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Background: Obesity-induced hypogonadism (OIH) is a prevalent, but often neglected condition in men, which aggravates the metabolic complications of overweight. While hypothalamic suppression of Kiss1-encoded kisspeptin has been suggested to contribute to OIH, the molecular mechanisms for such repression in obesity, and the therapeutic implications thereof, remain unknown., Methods: A combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models., Results: MiR-137/325 repressed human KISS1 3'-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1/kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1/ kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3'-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats., Conclusions: Our data disclose that the miR-137/325-Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity., Significance Statement: Up to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose in relation to the contents of this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the abundance of registered clinical trials worldwide, the availability of effective drugs for obesity treatment is limited due to their associated side effects. Thus, there is growing interest in therapies that stimulate energy expenditure in white adipose tissue. Recently, we demonstrated that the delivery of a miR-21 mimic using JetPEI effectively inhibits weight gain in an obese mouse model by promoting metabolism, browning, and thermogenesis, suggesting the potential of miR-21 mimic as a treatment for obesity. Despite these promising results, the implementation of more advanced delivery system techniques for miR-21 mimic would greatly enhance the advancement of safe and efficient treatment approaches for individuals with obesity in the future. Our objective is to explore whether a new delivery system based on gold nanoparticles and Gemini surfactants (Au@16-ph-16) can replicate the favorable effects of the miR-21 mimic on weight gain, browning, and thermogenesis. We found that dosages as low as 0.2 μg miR-21 mimic /animal significantly inhibited weight gain and induced browning and thermogenic parameters. This was evidenced by the upregulation of specific genes and proteins associated with these processes, as well as the biogenesis of beige adipocytes and mitochondria. Significant increases in miR-21 levels were observed in adipose tissue but not in other tissue types. Our data indicates that Au@16-ph-16 could serve as an effective delivery system for miRNA mimics, suggesting its potential suitability for the development of future clinical treatments against obesity., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: To assess the association between three different a priori dietary patterns adherence (17-item energy reduced-Mediterranean Diet (MedDiet), Trichopoulou-MedDiet and Dietary Approach to Stop Hypertension (DASH)), as well as the Protein Diet Score and kidney function decline after one year of follow-up in elderly individuals with overweight/obesity and metabolic syndrome (MetS)., Methods: We prospectively analyzed 5675 participants (55-75 years) from the PREDIMED-Plus study. At baseline and at one year, we evaluated the creatinine-based estimated glomerular filtration rate (eGFR) and food-frequency questionnaires-derived dietary scores. Associations between four categories (decrease/maintenance and tertiles of increase) of each dietary pattern and changes in eGFR (ml/min/1.73m 2 ) or ≥ 10% eGFR decline were assessed by fitting multivariable linear or logistic regression models, as appropriate., Results: Participants in the highest tertile of increase in 17-item erMedDiet Score showed higher upward changes in eGFR (β: 1.87 ml/min/1.73m 2 ; 95% CI: 1.00-2.73) and had lower odds of ≥ 10% eGFR decline (OR: 0.62; 95% CI: 0.47-0.82) compared to individuals in the decrease/maintenance category, while Trichopoulou-MedDiet and DASH Scores were not associated with any renal outcomes. Those in the highest tertile of increase in Protein Diet Score had greater downward changes in eGFR (β: - 0.87 ml/min/1.73m 2 ; 95% CI: - 1.73 to - 0.01) and 32% higher odds of eGFR decline (OR: 1.32; 95% CI: 1.00-1.75)., Conclusions: Among elderly individuals with overweight/obesity and MetS, only higher upward change in the 17-item erMedDiet score adherence was associated with better kidney function after one year. However, increasing Protein Diet Score appeared to have an adverse impact on kidney health., Trial Registration Number: ISRCTN89898870 (Data of registration: 2014)., (© 2022. The Author(s).)

