The impact of metabolic endotoxaemia on the browning process in human adipocytes.

BACKGROUND: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. METHODS: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. RESULTS: Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). CONCLUSIONS: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.

Obesity pharmacotherapy - update 2023.

The increasing prevalence of obesity and its associated complications leads to the need to intensify its prevention and treatment. The treatment of obesity is currently based on lifestyle modification, which often fails in the long term. For the next decade, the long-term administration of anti-obesity drugs, i.e. drugs that have a positive effect not only on the reduction of excess weight but also on the health risks associated with obesity, seems to be a necessary part of obesity treatment, along with surgical approaches. This text provides an overview of the current options for the pharmacotherapy of obesity, including their indications, appropriate patient selection and adverse effects of treatment. It also provides an overview of studies that demonstrate the long-term efficacy and safety of these treatments. Although effective and safe anti-obesity drugs are currently available, it is not even partially covered by general health insurance. However, the cost of treatment is unaffordable in the long term for a large proportion of the obese. The virtual unavailability of effective antiobesity drugs for indicated patients has serious health-economic consequences. Failure to take advantage of effective therapeutic options, confirmed by evidence-based medicine, results in a high prevalence of obesity-related diseases, which are even more costly to treat economically and, in the case of type 2 diabetes, even less effective. We consider at least partial reimbursement of antiobesity drugs from general health insurance for cooperating patients under clearly defined conditions to be a necessary step towards improving the situation, and clearly cost-effective in its consequences.

Adult obese patient in primary care.

Overweight and obesity prevalence in middle aged subjects in the Czech Republic is more than 50 per cent, obesity is found in around 26 per cent of population. Obesity management is a long-term and time-consuming process. Early start of the treatment can prevent continuous weight gain and development of co-morbidities. General practitioners see obese patients usually as the first and they represent the first point of contact for adults with obesity. The basis of obesity management is a change of the lifestyle with added pharmacotherapy and/or bariatric/metabolic surgery. The paper presents overview of methods in obesity diagnostics and management and possibilities of their use in GPs daily practice.

[Are the thyroid hormones and thyrotropin associated with cardiometabolic risks and insulin resistance even in euthyroid subjects?] / Jsou tyreoidální hormony a tyreotropin asociovány s kardiometabolickými riziky a inzulinovou rezistencí u eutyreoidních jedincu?

Associations of both hypothyroidism and subclinical hypothyroidism with metabolic syndrome are well established. Nowadays, more attention has been paid to the role of thyroid hormones and thyrotropin (TSH) within the euthyroid range on the development of cardiometabolic health risks. The paper summarizes current knowledge related to the associations of lower free thyroxine (fT4) level and higher levels of both free triiodothyronine (fT3) and TSH with body adiposity, metabolic syndrome and insulin resistance in euthyroid subjects. In our recent study of obese euthyroid adolescents, we revealed that fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) positively correlated with fT3 and TSH and negatively with fT4. The ratio of fT3 to fT4 was also significantly related to HOMA-IR both in girls (r = 0.347, p < 0.001) and boys (r = 0.267, p < 0.001). It is concluded that up-to-date conducted studies mostly confirmed that thyroid hormones and TSH even in euthyroid range may significantly affect the metabolic health and particularly insulin sensitivity.Key words: euthyroid range - insulin resistance - metabolic health - metabolic syndrome - obesity - thyrotropin - thyroxine - triiodothyronine.

[Genetic background in common forms of obesity - from studies on identical twins to candidate genes of obesity]. / Genetické pozadí bezných forem obezity - od studií identických dvojcat po studium kandidátních genu obezity*

Common obesity is a result of interaction between genes and environmental/lifestyle factors, with heritability estimates 40-70%. Not only the susceptibility to obesity but also the success of weight management depends on the genetic background of each individual. This paper summarizes the up-to-date knowledge on genetic causes of common obesities. Introduction of genome-wide association studies (GWAS) led to an identification of a total of 32 variants associated with obesity/BMI and 14 with body fat distribution. Further, a great progress in revealing the mechanisms regulating the energy balance was also noted. However, the proportion of explained variance for BMI is still low, suggesting other mechanisms such as gene-gene and gene-environment interactions, rare gene variants, copy number variants polymorphisms, or epigenetic modifications and microRNAs regulating gene transcription. In summary, we present results of our studies on obesity risk variants in Czech adults, children and adolescents including those evaluating the influence of selected gene variants on the outcomes of weight management.

