Thyroid hormone levels and BMI-SDS changes in adolescents with obesity.

Background: Thyroid hormones play an important role in energy metabolism and weight control, explained mostly by inducing thermogenesis and increasing basal metabolic rate. It has recently been shown that FT4 levels are associated with food preferences, which might also play a role in modulating body weight. The aim of this longitudinal follow-up study was to analyze the relationship of thyroid hormones levels (FT4, TSH) at baseline with weight/BMI-SDS changes in children and adolescents with obesity. Methods: Three hundred seventy-seven children and adolescents have been enrolled to this study and followed up without a systematic intervention program for 5.59 ± 1.85months. Children and adolescents were divided into three subgroups: 1) 144 adolescents with obesity (15-19 years), 2) 213 children with obesity (10-14.9 years), and 3) 20 lean adolescents (15-19 years). Thyroid hormones were measured at the baseline, and anthropometry was performed at the baseline and during the follow-up. For further analyses, participants were divided according to the BMI-SDS change into two groups: 1. with BMI-SDS decrease, and 2. with BMI-SDS increase. Results: Adolescents with obesity from the BMI-SDS decrease group had significantly lower baseline serum levels of TSH compared to the BMI-SDS increase group (2.4 ± 1.0 vs. 3.2 ± 2.0mIU/l; p=0.005). Similar difference was found for FT4 levels (14.7 ± 2.2 in the BMI-SDS decrease group vs. 15.5 ± 2.7pmol/l in the BMI-SDS increase group, p=0.048). Moreover, the BMI-SDS decrease was present in significantly higher percentage of adolescents with obesity with lower than median TSH level compared to those with higher than median TSH level at baseline (61.1% vs 38.6%, p=0.011). Likewise, the BMI-SDS decrease was present in significantly higher percentage of adolescent females with obesity and lower than median FT4 compared to those with higher than median FT4 level at baseline (70.6% vs. 23.5%, p<0.001). No associations of baseline thyroid hormones with the BMI-SDS change were observed in children with obesity or lean adolescents. Conclusion: Adolescents with obesity and increased BMI-SDS during the follow-up had significantly higher baseline levels of both TSH and FT4 compared to BMI-SDS decrease group. These results support the previous findings that higher FT4 in individuals with obesity may influence weight gain.

Food preferences and thyroid hormones in children and adolescents with obesity.

Background: Thyroid hormones profoundly affect energy metabolism but their interrelation with food preference, which might contribute to childhood obesity development, are much less understood. In this study, we investigated if thyroid hormone levels are associated with specific modulation of food preference and potentially linked to the level of obesity in children and adolescents. Methods: Interrelations between food preference and peripheral thyroid activity were examined in a population of 99 non-obese and 101 obese children and adolescents (12.8 ± 3.6 years of age, 111/89 F/M) randomly selected from the patients of the Obesity and Metabolic Disease Out-patient Research Unit at National Institute for Children's Diseases in Bratislava in a period between December 2017 and March 2020. Results: Children and adolescents with obesity had a lower preference for food rich in high sucrose and high-complex carbohydrates, while the preference for protein and fat-containing food and that for dietary fibers did not differ between obese and nonobese. In adolescents with obesity, free thyroxine (FT4) correlated positively with the preference for a high protein and high fat-rich diet, irrespective of the fatty acid unsaturation level. Moreover, FT4 correlated negatively with the preference for dietary fibers, which has been also exclusively found in obese adolescents. Individuals with obesity with higher FT4 levels had higher systemic levels of AST and ALT than the population with lower FT4. Multiple regression analysis with age, sex, BMI-SDS, and FT4 as covariates revealed that FT4 and male gender are the major predictors of variability in the preference for a diet high in protein, fat, and monounsaturated fatty acids. FT4 was the sole predictor of the preference for a diet containing saturated and polyunsaturated fatty acids as well as for a diet low in fiber. Conclusion: The link between free thyroxin levels and dietary preference for food rich in fat and protein is present exclusively in individuals with obesity. Higher serum FT4 was linked with elevated AST and ALT in children and adolescents with obesity, and FT4 was the best predictor for preference for food rich in fat and low in fiber. This may indicate that FT4 could contribute to the development of childhood obesity and its complications by modulating food preference.

Associations Between Anxiety, Body Mass Index, and Sex Hormones in Women.