Background and Purpose: Lifestyle and diet affect cardiovascular risk, although there is currently no consensus about the best dietary model for the secondary prevention of cardiovascular disease. The CORDIOPREV study (Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention) is an ongoing prospective, randomized, single-blind, controlled trial in 1002 coronary heart disease patients, whose primary objective is to compare the effect of 2 healthy dietary patterns (low-fat rich in complex carbohydrates versus Mediterranean diet rich in extra virgin olive oil) on the incidence of cardiovascular events. Here, we report the results of one secondary outcome of the CORDIOPREV study. Thus, to evaluate the efficacy of these diets in reducing cardiovascular disease risk. Intima-media thickness of both common carotid arteries (IMT-CC) was ultrasonically assessed bilaterally. IMT-CC is a validated surrogate for the status and future cardiovascular disease risk., Methods: From the total participants, 939 completed IMT-CC evaluation at baseline and were randomized to follow a Mediterranean diet (35% fat, 22% monounsaturated fatty acids, <50% carbohydrates) or a low-fat diet (28% fat, 12% monounsaturated fatty acids, >55% carbohydrates) with IMT-CC measurements at 5 and 7 years. We also analyzed the carotid plaque number and height., Results: The Mediterranean diet decreased IMT-CC at 5 years (−0.027±0.008 mm; P<0.001), maintained at 7 years (−0.031±0.008 mm; P<0.001), compared to baseline. The low-fat diet did not modify IMT-CC. IMT-CC and carotid plaquemax height were higher decreased after the Mediterranean diet, compared to the low-fat diet, throughout follow-up. Baseline IMT-CC had the strongest association with the changes in IMT-CC after the dietary intervention., Conclusions: Long-term consumption of a Mediterranean diet rich in extravirgin olive oil, if compared to a low-fat diet, was associated with decreased atherosclerosis progression, as shown by reduced IMT-CC and carotid plaque height. These findings reinforce the clinical benefits of the Mediterranean diet in the context of secondary cardiovascular prevention., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00924937.

Purpose: We examined the association between dietary folate intake and a score of MetS (metabolic syndrome) and its components among older adults at higher cardiometabolic risk participating in the PREDIMED-Plus trial., Methods: A cross-sectional analysis with 6633 with overweight/obesity participants with MetS was conducted. Folate intake (per 100 mcg/day and in quintiles) was estimated using a validated food frequency questionnaire. We calculated a MetS score using the standardized values as shown in the formula: [(body mass index + waist-to-height ratio)/2] + [(systolic blood pressure + diastolic blood pressure)/2] + plasma fasting glucose-HDL cholesterol + plasma triglycerides. The MetS score as continuous variable and its seven components were the outcome variables. Multiple robust linear regression using MM-type estimator was performed to evaluate the association adjusting for potential confounders., Results: We observed that an increase in energy-adjusted folate intake was associated with a reduction of MetS score (β for 100 mcg/day = - 0.12; 95% CI: - 0.19 to - 0.05), and plasma fasting glucose (β = - 0.03; 95% CI: - 0.05 to - 0.02) independently of the adherence to Mediterranean diet and other potential confounders. We also found a positive association with HDL-cholesterol (β = 0.07; 95% CI: 0.04-0.10). These associations were also observed when quintiles of energy-adjusted folate intake were used instead., Conclusion: This study suggests that a higher folate intake may be associated with a lower MetS score in older adults, a lower plasma fasting glucose, and a greater HDL cholesterol in high-risk cardio-metabolic subjects.

