The histone methyltransferase SMYD1 is induced by thermogenic stimuli in adipose tissue.

Aim: To study the expression of histone methyltransferase SMYD1 in white adipose tissue (WAT) and brown adipose tissue and during differentiation of preadipocytes to white and beige phenotypes. Methods: C57BL/6J mice fed a high-fat diet (and exposed to cold) and 3T3-L1 cells stimulated to differentiate into white and beige adipocytes were used. Results: SMYD1 expression increased in WAT of high-fat diet fed mice and in WAT and brown adipose tissue of cold-exposed mice, suggesting its role in thermogenesis. SMYD1 expression was higher in beige adipocytes than in white adipocytes, and its silencing leads to a decrease in mitochondrial content and in Pgc-1α expression. Conclusion: These data suggest a novel role for SMYD1 as a positive regulator of energy control in adipose tissue.

In this study, a protein called SMYD1 was examined in the adipose tissue of mice to understand its role in the development of different types of fat cells. The authors used mice fed a high-fat diet or mice exposed to a cold environment. The experiments were also performed on cultured cells that were stimulated to form specific types of fat cells (white adipocytes, which store energy; or beige adipocytes, which are responsible for releasing energy in the form of heat). The study found that SMYD1 increased in white adipose tissue particularly in response to cold exposure and high-fat diet, suggesting involvement in body temperature regulation. SMYD1 was higher in beige adipocytes than in white fat cells, and when SMYD1 was reduced, there was a decrease in certain factors related to energy control. Overall, these results suggest that SMYD1 plays a novel role in energy regulation in adipose tissues.

Epigenetic regulation of adipogenesis by histone-modifying enzymes.

Many studies investigating the transcriptional control of adipogenesis have been published so far; recently the research is focusing on the role of epigenetic mechanisms in regulating the process of adipocyte development. Histone-modifying enzymes and the histone tails post-transcriptional modifications catalyzed by them, are fundamentally involved in the epigenetic regulation of adipogenesis. In our review, we will discuss recent advances in epigenomic regulation of adipogenesis with a focus on histone-modifying enzymes implicated in the various phases of adipocytes differentiation process from mesenchymal stem cells to mature adipocytes. Understanding adipogenesis, may provide new ways to treat obesity and related metabolic diseases.

Flavor identification inversely correlates with body mass index (BMI).

BACKGROUND AND AIMS: Dietary choices are influenced by several factors including physiological, social, or genetic factors. Among these, flavor is the most important determinant modulating food preferences. The aim of the present study was to assess flavor identification abilities in patients with obesity (Ob) in comparison with matched normal weight (NW) and over-weight (OW) subjects using a specific and validated chemosensory test. METHODS AND RESULTS: The flavor test was administered to 140 Ob patients recruited in the obesity outpatient Unit at the Federico II University hospital and to the same number of NW and OW subjects matched by sex, age, and smoking habit. Flavor score (FS) inversely correlated with BMI. Median [Q1; Q3] FS was significantly higher in NW (14.5 [12; 16]) than in Ob (13 [10; 15] p < 0.001) and not significantly different from OW (14 [12; 16]) individuals. FS was also higher in OW than in Ob subjects (p < 0.005). When separated according to age quartiles, the BMI-related differences in FS were still significant in younger quartiles, while they were abolished in the older. CONCLUSIONS: BMI is a critical factor modulating flavor identification, particularly in young subjects. Further investigations are needed to explore the precise mechanism and the causal relationship between body weight and olfactory dysfunctions. CLINICALTRIAL ID: NCT03506074.

Iodine deficiency among Italian children and adolescents assessed through 24-hour urinary iodine excretion.