Background: Several studies have shown a positive association between anxiety and obesity, particularly in women. We aimed to study whether sex hormone alterations related to obesity might play a role in this association. Patients and methods: Data for this study were obtained from a population-based cohort study (the LIFE-Adult-Study). A total of 3,124 adult women (970 premenopausal and 2,154 postmenopausal) were included into the analyses. The anxiety symptomatology was assessed using the GAD-7 questionnaire (cut-off ≥ 10 points). Sex hormones were measured from fasting serum samples. Results: We did not find significant differences in anxiety prevalence in premenopausal obese women compared with normal-weight controls (4.8% vs. 5.5%). Both obesity and anxiety symptomatology were separately associated with the same sex hormone alteration in premenopausal women: higher total testosterone level (0.97 ± 0.50 in obese vs. 0.86 ± 0.49 nmol/L in normal-weight women, p = 0.026 and 1.04 ± 0.59 in women with vs. 0.88 ± 0.49 nmol/L in women without anxiety symptomatology, p = 0.023). However, women with anxiety symptomatology had non-significantly higher estradiol levels than women without anxiety symptomatology (548.0 ± 507.6 vs. 426.2 ± 474.0 pmol/L), whereas obesity was associated with lower estradiol levels compared with those in normal-weight group (332.7 ± 386.5 vs. 470.8 ± 616.0 pmol/L). Women with anxiety symptomatology had also significantly higher testosterone and estradiol composition (p = 0.006). No associations of sex hormone levels and BMI with anxiety symptomatology in postmenopausal women were found. Conclusions: Although both obesity and anxiety symptomatology were separately associated with higher testosterone level, there was an opposite impact of anxiety and obesity on estradiol levels in premenopausal women. We did not find an evidence that the sex hormone alterations related to obesity are playing a significant role in anxiety symptomatology in premenopausal women. This could be the explanation why we did not find an association between obesity and anxiety. In postmenopausal women, other mechanisms seem to work than in the premenopausal group.

Testosterone imbalance may link depression and increased body weight in premenopausal women.

Accumulating evidence supports a link between depression and being overweight in women. Given previously reported sex differences in fat accumulation and depression prevalence, as well as the likely role of sex hormones in both overweight and mood disorders, we hypothesised that the depression-overweight association may be mediated by sex hormones. To this end, we investigated the association of being overweight with depression, and then considered the role of sex hormones in relation to being overweight and depression in a large population-based cohort. We included a total of 3124 women, 970 premenopausal and 2154 postmenopausal from the LIFE-Adult cohort study in our analyses. We evaluated associations between being overweight (BMI >25 kg/m2), sex hormone levels, and depressive symptomatology according to Centre for Epidemiologic Studies Depression (CES-D) scores, and explored mediation of depression in a mediation model. Being overweight was significantly associated with depressive symptoms in premenopausal but not postmenopausal women. Both premenopausal and postmenopausal overweight women had higher free testosterone levels compared with normal weight women. Premenopausal women with depressive symptomatology had higher free testosterone levels compared to women without. We found a significant mediation effect of depressive symptomatology in overweight premenopausal women through free testosterone level. These findings highlight the association between being overweight and depressed, and suggest that high free testosterone levels may play a significant role in depression of overweight premenopausal women. Based on this, pharmacological approaches targeting androgen levels in overweight depressed females, in particular when standard anti-depressive treatments fail, could be of specific clinical relevance.

Increased estrogen level can be associated with depression in males.

BACKGROUND: Several studies have shown a positive association between depression and obesity; however the underlying mechanisms are not fully understood. It is not known if this association is driven by altered sex hormone levels in men due to increased BMI. PATIENTS AND METHODS: Data were obtained from the LIFE-Adult-Study, a population-based cohort study. A total of 3925 men (2244<60years and 1681>60years) were included into analyses. Associations between BMI, sex hormones and depressive symptomatology according to CES-D score were evaluated. RESULTS: Obese men had compared to normal weight controls lower total testosterone (12.6±4.7 vs 19.4±5.5 nmol/L, p<0.001 in <60years, and 13.8±6.9 vs 18.3±5.9 nmol/L, p<0.001 in >60years group) and free testosterone (249.0±73.9 vs 337.2±82.0pmol/L, p<0.001, and 217.8±71.2 vs 263.4±72.2pmol/L, p<0.001), and increased estradiol in older group only (97.3±43.0 vs 82.3±34.2pmol/L, p<0.001 in obese). Men <60years old with depressive symptomatology had higher estradiol levels compared to those without depressive symptomatology (96.3±40.7 vs 84.4±36.6pmol/L, p<0.001), however no association with BMI was observed. CONCLUSIONS: Selected sex hormone parameters were significantly different in overweight and obese compared to normal weight males and certain differences could be seen between younger and older males. Depressive symptomatology was associated with increased estradiol levels in younger men, regardless of BMI.

