Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R).

Leptin-melanocortin pathway plays an essential role in the body weight regulation. Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. The discovery of monogenic obesities with dysfunction of melanocortin-4 receptor (MC4R) greatly contributed to understanding of energy balance regulation. This review presents phenotypical characterization and prevalence of the MC4R gene mutations. Genome-wide association studies revealed that MC4R gene is significantly related not only to monogenic obesities but also to common obesity. An interaction of variants in the MC4R gene with fat mass and obesity associated (FTO) gene significantly increases the risk for obesity, particularly in adolescence. On the other hand, about 15 % of the MC4R gene variants result in a gain of function that protects against obesity and is associated with favorable metabolic profile. Long-term attempts to activate the MC4R have recently been finalized by a discovery of setmelanotide, a novel specific MC4R agonist that is devoid of untoward cardiovascular side-effects. The employment of specific MC4R agonists may open new horizons not only in the treatment of rare monogenic obesities but also in some common obesities where stimulation of MC4R could be achieved.

Impact of dietary intake, lifestyle and biochemical factors on metabolic health in obese adolescents.

BACKGROUND AND AIMS: Obesity devoid of metabolic abnormalities is known as metabolically healthy obesity (MHO). The aim of the study was to examine determinants of MHO during adolescence. METHODS AND RESULTS: From among 710 obese adolescents, 43 girls and 57 boys were classified as metabolically unhealthy (abdominal obesity and ≥2 risk components of metabolic syndrome). MHO (absence of any cardiometabolic risk factor) was found in 211 girls and 131 boys (regardless of waist circumference) and in 33 girls and 27 boys (without abdominal obesity). Laboratory and anthropometric parameters, dietary records and various lifestyle factors were compared between MHO vs. those unhealthy. The prevalence of MHO regardless of waist circumference was higher in girls than in boys (53.1 vs. 41.9%) but comparable when abdominal obesity was excluded (8.3 vs. 8.6%). Anthropometric variables, levels of gamma-glutamyl transferase, total and low-density lipoprotein cholesterol in both genders, hs-C-reactive protein in girls and alanine aminotransferase in boys differentiated the two metabolic phenotypes. Uric acid was related to metabolic health only in the analysis of MHO without abdominal obesity. Total hours of sleep, bedtime, time of the last daily meal, regular meal consumption and protein intake in boys and screen time, the score of disinhibition and diet composition in girls were found to impact cardiometabolic health. CONCLUSIONS: In obese adolescents, metabolic health was related to anthropometric and biochemical parameters and only weak associations were found with most of the lifestyle factors studied. Uric acid concentration associated with metabolic health when abdominal obesity was excluded.

Obesity and infection: reciprocal causality.

Associations between different infectious agents and obesity have been reported in humans for over thirty years. In many cases, as in nosocomial infections, this relationship reflects the greater susceptibility of obese individuals to infection due to impaired immunity. In such cases, the infection is not related to obesity as a causal factor but represents a complication of obesity. In contrast, several infections have been suggested as potential causal factors in human obesity. However, evidence of a causal linkage to human obesity has only been provided for adenovirus 36 (Adv36). This virus activates lipogenic and proinflammatory pathways in adipose tissue, improves insulin sensitivity, lipid profile and hepatic steatosis. The E4orf1 gene of Adv36 exerts insulin senzitizing effects, but is devoid of its pro-inflammatory modalities. The development of a vaccine to prevent Adv36-induced obesity or the use of E4orf1 as a ligand for novel antidiabetic drugs could open new horizons in the prophylaxis and treatment of obesity and diabetes. More experimental and clinical studies are needed to elucidate the mutual relations between infection and obesity, identify additional infectious agents causing human obesity, as well as define the conditions that predispose obese individuals to specific infections.

Association of adenovirus 36 infection with obesity-related gene variants in adolescents.