BACKGROUND: Iodine is an essential micronutrient for intellectual development in children. Information on iodine intakes based on 24-h urinary iodine excretion (UIE) is scant, because iodine status is only assessed by the measurement of urinary iodine concentration (UIC) in spot urine samples. OBJECTIVES: The aim of our study was to evaluate the iodine intake of school-age children and adolescents, using UIE measurement in 24-h urine collections. METHODS: The study population included 1270 healthy subjects (677 boys, 593 girls) aged 6-18 y (mean age ± SD: 10.3 ± 2.9) from 10 Italian regions. Daily iodine intake was estimated as UIE/0.92, based on the notion that $\sim$92% of the dietary iodine intake is absorbed. The adequacy of intakes was assessed according to the Dietary Reference Values for iodine of the European Food Safety Authority (EFSA). Body mass index (BMI) and UIC were also measured for each subject. RESULTS: Based on the scientific opinion of EFSA, 600 of 1270 subjects (47.2%) had a lower than adequate iodine intake, with a higher prevalence among girls (54.6%) compared with boys (40.2%) (P < 0.001). Although UIE and 24-h urinary volumes increased with age (P < 0.001), a progressive decrease in the percentage of subjects with iodine excretion <100 µg/24 h (P < 0.001) was observed, without any significant difference in the percentage of subjects with UIC <100 µg/L. No significant association was detected between BMI z-score and UIE (P = 0.603) or UIC (P = 0.869). CONCLUSIONS: A sizable proportion of our population, especially girls, appeared to be at risk of iodine inadequacy. The simple measurement of UIC could lead to underestimation of the occurrence of iodine deficiency in younger children, because of the age-related smaller urine volumes producing spuriously higher iodine concentrations.

Selenium supplementation modulates apoptotic processes in thyroid follicular cells.

Selenium (Se) is an essential micronutrient modulating several physiopathological processes in the human body. The aim of the study is to characterize the molecular effects determined by Se-supplementation in thyroid follicular cells, using as model the well-differentiated rat thyroid follicular cell line FRTL5. Experiments have been performed to evaluate the effects of Se on cell growth, mortality and proliferation and on modulation of pro- and antiapoptotic pathways. The results indicate that Se-supplementation improves FRTL5 growth rate. Furthermore, Se reduces the proportion of cell death and modulates both proapoptotic (p53 and Bim) and antiapoptotic (NF-kB and Bcl2) mRNA levels. In addition, incubation with high doses of Na-Se might prevent the ER-stress apoptosis induced by tunicamycin, as assessed by membrane integrity maintenance, reduction in caspase 3/7 activities, and reduction in Casp-3 and PARP cleavage. Taken together, these results provide molecular evidences indicating the role of Se supplementation on cell death and apoptosis modulation in thyroid follicular cells. These observations may be useful to understand the effects of this micronutrient on the physiopathology of the thyroid gland. © 2016 BioFactors, 43(3):415-423, 2017.

Benign hereditary chorea: clinical and neuroimaging features in an Italian family.

Benign hereditary chorea is an autosomal dominant disorder characterized by early onset nonprogressive chorea, caused by mutations of the thyroid transcription factor-1 (TITF-1) gene. Clinical heterogeneity has been reported and thyroid and respiratory abnormalities may be present. We describe 3 patients of an Italian family carrying the S145X mutation in the TITF-1 gene with mild motor delay, childhood onset dyskinesias, and subtle cognitive impairment. A child in the third generation presented with congenital hypothyroidism and neonatal respiratory distress. Imaging studies in 2 patients showed mild ventricular enlargement and empty sella at magnetic resonance imaging and hypometabolism of basal ganglia and cortex at 18-Fluoro-2-deoxy-glucose positron emission tomography.

Thyroid nodules and related symptoms are stably controlled two years after radiofrequency thermal ablation.

BACKGROUND: Percutaneous radiofrequency thermal ablation (RTA) is a promising new therapeutic approach to manage thyroid nodules (TNs). The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs. METHODS: Ninety-four elderly patients with cytologically benign compressive TNs were prospectively enrolled in the study; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter. RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance. TN volume, TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA. RESULTS: All TNs significantly decreased in size after RTA. The mean decrease in TN volume 12 months after RTA was from 24.5 +/- 2.1 to 7.5 +/- 1.2 mL (p < 0.001), with a mean percent decrease of 78.6 +/- 2.0%. Two years after RTA, a 79.4 +/- 2.5% decrease of TNs size was observed. Compressive symptoms improved in all patients and completely disappeared in 83 of 94 (88%) patients. Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79% of patients with pretoxic and toxic TNs (100% with pretoxic TNs and 53% with toxic TNs). The treatment was well tolerated by all patients. No patient needed hospitalization after RTA and no major complications were observed. CONCLUSIONS: RTA is an effective and simple procedure for obtaining lasting shrinkage of TNs, controlling compressive symptoms, and treating thyroid hyperfunction. When performed in experienced medical centers, RTA may be a valid alternative to conventional treatments for nontoxic and pretoxic TNs. It is particularly attractive for elderly people for whom surgery and radioiodine therapy are often contraindicated or ineffective.

Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci.