Genetic analysis of single-minded 1 gene in early-onset severely obese children and adolescents.

BACKGROUND: Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of SIM1 mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of SIM1 in severely obese children of Slovak and Moravian descent to determine if genetic variants within SIM1 may influence the development of obesity in these populations. METHODS: The SIM1 promoter region, exons and exon-intron boundaries were sequenced in 126 unrelated obese children and adolescents (2-18 years of age) and 41 adult lean controls of Slovak and Moravian origin. Inclusion criteria for the children and adolescents were a body mass index standard deviation score higher than 2 SD for an appropriate age and sex, and obesity onset at less than 5 years of age. The clinical phenotypes of the SIM1 variant carriers were compared with clinical phenotypes of 4 MC4R variant carriers and with 27 unrelated SIM1 and MC4R mutation negative obese controls that were matched for age and gender. RESULTS: Seven previously described SIM1 variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7 in silico software analyses and is located at a highly conserved position of the SIM1 protein. The p.D134N variant was found in an 18 year old female proband (BMI 44.2kg/m2; +7.5 SD), and in 3 obese family members. Regardless of early onset severe obesity, the proband and her brother (age 16 years) did not fulfill the criteria of metabolic syndrome. Moreover, the variant carriers had significantly lower preferences for high sugar (p = 0.02) and low fat, low carbohydrate, high protein (p = 0.02) foods compared to the obese controls. CONCLUSIONS: We have identified a novel SIM1 variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.

EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.

Impairment of translation initiation and its regulation within the integrated stress response (ISR) and related unfolded-protein response has been identified as a cause of several multisystemic syndromes. Here, we link MEHMO syndrome, whose genetic etiology was unknown, to this group of disorders. MEHMO is a rare X-linked syndrome characterized by profound intellectual disability, epilepsy, hypogonadism and hypogenitalism, microcephaly, and obesity. We have identified a C-terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. The EIF2S3 gene encodes the γ subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the ISR. Studies in patient fibroblasts confirm increased ISR activation due to the Ile465Serfs mutation and functional assays in yeast demonstrate that the Ile465Serfs mutation impairs eIF2γ function to a greater extent than tested missense mutations, consistent with the more severe clinical phenotype of the Ile465Serfs male mutation carriers. Thus, we propose that more severe EIF2S3 mutations cause the full MEHMO phenotype, while less deleterious mutations cause a milder form of the syndrome with only a subset of the symptoms.

Lack of association between peripheral activity of thyroid hormones and elevated TSH levels in childhood obesity.

OBJECTIVE: An elevated thyroid stimulating hormone (TSH) level is a frequent finding in obese children, but its association with peripheral hormone metabolism is not fully understood. We hypothesized that in obesity, the changes in thyroid hormone metabolism in peripheral tissues might lead to dysregulation in the thyroid axis. The purpose of this study was to investigate the association of TSH with thyroid hormones in a group of obese children as compared to normal-weight controls. METHODS: Serum TSH, free thyroxine (fT4) and free triiodothyronine (fT3) levels were measured in 101 obese children and in 40 controls. Serum reverse T3 (rT3) levels were also measured in a subgroup of 51 obese children and in 15 controls. RESULTS: Serum TSH level was significantly higher in obese children compared to controls (2.78 vs. 1.99 mIU/L, p<0.001), while no difference was found in fT4, fT3, rT3 levels and in fT3/rT3 ratio. In the obese group, fT3 level positively correlated with fT4 (r=0.217, p=0.033) and inversely with rT3 (r=-0.288, p=0.045). However, thyroid hormone levels and TSH levels were not correlated. CONCLUSION: In obese children, normal fT4, fT3 and rT3 levels suggest an undisturbed peripheral hormone metabolism. These levels show no correlation with elevated TSH levels.

De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed.

AIMS/HYPOTHESIS: MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A). METHODS: Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing. RESULTS: Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo. CONCLUSIONS/INTERPRETATION: In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.