Both, common gene variants and human adenovirus 36 (Adv36) are involved in the pathogenesis of obesity. The potential relationship between these two pathogenic factors has not yet been investigated. The aim of our study was to examine the association of obesity susceptibility loci with Adv36 status. Genotyping of ten gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, FTO) and analysis of Adv36 antibodies was performed in 1,027 Czech adolescents aged 13.0-17.9 years. Variants of two genes (PCSK1 and BDNF) were associated with Adv36 seropositivity. A higher prevalence of Adv36 antibody positivity was observed in obesity risk allele carriers of PCSK1 rs6232, rs6235 and BDNF rs4923461 vs. non-carriers (chi(2)=6.59, p=0.010; chi(2)=7.56, p=0.023 and chi(2)=6.84, p=0.033, respectively). The increased risk of Adv36 positivity was also found in PCSK1 variants: rs6232 (OR=1.67, 95 % CI 1.11-2.49, p=0.016) and rs6235 (OR=1.34, 95 % CI 1.08-1.67, p=0.010). PCSK1 rs6232 and BDNF rs925946 variants were closely associated with Adv36 status in boys and girls, respectively (chi(2)=5.09, p=0.024; chi(2)=7.29, p=0.026). Furthermore, PCSK1 rs6235 risk allele was related to Adv36 seropositivity (chi(2)=6.85, p=0.033) in overweight/obese subgroup. In conclusion, our results suggest that obesity risk variants of PCSK1 and BDNF genes may be related to Adv36 infection.

Adenovirus 36 infection: a role in dietary intake and response to inpatient weight management in obese girls.

Human adenovirus 36 (Adv36) increases adiposity and is more prevalent in overweight and obese children. Dietary intake in animal models is comparable regardless of Adv36 status. The effects of Adv36 on obesity treatment outcomes have not been clarified. The aim of this study is to investigate the pre-treatment dietary intake and the response to a 4-week inpatient weight management in 184 obese adolescent girls aged 13.0-17.9 years with respect to the presence of Adv36 antibodies. Evaluation of 3-day dietary records did not show any difference in daily intake of energy and essential nutrients between Adv36 antibody positive and negative girls. After the intervention Adv36 positive girls presented with significantly greater decrease of waist circumference (P=0.020), z-score of waist circumference (P=0.024), waist-to-hip ratio (P=0.007) and weight-to-height ratio (P=0.019) compared with Adv36 negative girls. On the contrary, the sum of four skinfolds decreased significantly more in Adv36 negative than in Adv36 positive individuals (P=0.013). Neither body fat percentage nor metabolic and hormonal parameters showed any significant relevance to Adv36 status in response to weight loss intervention. In conclusion, energy restriction in Adv36 antibody positive girls was associated with greater decrease of abdominal obesity and preservation of subcutaneous fat tissue than in those antibody negative.

Clinical and laboratory characteristics of 1179 Czech adolescents evaluated for antibodies to human adenovirus 36.

BACKGROUND: Human adenovirus 36 (Adv36) is associated with obesity in children. Most prior studies have been small and the association of Adv36 status with markers of metabolic risks has been inconsistent. OBJECTIVES: To determine the prevalence of Adv36 antibodies in different weight categories of adolescents and to evaluate the association of Adv36 infection with anthropometric parameters and cardiometabolic health risks. SUBJECTS AND METHODS: In 1179 Czech adolescents (85 underweight, 506 normal weight, 160 overweight and 428 obese), the following variables were evaluated: anthropometric (body weight, height, body mass index, circumferences, fat mass), blood pressure, biochemical and hormonal (lipid profile, glucose, insulin, liver enzymes, adiponectin) and Adv36 antibodies (enzyme-linked immunosorbent assay). RESULTS: Of the total cohort, 26.5% were positive for Adv36 antibodies (underweight: 22.3%; normal weight: 21.5%; overweight: 40.0% and obese: 28.0%). The odds ratio for Adv36 antibody positivity evaluated vs normal weight was 2.61 for overweight (95% confidence interval (CI): 1.77-3.86, P<0.001) and 1.46 for obesity (95% CI: 1.07-1.99, P=0.016). A significantly higher prevalence of Adv36 infection was observed in female subjects (32.5%) in comparison to male subjects (19.7%; P<0.001). Adv36 positivity of the whole cohort was significantly related to body weight (P=0.042), body mass index (P=0.015), hip circumference (P=0.004), body height z-score (P=0.029), and total body fat (P=0.000) and trunk fat (P=0.000). Adv36 antibody-positive girls demonstrated significantly higher body height (167.8 vs 165.0 cm, P=0.01) and waist circumference (77.0 vs 72.0 cm, P=0.01). Infected adolescents exhibited significantly higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), but lower levels of blood glucose. Liver enzymes were significantly increased only in Adv36-positive boys. CONCLUSION: These results demonstrated an association of Adv36 antibodies with obesity and an even greater association with overweight. Adv36 positivity was related to increased fat mass, levels of TC and LDL-C, but to decreased level of blood glucose. No relation to adiponectin levels was revealed.