Lifestyle intervention discloses an association of the Eating Inventory-51 factors with cardiometabolic health risks.

Factors of the Eating Inventory-51 (EI) were revealed as significant predictors of health risks. Associations of EI factors (restraint, disinhibition, hunger) with cardiometabolic risk parameters and selected hormones were analysed before and after an in-patient weight reduction programme. Sixty-seven women (age: 48.7 ± 12.2 years; body mass index: 32.4 ± 4.4 kg/m(2)), who exhibited stable weight on a 7 MJ/day diet during the first week, obtained a 4.5 MJ/day diet over the subsequent 3-week period. No significant relations were observed before the weight reduction. After weight loss, restraint score negatively correlated with total cholesterol, fasting blood glucose, C peptide, insulin and neuropeptide Y. Hunger score was positively related to insulin and neuropeptide Y. Disinhibition score correlated positively with lipid profile and neuropeptide Y, while negatively with adiponectin. An implementation of a standard dietary and lifestyle pattern for 3 weeks revealed significant associations between EI factors and metabolic risks in women.

Do we need anti-obesity drugs?

The increasing global prevalence of obesity urgently requires an implementation of efficient preventive and therapeutic measures. Weight loss and its maintenance should be considered one of the most important strategies to reduce the incidence of obesity-related co-morbidities such as diabetes and cardiovascular diseases. Lifestyle modification focused on diet and physical activity represents the essential component of any kind of weight management. However, only an intensive lifestyle intervention can be efficient in terms of long-term weight loss. Anti-obesity drugs affect different targets in the central nervous system or peripheral tissues and improve regulatory and metabolic disturbances that contribute to the development of obesity. Anti-obesity medications provide modest additional fat loss to that achieved by lifestyle modification alone, reduce visceral fat stores, improve programme adherence, weight loss maintenance, diminish obesity-related health risks and improve a quality of life. Anti-obesity drugs do play a role in weight management. Their replacement with placebo is followed by weight regain. Due to adverse events, several anti-obesity drugs were withdrawn from the market over the past few years and currently only orlistat remains available for long-term obesity management. Drug withdrawals, failure of clinical trials with several new anti-obesity compounds as well as inappropriate demands of drug regulating agencies concerning the study protocol led to scepticism about the perspectives in the pharmacotherapy of obesity. However, recently developed anti-obesity medications such as gut hormone analogues and drug combinations provided encouraging results in terms of weight loss, safety and improvement of cardio-metabolic health risks.

[Role of infection in the pathogenesis of obesity]. / Úloha infekce v patogenezi obezity.

Current global epidemic of obesity is mainly related to increased consumption of high energy density foods and sedentary lifestyle that leads to a positive energy balance with subsequent accumulation of fat stores, primarily in genetically predisposed individuals. However, additional pathogenetic factors should be considered, including an infection. Several viruses causing obesity have been described in mice, chicken, rats, hamsters and monkeys. In humans, a significant positive association between being overweight and IgG antibodies was found for Helicobacter pylori and Chlamydia pneumoniae. This association of bacterial infections with increased BMI might not represent a causal relationship but could be a marker for greater susceptibility of obese individuals to infection. Crucial role in the development of "infectious obesity" in humans may be played by adenovirus infection, particularly AD-36 type that is also capable of inducing obesity in experimental animals as chicken, mice and monkeys. AD-36-induced obesity is paradoxically associated with lower levels of serum cholesterol and triglycerides both in humans and in experimental animals. Moreover, AD-36 enhances insulin sensitivity and improves hepatic steatosis. AD-36 effects in target organs as adipose tissue, liver and skeletal muscle are mediated through the viral protein E4orf1. This way AD-36 improves metabolic profile, as indicated by a greater glucose uptake by adipose tissue and skeletal muscle, reduced glucose output by hepatocytes, increased adiponectin levels and increased expression of adipogenic genes as peroxisome proliferator-activated receptor gamma. If E4orf1 improves glycemic control without reducing dietary fat intake and body fat stores, this viral protein would be highly valuable to develop novel anti-diabetic agents that mimic its effects.Key words: obesity, infection, adenovirus AD-36, diabetes mellitus, lipid profile, insulin sensitivity.

