmenopausal osteopenic women were randomly assigned to 3 treatment arms: (1) Placebo (430 mg olive oil/day), (2) Low tocotrientol (Low TT) (430 mg tocotrienol/day from DeltaGold 70 containing 300 mg tocotrienol) and (3) High tocotrienol (High TT) (860 mg tocotrienol/day from DeltaGold 70 containing 600 mg tocotrienol) for 12 weeks. DeltaGold 70 is an extract from annatto seed with 70% tocotrienol consisting of 90% delta-tocotrienol and 10% gamma-tocotrienol. Safety was examined by assessing liver enzymes (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase, bilirubin, kidney function (blood urea nitrogen and creatinine), electrolytes, glucose, protein, albumin, and globulin at 0, 6, and 12 weeks. Serum tocotrienol and tocopherol concentrations were assessed and pills counted at 0, 6, and 12 weeks. Quality of life, body composition, physical activity, and dietary macro- and micro-nutrient intake were evaluated at 0 and 12 weeks. A mixed model of repeated measures ANOVA was applied for analysis. RESULTS: Eighty seven subjects completed the study. Tocotrienol supplementation did not affect liver or kidney function parameters throughout the study. No adverse event due to treatments was reported by the participants. Tocotrienol supplementation for 6 weeks significantly increased serum delta-tocotrienol level and this high concentration was sustained to the end of study. There was no difference in serum delta-tocotrienol levels between the Low TT and the High TT groups. No effects of tocotrienol supplementation were observed on quality of life, body composition, physical activity, and nutrient intake. CONCLUSIONS: Annatto-derived tocotrienol up to 600 mg per day for 12 weeks appeared to be safe in postmenopausal osteopenic women, particularly in terms of liver and kidney functions. Tocotrienol supplementation for 12 weeks did not affect body composition, physical activity, quality of life, or intake of macro- and micro-nutrients in these subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02058420 . TITLE: Tocotrienols and bone health of postmenopausal women.

The relationship between MnSOD Val16Ala gene polymorphism and the level of serum total antioxidant capacity with the risk of chronic kidney disease in type 2 diabetic patients: a nested case-control study in the Tehran lipid glucose study.

BACKGROUND: Several studies have shown significant associations between manganese superoxide dismutase (MnSOD) Val16Ala polymorphism and diabetic complications, but this association has not been explored in relation with chronic kidney disease (CKD) in Type 2 diabetes mellitus (T2DM) patients. Total antioxidant capacity (TAC) level changes in diabetic condition and may play important role in onset or progression of the disease and its complications. The present study investigated the association of MnSOD Val16Ala polymorphism and serum TAC with the risk of CKD in T2DM patients. METHODS: This nested case-control study included 280 type 2 diabetic patients with CKD and 280 age, sex and diabetes duration-matched control subjects selected from the participants of the Tehran Lipid and Glucose Study. MnSOD val16Ala (rs4880) SNP was genotyped by the Tetra-Primer ARMS-polymerase chain reaction analysis. Serum TAC was measured using ferric-reducing antioxidant power assay. Statistical analysis was performed using STATA statistical package v.12.0 or SPSS (Version 22.0). RESULTS: The Ala allele of the MnSOD Val16Ala polymorphism was associated with a lower risk of CKD (odds ratio (OR), 0.55; 95% confidence interval (CI), 0.36-0.84; P = 0.006). Median serum TAC in CKD group was 920 µmol/L and was significantly lower (p < 0.001) compared to the control group (1045 µmol/L). Using an adjusted conditional logistic regression, we didn't observe any significant interaction between MnSOD Val16Ala SNP with quartiles of serum TAC in relation to CKD. CONCLUSION: A significant association was found between the MnSOD Val16Ala polymorphism and CKD, but this association is not affected by serum TAC level in T2DM patients.

Role of Superoxide Dismutase 2 Gene Ala16Val Polymorphism and Total Antioxidant Capacity in Diabetes and its Complications.

Diabetes Mellitus (DM) is a chronic heterogeneous disorder and oxidative stress is a key participant in the development and progression of it and its complications. Anti-oxidant status can affect vulnerability to oxidative damage, onset and progression of diabetes and diabetes complications. Superoxide dismutase 2 (SOD2) is one of the major antioxidant defense systems against free radicals. SOD2 is encoded by the nuclear SOD2 gene located on the human chromosome 6q25 and the Ala16Val polymorphism has been identified in exon 2 of the human SOD2 gene. Ala16Val (rs4880) is the most commonly studied SOD2 single nucleotide polymorphism (SNP) in SOD2 gene. This SNP changes the amino acid at position 16 from valine (Val) to alanine (Ala), which has been shown to cause a conformational change in the target sequence of manganese superoxide dismutase (MnSOD) and also affects MnSOD activity in mitochondria. Ala16Val SNP and changes in the activity of the SOD2 antioxidant enzyme have been associated with altered progression and risk of different diseases. Association of this SNP with diabetes and some of its complications have been studied in numerous studies. This review evaluated how rs4880, oxidative stress and antioxidant status are associated with diabetes and its complications although some aspects of this line still remain unclear.

High Body Mass Index and Young Age Are not Associated with Post-Mastectomy Pain Syndrome in Breast Cancer Survivors: A Case-Control Study.

BACKGROUND: Surgery is usually the first treatment for breast cancer which is followed by some complications such as chronic pain. Post mastectomy pain syndrome (PMPS) is a common complication among breast cancer survivors and is considered as a chronic neuropathic pain in the side of surgery which persists more than three months. The exact mechanisms and related risk factors of the chronic pain after breast surgery are unknown. The aim of this study was to investigate the association of body mass index (BMI) and age with PMPS. METHODS: In this case-control study, a total of 122 women were assessed; of these, 61 women were diagnosed with PMPS and selected as cases and 61 pain-free patients were selected as controls. The demographic and clinical characteristics of participants were collected through questionnaires and medical record of patients. Logistic regression model was used to determine the association of BMI and age with PMPS, adjusted for demographic and clinical characteristics. RESULTS: No significant differences were found in means of weight (68.02±8.80 vs. 68.67±11.82, p=0.726), BMI (26.38±3.28 vs. 27.10±6.03, p=0.410), and age (46.34±11.67 vs. 48.54±12.57, p=0.319) between those with PMPS and those not reporting PMPS. A non-significant slight increase in odds ratio of PMPS was observed in obese category compared to normal weight category [OR=1.152 (95% CI 0.405-3.275), p=0.908], but after adjusting the confounding factors, the risk of pain development was attenuated in obese subjects [OR=0.748 (95% CI 0.228-2.459), p=0.633]. Also, non-significant decrease in odds ratios of PMPS was found in 20-39 y, 40-49 y, and 50-59 y ages categories compared to oldest age category [adjusted OR= 0.781 (95% CI 0.213-2.866), p=0.576; adjusted OR=0.485 (95% CI 0.152- 1.554), p=0.183; adjusted OR=0.735 (95% CI 0.206-2.627), p=0.628; respectively]. CONCLUSION: In contrast with some observational studies, present study showed that high BMI and younger age might not be associated with increased risk of PMPS development. Further research is necessary to determine the main risk factors and directionality and causal mechanisms for associations of these risk factors with chronic pain after mastectomy.