Background and Aims: The aim of this study was to ascertain the association between the consumption of different categories of edible olive oils (virgin olive oils and olive oil) and olive pomace oil and ankle-brachial pressure index (ABI) in participants in the PREDIMED-Plus study, a trial of lifestyle modification for weight and cardiovascular event reduction in individuals with overweight/obesity harboring the metabolic syndrome., Methods: We performed a cross-sectional analysis of the PREDIMED-Plus trial. Consumption of any category of olive oil and olive pomace oil was assessed through a validated food-frequency questionnaire. Multivariable linear regression models were fitted to assess associations between olive oil consumption and ABI. Additionally, ABI ≤1 was considered as the outcome in logistic models with different categories of olive oil and olive pomace oil as exposure., Results: Among 4330 participants, the highest quintile of total olive oil consumption (sum of all categories of olive oil and olive pomace oil) was associated with higher mean values of ABI (beta coefficient: 0.014, 95% confidence interval [CI]: 0.002, 0.027) (p for trend = 0.010). Logistic models comparing the consumption of different categories of olive oils, olive pomace oil and ABI ≤1 values revealed an inverse association between virgin olive oils consumption and the likelihood of a low ABI (odds ratio [OR] 0.73, 95% CI [0.56, 0.97]), while consumption of olive pomace oil was positively associated with a low ABI (OR 1.22 95% CI [1.00, 1.48])., Conclusions: In a Mediterranean population at high cardiovascular risk, total olive oil consumption was associated with a higher mean ABI. These results suggest that olive oil consumption may be beneficial for peripheral artery disease prevention, but longitudinal studies are needed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Obesity has been associated with increased risk of presenting hypogonadism. Free testosterone (FT) is the fraction of testosterone that carries out the biological function of testosterone, and is determined from total testosterone (TT) and sex-hormone binding globulin (SHBG) levels. We aimed to study the SHBG polymorphism rs1799941 in a cohort of young non-diabetic obese males to unravel the possible implication of this polymorphism in obesity-related hypogonadism., Methodology: 212 young (<45 years) non-diabetic obese (BMI ≥ 30 kg/m 2 ) males participated in this study. Subjects were classified according to TT and FT levels in: Eugonadal ( n = 55, TT > 3.5 ng/mL and FT ≥ 70 pg/mL; EuG), normal FT hypogonadism ( n = 40, TT < 3.5 and FT ≥ 70 pg/mL; normal FT HG) and hypogonadism ( n = 117, TT < 3.5 ng/mL and TL < 70 pg/mL; HG). The SHBG rs1799941 polymorphism (GG/GA/AA) was analyzed using the Taqman Open Array (Applied biosystem)., Results: The rs1799941 frequencies were different among the groups. Higher proportion of the allele (A) was found in HG, compared to EuG and normal FT HG. Among the genotypes, the rare homozygous (AA) were found in the normal FT HG group and higher levels of serum SHBG and lower of FT were observed. The presence of the allele A was related (according to lineal regression models) to an increased of SHBG levels ((GA) β = 3.28; (AA) β = 12.45) and a decreased of FT levels ((GA) β = -9.19; (AA) β = -18.52). The presence of the allele (A) increased the risk of presenting HG compared to normal FT HG (OR = 2.54)., Conclusions: The rs1799941 of the SHBG gene can partially determine the presence of obesity-related hypogonadism in young non-diabetic males and whether these subjects have normal FT HG.

Objective: Polyamines are naturally occurring cationic molecules present in all living cells. Dysregulation of circulating polyamines has been reported in several conditions, but little is known about the levels of serum polyamines in chronic metabolic disorders such as type 2 diabetes (T2D). Therefore, the aim of this study was to evaluate the polyamine-related metabolome in a cohort of metabolic syndrome individuals with and without T2D. Design and methods: This was a nested case⁻control study within the PREDIMED-Plus trial that included 44 patients with T2D and 70 patients without T2D. We measured serum levels of arginine, ornithine, polyamines, and acetyl polyamines with an ultra-high performance liquid chromatography tandem mass spectrometry platform. Results: Our results showed that serum putrescine, directly generated from ornithine by the catalytic action of the biosynthetic enzyme ornithine decarboxylase, was significantly elevated in patients with T2D compared to those without T2D, and that it significantly correlated with the levels of glycosylated hemoglobin (HbA1c). Correlation analysis revealed a significantly positive association between fasting insulin levels and spermine. Multiple logistic regression analysis (adjusted for age, gender and body weight index) revealed that serum putrescine and spermine levels were associated with a higher risk of T2D. Conclusions: Our study suggests that polyamine metabolism is dysregulated in T2D, and that serum levels of putrescine and spermine are associated with glycemic control and circulating insulin levels, respectively.

The purpose of this study was to compare the effects of land- vs. aquatic based plyometric training programs on the drop jump, repeated jump performance and muscle damage. Sixty-five male students were randomly assigned to one of 3 groups: aquatic plyometric training group (APT), plyometric training group (PT) and control group (CG). Both experimental groups trained twice a week for 10 weeks performing the same number of sets and total jumps. The following variables were measured prior to, halfway through and after the training programs: creatine kinase (CK) concentration, maximal height during a drop jump from the height of 30 (DJ30) and 50 cm (DJ50), and mean height during a repeated vertical jump test (RJ). The training program resulted in a significant increase (P<0.01-0.001) in RJ, DJ30, and DJ50 for PT, whereas neither APT nor CG reached any significant improvement APT showed likely/possibly improvements on DJ30 and DJ50, respectively. Greater intra-group Effect Size in CK was found for PT when compared to APT. In conclusion, although APT seems to be a safe alternative method for reducing the stress produced on the musculoskeletal system by plyometric training, PT produced greater gains on reactive jumps performance than APT., Competing Interests: The authors declare no conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Epigenetic marks, and especially DNA methylation, are becoming an important factor in obesity, which could help to explain its etiology and associated comorbidities. Adipose tissue, now considered as an important endocrine organ, produces complement system factors. Complement component 3 ( C3 ) turns out to be an important protein in metabolic disorders, via either inflammation or the C3 subproduct acylation stimulating protein (ASP) which directly stimulates lipid storage. In this study, we analyze C3 DNA methylation in adipose tissue from subjects with a different grade of obesity. Adipose tissue samples were collected from subjects with a different degree of obesity determined by their body mass index (BMI) as: Overweight subjects (BMI ≥ 25 and <30), obese class 1/2 subjects (BMI ≥ 30 and <40) and obese class 3 subjects (BMI ≥ 40). C3 DNA methylation was measured for 7 CpGs by pyrosequencition using the Pyromark technology (Qiagen, Madrid Spain). C3 messenger RNA (mRNA) levels were analyzed by pre-designed Taqman assays (Applied biosystems, Foster City, CA, USA) and ASP/C3a was measured using a ELISA kit. The data were analyzed using the statistic package SPSS. C3 DNA methylation levels were lower in the morbid obese group. Accordingly, C3 methylation correlated negatively with BMI and leptin. However, C3 mRNA levels were more associated with insulin resistance, and positive correlations with insulin, glucose and homeostasis model assessment-estimated insulin resistance (HOMA-IR) existed. ASP correlated negatively with high density lipoprotein (HDL) cholesterol. C3 methylation levels were associated to adiposity variables, such as BMI and leptin, while the C3 mRNA levels were associated to glucose metabolism., Competing Interests: The authors declare no conflict of interest.