FADS1 gene polymorphism(s) and fatty acid composition of serum lipids in adolescents.

Polyunsaturated fatty acids (PUFA) influence many physiological functions. Associations have been found between single nucleotide polymorphisms (SNP) in the FADS1 (Fatty acid desaturase 1) gene and the relative abundance of PUFA in serum lipids. This study examines the relationship between two SNPs in the FADS1 gene (rs174546, rs174537) and the fatty acid (FA) composition of serum lipids in adolescents (13-18 years). We used DNA samples (670 children; 336 girls and 334 boys) from the Childhood Obesity Prevalence and Treatment (COPAT) project. Genomic DNA was extracted from peripheral blood leukocytes in whole blood samples. For genotype analysis, TaqMan SNP Genotyping assays (Applied Biosystems) were used. Fatty acid composition of serum lipids was assessed using gas chromatography. The T-statistic and regression were used for statistical evaluations. Minor allele T carriers in both SNPs had significant lower level of palmitic acid (16:0, phospholipids) and arachidonic acid (20:4[n-6], phospholipids) in both sexes. In girls, we found a significant positive association between minor allele T carriers and eicosadienoic acid (20:2[n-6], cholesteryl esters) in both SNPs. Being a minor allele T carrier was significantly positively associated with dihomo-γ-linolenic acid (20:3[n-6], phospholipids) in boys in both SNPs. SNPs (including rs174546, rs174537) in the FADS gene cluster should have impacted desaturase activity, which may contribute to different efficiency of PUFA synthesis.

Waist circumference and waist-to-height ratio in 7-year-old children-WHO Childhood Obesity Surveillance Initiative.

Childhood obesity is a serious global health problem. Waist circumference (WC) and waist-to-height ratio (WHtR) reflect body fat distribution in children. The objectives of this study were to assess WC and WHtR in 7-year-old children and to determine body mass index (BMI), WC, and WHtR differences in children from 10 selected countries across Europe (Bulgaria, Czechia, Greece, Ireland, Latvia, Lithuania, North Macedonia, Norway, Spain, and Sweden) participating in the World Health Organization (WHO) Europe Childhood Obesity Surveillance Initiative (COSI). The 50th and 90th percentile of WC (according to COSI and "Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS" (IDEFICS) cutoff values) and WHtR above 0.5 were used as measures of abdominal obesity in a unique sample of 38,975 children aged 7.00-7.99 years. Southern European countries, including Greece and Spain, showed significantly higher BMI, WC, and WHtRin both genders (p < 0.0001) than Eastern and Northern Europe. The highest values for WC were observed in Greece (60.8 ± 7.36 cm boys; 60.3 ± 7.48 cm girls), North Macedonia (60.4 ± 7.91 cm boys; 59.0 ± 8.01 cm girls), and Spain (59.7 ± 6.96 cm boys; 58.9 ± 6.77 cm girls). WC and WHtRin may add an information about the occurrence of central obesity in children.

[Drug treatment of obesity--current situation and perspectives]. / Farmakoterapie obezity--soucasné moznosti a perspektivy.

Pharmacotherapy of obesity should be an integral part of the comprehensive obesity management program which includes diet, exercise and cognitive behavioural intervention. Currently available antiobesity drugs result in only modest weight loss, however it is still accompanied by reduction of cardiometabolic health risks. In the past several antiobesity drugs were removed from the market because of serious adverse effects (psychostimulatory, cardiovascular, pulmonary hypertension, valvular disease, depression, addiction etc.). Such situations led some investigators and clinicians to nihilistic approaches to the drug treatment of obesity. This paper aims to review the data on clinical efficiency and safety of currently available antiobesity drugs and to summarize our knowledge on the recently discovered antiobesity agents which underwent clinical trials (such as lorcaserin, tesofensine, cetilistat, combination drugs, gut hormone analogues etc.). Approaches with two drug combination of decreased doses were recommended to increase both safety and efficacy of antiobesity treatment. However, previous experiences that antiobesity drug combinations (e.g. fenfluramine/phentermine) may also potentiate adverse events should be carefully considered in the evaluation of recently tested compounds. Administration of physiological doses of gut hormones - derived appetite regulating agents seems to be a promising, efficient, specific and thus, low side-effect approach in the treatment of obesity. To confirm the strong role of antiobesity drugs in the treatment of obesity and its complications further long-term studies evaluating their effect on morbidity and mortality end points in appropriate target populations are needed.