Association of obesity susceptibility gene variants with metabolic syndrome and related traits in 1,443 Czech adolescents.

Genome-wide association studies have revealed several gene variants associated with obesity; however, only a few studies have further investigated their association with metabolic syndrome. We performed a study of eleven variants in/near genes TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, and FTO in Czech adolescents and analysed their association with obesity, metabolic syndrome and related traits. Genotyping was performed in 1,443 adolescents aged 13.0-17.9 years. Anthropometric parameters, biochemical parameters and blood pressure were assessed. Metabolic syndrome was defined according to the International Diabetes Federation. The FTO rs9939609 variant was associated with overweight/obesity (OR 1.40, 95% CI 1.21-1.63, P < 0.001). The minor allele of TMEM18 rs7561317 was related to underweight (OR 1.78, 95% CI 1.14-2.79, P = 0.015). BDNF rs925946 and MC4R rs17782313 were associated with metabolic syndrome (OR 1.53, 95% CI 1.14-2.04, P = 0.005; 1.51, 95% CI 1.12-2.04, P = 0.009). The PCSK1 rs6235 variant was negatively related to increased blood glucose (OR 0.69, 95% CI 0.49-0.97, P = 0.040). In conclusion, the FTO variant was associated with overweight/obesity in Czech adolescents. Moreover, MC4R and BDNF variants increased the risk of metabolic syndrome, probably through their effect on abdominal obesity. The PCSK1 variant may have a protective role in the development of type 2 diabetes.

Role of the PPARalpha Leu162Val and PPARgamma2 Pro12Ala gene polymorphisms in weight change after 2.5-year follow-up in Czech obese women.

The aim of this study was to investigate the possible effect of PPARalpha and PPARgamma2 variants on weight and eating attitudes as well as on their changes after 2.5-year follow-up. The study was carried out in 246 Czech non-diabetic obese women (age 49.0 +/- 11.9 years; BMI 38.1 +/- 7.0 kg/m(2)). The comprehensive weight management programme included lowenergy diet, increased physical activity and lifestyle modification. Anthropometric parameters (body weight and height, waist and hip circumferences) and body composition were measured. The Three-Factor Eating Questionnaire and Beck Depression Inventory were evaluated. At baseline and after the follow-up period, fasting levels of serum glucose, plasma adiponectin, ghrelin, leptin, and lipid profile were determined. The dependence of monitored parameters on the Pro12Ala in PPARgamma2 and Leu162Val in PPARalpha and stage of the treatment (baseline; 2.5- year follow-up) was evaluated using the repeated measures ANOVA model. The cohort was re-examined after 2.5 years, independent of regular checkups and adherence to lifestyle recommendation. Significant favourable changes in anthropometric indexes, lipid profile, leptin, ghrelin and adiponectin levels as well as in dietary restraint and hunger scores were revealed at 2.5-year check-up. However, no changes in the scores of disinhibition and depression were demonstrated. Despite several observed significant differences between carriers and non-carriers of the minor alleles at baseline and at the follow-up, the repeated measures ANOVA did not reveal any significant effect of the PPARalpha and PPARgamma2 polymorphisms on anthropometric, biochemical, hormonal and psycho-behavioural characteristics, neither at baseline nor at the 2.5-year follow-up.