Objective: There is a lack of consensus when it comes to establishing the biochemical parameters that define metabolically healthy obese (MHO) subjects. Indeed, most studies do not include subjects' lipid profiles. Our objective was to characterize lipoprotein size, particle and subclass concentration using 1 H NMR in MHO women after two years of weight loss with a hypocaloric Mediterranean diet and physical exercise., Methods: 115 non-diabetic women (aged 35-55 years) with a body mass index (BMI) of 30-40 kg/m 2 and ≤1 of the following criteria: blood pressure ≥135/85 mmHg, fasting plasma glucose ≥100 mg/dL, HDL cholesterol ≤50 mg/dL and triglycerides ≥150 mg/dL were included. After two years of intensive lifestyle modification (Mediterranean diet and physical exercise), they were classified according to their weight loss: <5%, ≥5%-<10% and ≥10%. Lipoprotein size, particle and subclass concentrations were measured using 1 H NMR., Results: The final population, after dropouts, were 67 women (age: 44.5 ± 3.7 years, BMI: 36.3 ± 4.7 kg/m 2 ), of whom 23 (38.3%) lost <5%, and 22 (36.7%), lost ≥5% to <10% and ≥10% of baseline body weight, respectively. The lipid profile showed no significant changes after intervention, especially in small LDL particles or in production of HDL. The diameter of LDL and HDL particles did not change after two years of a Mediterranean diet and physical exercise., Conclusion: These results indicate that intensive lifestyle modification does not produce significant changes in the lipid profile of MHO women. Levels of more atherogenic or atheroprotective particles did not change after two years, despite the intervention., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Adipose tissue has traditionally only been considered as an energy storage organ. Nevertheless, the importance of this tissue in systemic physiology and, especially, in systemic inflammation has been highlighted in recent years. Adipose tissue expresses proteins related to vitamin D (VD) metabolism, and it has been proposed that it can act as a VD storage tissue. The active form of VD, 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃), is able to modify adipocyte and adipose tissue physiology via the VD receptor (VDR), decreasing the expression of pro-inflammatory cytokines in adipose tissue. Moreover, VD deficiency and VDR has been reported to be associated with obesity and diabetes. However, the results of the different studies are not conclusive. Insulin growth binding proteins (IGFBPs) have been identified in adipose tissue, but their roles are poorly understood. Therefore, the objective of this study was to analyze the plasma levels of VD and the gene expression of VDR in the adipose tissue of subjects with morbid obesity (MO) and with different degrees of insulin resistance (IR), as well as the functionality of direct interaction between IGFBP-3 and VDR, which could explain its inhibitory role in adipogenesis. Our results show a novel role of the VD system in the regulation and activation of IGFBP-3 in visceral adipose tissue (VAT) of patients with MO, as a new and alternative mechanism proposed in the insulin signaling associated with obesity., Competing Interests: The authors declare no conflict of interest.