[Reduction of abdominal obesity and cardiometabolic health risks in obese adolescents in response to a short-term spa weight management program]. / Redukce abdominální obezity a kardiometabolických rizik u obézních adolescentu krátkodobým lázenským redukcním programem.

BACKGROUND: Overweight and obesity is associated with metabolic and cardiovascular complications even in children and adolescents. Obesity in childhood represents a serious health problem, as an obese child frequently remains obese subject in adulthood. Obesity is also an important early risk factor for morbidity and mortality in adulthood. The aim of this study was to follow changes in selected anthropometric parameters and cardiometabolic risks in overweight and obese adolescents in response to a 4-week spa weight management program. METHODS AND RESULTS: The studied cohort included 342 adolescents (boys, n = 121, girls, n = 221); mean age (+/- SD) 14.9 +/- 1.4 years (range 13.0 to 17.9 years) with overweight or obesity, mean BMI (+/- SD) 30.1 +/- 4.4 kg/m2 who underwent a 4-week spa weight management program. Anthropometric (body height and weight, waist circumference, sagittal abdominal diameter, total body fat and intra-abdominal fat), clinical (blood pressure) and biochemical (total cholesterol, HDL and LDL cholesterol, triglycerides, glucose, insulin) parameters were studied. All examinations were conducted before and after a 4-week weight management program. Statistical evaluation of the data was performed by ANOVA. The data are expressed as means +/- SD. In response to treatment all subjects demonstrated significant decreases in initial body weight (-6.3 +/- 2.3 %), percent of total fat (-2.7 +/- 2.5 %), percent of trunk fat (-2.5 +/- 1.5 %), degree of enlargement in visceral fat stores (-2.1 +/- 2.8), as well as reductions in waist circumference (-4.7 +/- 3.2 cm) and sagittal abdominal diameter (-1.0 +/- 1.8 cm). Positive changes in lipid profile and decrease in insulin resistance as measured by HOMA-IR were also recorded together with significant reductions in both systolic and diastolic blood pressures. CONCLUSIONS: Short-term weight management program in adolescents led to significant reductions in body weight, trunk and visceral fat and cardiometabolic health risks.

[A new simple method for estimating trunk and visceral fat by bioelectrical impedance: comparison with magnetic resonance imaging and dual X-ray absorptiometry in Czech adolescents]. / Nová jednoduchá metoda stanovení viscerálního a trunkálního tuku pomocí bioelektrické impedance: srovnání s magnetickou rezonancí a duální rentgenovou absorpciometrií u ceských adolescentu.

BACKGROUND: The enlargement of visceral fat (VF) in abdominal obesity is associated with increased cardiometabolic health risks in both adults and adolescents. A precise measurement of VF by sophisticated methods as computed tomography (CT) and magnetic resonance imaging (MRI) cannot be applied in routine clinical practice. The aim of our study was to compare estimates on visceral and trunk fat in adolescents obtained by a new bioimpedance analysis instrument (BIA)--Tanita AB-140 ViScan--with those obtained by MRI, dual X-ray absorptiometry (DEXA) and anthropometry. METHODS AND RESULTS: Investigated cohort: 39 adolescent secondary school students; median (lower quartile; upper quartile)--age: 16.4 (15.4; 17.4) years; body weight: 63.8 (54.1; 79.0) kg; BMI: 21.4 (19.5; 27.4) kg/m2. Investigated parameters: BMI, body circumferences and sagittal abdominal diameter (SAD), trunk, visceral and subcutaneous fat determined by BIA, MRI and DEXA. STATISTICS: Spearman's correlations. The assessment of trunk fat by BIA correlated with DEXA estimates (r = 0.979, p < 0.0001) and with abdominal fat measured by MRI (r = 0.930, p < 0.0001). The visceral fat amount derived from abdominal BIA exhibited lower, however significant correlation with visceral fat determined by MRI (r = 0.791, p < 0.001). The visceral fat area presumed by abdominal BIA significantly correlated with anthropometric parameters as abdominal circumference (r = 0.923, p < 0.0001), waist circumference (r = 0.913, p < 0.0001) and SAD (r= 0.891, p < 0.0001). CONCLUSIONS: The new method estimating abdominal fat by BIA represents a reliable tool for clinical evaluation of the trunk fat in adolescents. However, its advantages over anthropometric measurements in evaluation of VF require further validation studies.