CONTEXT: Resistance to TSH (RTSH) is an inherited disorder of variable hyposensitivity to TSH. The metabolic consequences can range from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Although subclinical and mild hypothyroidism fitting the RTSH phenotype is common in the population, the role of genetic factors is far from being understood. Only in rare cases has RTSH been attributed to TSHR or PAX8 gene mutations. OBJECTIVE, SETTING, AND PARTICIPANTS: Toward the identification of novel RTSH genes, we studied five large, unrelated families comprising 102 individuals, 56 of whom were affected. RESULTS: Inheritance of RTSH in these families followed an autosomal dominant pattern without evidence for incomplete penetrance, yet expressivity was variable. Considering only fully phenotyped generations, 64% of the progeny was affected, with a 1:1.4 male-to-female ratio. Of 18 affected individuals tested in the neonatal period, two were undetected because of borderline results. The thyroid phenotype was indistinguishable from that observed with PAX8 and TSHR defects. In four families, untreated affected subjects of all ages had elevated serum thyroglobulin levels, consistent with a defect in the thyroid follicle cells. Linkage of RTSH to TSHR and PAX8 was excluded in all five families. For the largest families, we likewise excluded a contribution of genes previously only associated with syndromic forms of RTSH, namely TITF1, GNAS, and FOXE1. CONCLUSIONS: These kindreds represent a distinct etiological entity of autosomal dominant RTSH. According to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated.

RXR receptor agonist suppression of thyroid function: central effects in the absence of thyroid hormone receptor.

High-affinity agonists for the retinoic acid X receptors (RXR) have pleotropic effects when administered to humans. These include induction of hypertriglyceridemia and hypothyroidism. We determined the effect of a novel high-affinity RXR agonist with potent antihyperglycemic effects on thyroid function of female Zucker diabetic rats and nondiabetic littermates and in db/db mice. In both nondiabetic and ZFF rats, AGN194204 causes a 70-80% decrease in thyrotropin (TSH), 3,3',5-triiodothyronine, and thyroxine (T(4)) concentrations. In the db/db mouse, AGN194204 causes a time-dependent decrease in thyroid hormone levels with the fall in TSH that was significant after 1 day of treatment preceding the fall in T(4) levels that was significant at 3 days of treatment. Treatment with AGN194204 caused an initial increase in hepatic 5'-deiodinase mRNA levels which then fell to undetectable levels by 3 days of treatment and continued to be low at 7 days of treatment. After treatment for 5 days with AGN194204, both wild-type and thyroid hormone receptor beta (TR beta(-/-))-deficient mice demonstrated a nearly 50% decrease in serum TSH and T(4) concentrations. The results suggest that a high-affinity RXR agonist with antihyperglycemic activity can cause central hypothyroidism independently of TR beta, the main mediator of hormone-induced TSH suppression.

Complete thyroxine-binding globulin (TBG) deficiency in two families without mutations in coding or promoter regions of the TBG genes: in vitro demonstration of exon skipping.

Inherited thyroxine-binding globulin (TBG) deficiency is caused by mutations in the TBG gene located on the X-chromosome. We now describe two families (K and H) with X-linked complete TBG deficiency without mutations in the coding or promoter regions of the TBG gene. The propositi of both families presented with euthyroid hypothyroxinemia and were found to have undetectable TBG in serum. Affected females had approximately half the normal serum TBG concentration except for one woman who also had undetectable TBG (family H). All four of her children (two boys and two girls) were affected. Affected members of family K had no mutations in any of the five exons or in the minimal promoter region of the TBG gene. However, a G to A substitution, five base pairs downstream from exon 3, was associated to the phenotype of TBG deficiency (TBG-Jackson) and was not present in 100 normal alleles. In contrast to individuals without this mutation, no TBG mRNA could be detected in fibroblasts of the propositus, expressing solely TBG-Jackson. In vitro transcription of genomic DNA containing the mutant intron in an exon trapping system showed that this mutation, reducing the consensus value on the 5' donor splice site, affects the normal splicing process. The transcript of TBG-Jackson lacks exon 3 and is unstable. The deduced amino acid sequence has a frameshift and an early stop codon at position 325. Affected subject of family H had no mutations in the TBG gene including all exons, all introns, the minimal promoter, and the 3' untranslated sequence. However, an intragenic A/G polymorphism (125 bp upstream from exon 2) was identified. It allowed us to confirm a cosegregation of the phenotype to the TBG gene and to show that the single female with complete TBG deficiency was homozygous for the polymorphic TBG allele. The cause of TBG deficiency in this family remains unknown.