Obesity is associated with an atherogenic lipid profile. No data exists on lipoprotein particle profiles in metabolically healthy obese (MHO) individuals. Our aim is to characterize lipoprotein size, particle, and subclass concentrations in MHO women after 3 months of weight loss through dietary restriction and physical exercise.A total of 115 nondiabetic women (aged 35-55 years) with a body mass index (BMI) of 30 to 40 kg/m and ≤1 of the following criteria: blood pressure ≤135/85 mm Hg, fasting plasma glucose ≤100 mg/dL, HDL-cholesterol ≤50 mg/dL, and triglycerides ≤150 mg/dL were included. After 3 months of intensive lifestyle modification (Mediterranean diet and physical exercise), they were classified according to their weight loss: <5%, ≥5% to <10%, and ≥10%. Lipoprotein size, particle, and subclass concentrations were measured using H NMR.The final sample, after dropouts, comprised 104 women (age: 44.4 ± 3.7 years, BMI: 36.3 ± 4.7 kg/m), of whom 47 (45.2%), 27 (26%), and 30 (28.8%) lost <5%, ≥5% to <10%, and ≥10% of baseline body weight, respectively. All participants experienced significant weight loss and decreases in BMI. The lipid profiles showed an increase in small, medium, and large very low density lipoprotein (VLDL) particles in all groups of study with the exception of small VLDL particles in women with ≥10% of weight loss, in which it decreased. The number of VLDL particles decreased in women who had ≥10% weight loss. On the other hand, we detected a decrease in all low density lipoprotein (cLDL) and high density lipoprotein (cHDL) concentrations.These results indicate that intensive lifestyle modification alters lipid profiles. In particular, it decreases small LDL and HDL particle numbers and does not increase medium or large HDL particles numbers.

[This corrects the article DOI: 10.1371/journal.pone.0171204.].

Introduction: Sensory factors may play an important role in the determination of appetite and food choices. Also, some adipokines may alter or predict the perception and pleasantness of specific odors. We aimed to analyze differences in smell-taste capacity between females with different weights and relate them with fat and fat-free mass, visceral fat, and several adipokines., Materials and Methods: 179 females with different weights (from low weight to morbid obesity) were studied. We analyzed the relation between fat, fat-free mass, visceral fat (indirectly estimated by bioelectrical impedance analysis with visceral fat rating (VFR)), leptin, adiponectin and visfatin. The smell and taste assessments were performed through the "Sniffin' Sticks" and "Taste Strips" respectively., Results: We found a lower score in the measurement of smell (TDI-score (Threshold, Discrimination and Identification)) in obese subjects. All the olfactory functions measured, such as threshold, discrimination, identification and the TDI-score, correlated negatively with age, body mass index (BMI), leptin, fat mass, fat-free mass and VFR. In a multiple linear regression model, VFR mainly predicted the TDI-score. With regard to the taste function measurements, the normal weight subjects showed a higher score of taste functions. However a tendency to decrease was observed in the groups with greater or lesser BMI. In a multiple linear regression model VFR and age mainly predicted the total taste scores., Discussion: We show for the first time that a reverse relationship exists between visceral fat and sensory signals, such as smell and taste, across a population with different body weight conditions., Competing Interests: The authors have declared that no competing interests exist.

Objective: Munc18c is associated with glucose metabolism and could play a relevant role in obesity. However, little is known about the regulation of Munc18c expression. We analyzed Munc18c gene expression in human visceral (VAT) and subcutaneous (SAT) adipose tissue and its relationship with obesity and insulin., Materials and Methods: We evaluated 70 subjects distributed in 12 non-obese lean subjects, 23 overweight subjects, 12 obese subjects and 23 nondiabetic morbidly obese patients (11 with low insulin resistance and 12 with high insulin resistance)., Results: The lean, overweight and obese persons had a greater Munc18c gene expression in adipose tissue than the morbidly obese patients (p<0.001). VAT Munc18c gene expression was predicted by the body mass index (B = -0.001, p = 0.009). In SAT, no associations were found by different multiple regression analysis models. SAT Munc18c gene expression was the main determinant of the improvement in the HOMA-IR index 15 days after bariatric surgery (B = -2148.4, p = 0.038). SAT explant cultures showed that insulin produced a significant down-regulation of Munc18c gene expression (p = 0.048). This decrease was also obtained when explants were incubated with liver X receptor alpha (LXRα) agonist, either without (p = 0.038) or with insulin (p = 0.050). However, Munc18c gene expression was not affected when explants were incubated with insulin plus a sterol regulatory element-binding protein-1c (SREBP-1c) inhibitor (p = 0.504)., Conclusions: Munc18c gene expression in human adipose tissue is down-regulated in morbid obesity. Insulin may have an effect on the Munc18c expression, probably through LXRα and SREBP-1c.