[Changes of plasma obestatin and ghrelin levels after soluble fiber with glucose and after fiber alone in healthy women and in patients with bulimia nervosa]. / Zmeny plazmatických hladin obestatinu a ghrelinu po podání rozpustné vlákniny s glukózou a samotné vlákniny zdravým zenám a pacientkám s bulimia nervosa.

BACKGROUND: The recent identification of obestatin, a novel peptide hormone derived from the same gene as ghrelin, has added further complexity to ghrelin physiology. Despite the rapid progress, many questions remain unanswered, including the regulation of orexigen ghrelin and putative anorexigen obestatin secretion by food composition in humans. The present study was undertaken to investigate the influence of caloric and noncaloric food on plasma ghrelin and obestatin concentrations in healthy women (n = 6; age 23.83 +/- 1.1 years; BMI 20.85 +/- 0.87 kg/m2) and in bulimia nervosa patients (n = 6; age 26.6 +/- 5.2 years; BMI 19.2 +/- 1.44 kg/m2), characterized by abnormal eating behaviour and imbalance in energy homeostasis. METHODS AND RESULTS: After overnight fasting, plasma ghrelin and obestatin were measured by commercial radioimmunoassay kits before and after consumption of soluble fiber alone or with glucose. In both groups plasma ghrelin and obestatin levels did not change after fiber alone, but decreased after fiber with glucose. During 30-90 min after ingestion we observed significant decrease (p < 0.05) of plasma ghrelin and obestatin levels after soluble fiber with glucose in healthy women and also in patients with bulimia nervosa, after then the levels of both hormones started to increase to preprandial levels. CONCLUSIONS: We conclude that postprandial ghrelin and obestatin plasma levels decrease in relation to caloric content of the meal in healthy women and in patients with bulimia nervosa.

Acipimox Administration With Exercise Induces a Co-feedback Action of the GH, PP, and PYY on Ghrelin Associated With a Reduction of Peripheral Lipolysis in Bulimic and Healthy-Weight Czech Women: A Randomized Study.

Objective: Anti-lipolytic drugs and exercise are enhancers of growth hormone (GH) secretion. Decreased circulating free fatty acids (FFA) have been proposed to exert ghrelin-GH feedback loop after administration of an anti-lipolytic longer-acting analog of nicotinic acid, Acipimox (OLB, 5-Methylpyrazine-2-carboxylic acid 4-oxide, molecular weight of 154.1 Da). OLB administration strongly suppresses plasma FFA during exercise. Neuroendocrine perturbations of the adipose tissue (AT), gut, and brain peptides may be involved in the etiopathogenesis of eating disorders including bulimia nervosa (BN) and anorexia nervosa. BN is characterized by binge eating, self-induced vomiting or excessive exercise. Approach: To test the hypothesis that treatment with OLB together with exercise vs. exercise alone would induce feedback action of GH, pancreatic polypeptide (PP), peptide tyrosine tyrosine (PYY), and leptin on ghrelin in Czech women with BN and in healthy-weight Czech women (HW). The lipolysis rate (as glycerol release) in subcutaneous abdominal AT was assessed with microdialysis. At an academic medical center, 12 BN and 12 HW (the control group) were randomized to OLB 500 mg 1 h before a single exercise bout (45 min, 2 W/kg of lean body mass [LBM]) once a week vs. identical placebo over a total of 2 weeks. Blood plasma concentrations of GH, PP, PYY, leptin, ghrelin, FFA, glycerol, and concentrations of AT interstitial glycerol were estimated during the test by RIA utilizing 125I-labeled tracer, the electrochemiluminescence technique (ECLIA) or colorimetric kits. Results: OLB administration together with short-term exercise significantly increased plasma GH (P < 0.0001), PP (P < 0.0001), PYY, and leptin concentrations and significantly decreased plasma ghrelin (P < 0.01) concentrations in both groups, whereas short-term exercise with placebo resulted in plasma ghrelin (P < 0.05) decrease exclusively in BN. OLB administration together with short-term exercise significantly lowered local subcutaneous abdominal AT interstitial glycerol (P < 0.0001) to a greater extent in BN. Conclusion: OLB-induced suppression of plasma ghrelin concentrations together with short-term exercise and after the post-exercise recovering phase suggests a potential negative co-feedback of GH, PP, PYY, and leptin on ghrelin secretion to a greater extent in BN. Simultaneously, the exercise-induced elevation in AT interstitial glycerol leading to a higher inhibition of peripheral lipolysis by OLB in BN. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03338387.

Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis.

BACKGROUND: Mutations in the melanocortin 4 receptor gene (MC4R) represent the most common known cause of monogenic human obesity. AIMS: The aims of this study were the following: 1) to estimate the prevalence of MC4R mutations in obese Czech children; 2) to evaluate phenotypic features of the mutation carriers; 3) to compare weight, height, and body mass index of MC4R mutation carriers with noncarriers in longitudinal studies; 4) to determine the effect of a weight management program among MC4R mutation carriers; and 5) to perform a functional analysis of a novel variant. SUBJECTS AND METHODS: We analyzed the coding region of MC4R in a cohort of 289 Czech children and adolescents with early-onset obesity by direct sequencing. Information on weight, height, body mass index, baseline biochemical data, and a weight loss follow-up study was obtained. In vitro functional analysis of one novel variant was performed. RESULTS: We identified six different mutations in seven probands: one novel missense mutation Cys84Arg and five previously reported variants, Arg7Cys, Ser19fsdelA, Phe51Leu, Ser127Leu, and Gly181Asp. The Gly181Asp variant was detected in one homozygous carrier from unrelated parents. None of the mutation carriers fulfilled the MC4R syndrome criteria. A comparison of anthropometrics in mutation carriers and noncarriers during 13 yr of follow-up did not reveal any significant differences. MC4R mutation carriers exhibited a similar ability to lose weight as obese noncarriers. The novel variant Cys84Arg showed a significant reduction in cAMP signal properties of the MC4R. CONCLUSIONS: Among obese Czech children, we found a prevalence of 2.4% of MC4R homozygous and heterozygous mutations and showed a similar response to diet management of MC4R mutation carriers and noncarriers.

Insulin sensitivity and its relation to hormones in adolescent boys and girls.

BACKGROUND AND AIMS: A subset of obese individuals lacks cardiometabolic impairment. We aimed to analyze hormonal profiles of insulin-sensitive obese (ISO) and insulin-resistant obese (IRO) adolescents and determine hormonal predictors of homeostasis model of insulin resistance (HOMA-IR). MATERIALS AND METHODS: A threshold of 3.16 of HOMA-IR was used to classify ISO (<3.16) IRO (≥3.16). In 702 individuals aged 13-18years (55.8% girls) anthropometric and laboratory [blood glucose, insulin, thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), sex hormone-binding globulin (SHBG), steroid hormones, luteinizing hormone, follicle stimulating hormone, prolactin, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like-peptide 1glucagon, leptin, resistin, visfatin, leptin, adiponectin and adipsin] assessments were performed. Orthogonal projections to latent structures and Mann-Whitney tests with Bonferroni correction were applied for statistical analysis. RESULTS: 52.6% girls and 42.9% boys were insulin sensitive. In the predictive model of HOMA-IR thyroid function tests, adiponectin, ghrelin and leptin concentrations played an important role in both genders. Prolactin, testosterone and glucagon contributed to the model only in boys, while progesterone and dehydroepiandrosterone sulfate levels only in girls. After Bonferroni correction levels of leptin, adiponectin, leptin/adiponectin ratio, SHBG and fT4/TSH ratio in both genders, testosterone and glucagon levels in boys and levels of TSH and fT3 in girls were related to insulin sensitivity. CONCLUSION: Metabolic health defined by HOMA-IR is partly predicted by various hormones. Some of them are gender specific. Free T4/TSH and leptin/adiponectin ratios are related to insulin sensitivity in both genders.

Serotonin and norepinephrine reuptake inhibition and eating behavior.

Brain neurotransmitters, serotonin and norepinephrine, play an important role in the central nervous control of energy balance and are involved in symptomatology related to both obesity and depression. Therefore both serotonin and norepinephrine neural pathways have been paid a special attention as targets for the antiobesity drugs, antidepressants, and drugs used in the treatment of eating disorders. Selective serotonin reuptake inhibitors (SSRI) have been used in the treatment of depression and eating disorders but have failed to achieve sustained weight loss in the treatment of obesity. Sibutramine, a serotonin and norepinephrine reuptake inhibitor, which induces satiety and prevents decline in metabolic rate associated with a hypocaloric diet, is currently the sole centrally acting drug indicated for the long-term treatment of obesity. Depression, dietary disinhibition (evaluated by the Eating Inventory [EI]), and stress are associated with the accumulation of abdominal fat and the development of metabolic syndrome and related diseases. Subjects with abdominal obesity demonstrate neuroendocrine abnormalities which result in disturbances in hypothalamo-pituitary-adrenal (HPA) function. Treatment with SSRI might interrupt the vicious circle which leads to endocrine abnormalities and the accumulation of abdominal fat. Obesity treatment with sibutramine results, not only in significant weight loss, but also in reduction of abdominal fat and in the improvement of health risks associated with metabolic syndrome (lipid profile, blood glucose, insulin, HbA1c, and uric acid), as well as in the decline in disinhibition score of the EI. In a 1-year sibutramine trial, only a decrease in the disinhibition score remained a significant correlate of weight loss among the psychobehavioral and nutritional factors which were taken into account.

Cardiometabolic Health in Obese Adolescents Is Related to Length of Obesity Exposure: A Pilot Study.

CONTEXT: Metabolically healthy obesity (MHO) is found in a subset of obese individuals. OBJECTIVE: This study sought to examine possible determinants of MHO related to the length of exposure to obesity, lifestyle factors, and dietary intake in adolescent boys. DESIGN: This was a cross-sectional Childhood Obesity Prevalence And Treatment study. Participants and Main Measures: Of 313 boys age 13.0-17.9 years with a body mass index (BMI) ≥ 97th percentile for age, two study cohorts were established based on two definitions of metabolically unhealthy obesity (MUO). Cohort 1 included 18 boys with at least three risk factors (hypertension, dyslipidemia, dysglycemia) who were matched for age, weight, height, and BMI with 18 boys with MHO. Cohort 2 included 35 boys with at least two risk factors who were compared with 31 boys with MHO. MHO was defined by the absence of cardiometabolic risk factors (excluding waist). Data on lifestyle factors and BMI growth trajectories were compared (MHO vs MUO). RESULTS: Boys with MUO (Cohort 1) presented with an earlier onset (4.3 vs 9.1 y; P = .005) and a longer duration of obesity (11.2 vs 6.4 y; P = .003) compared with those with MHO in both group comparisons using different MUO definitions. We found an overall trend toward higher BMI z scores (significant from 3-7 y; P < .001) in metabolically unhealthy compared with their healthy counterparts (Cohort 1). Boys with MHO had higher carbohydrate intake (P < .001). No additional determinants of MHO were observed. CONCLUSIONS: Increased cardiometabolic risk in boys is related to an earlier onset and a longer duration of obesity.

Insulin Sensitivity and Secretion in Obese Type 2 Diabetic Women after Various Bariatric Operations.

OBJECTIVE: To compare the effects of biliopancreatic diversion (BPD) and laparoscopic gastric banding (LAGB) on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P). METHODS: A total of 52 obese women (age 30-66 years) suffering from type 2 diabetes mellitus (T2DM) were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. RESULTS: Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity) increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. CONCLUSION: We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion), but without increasing the beta cell glucose sensitivity.