RESUMO
HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism (H), deafness (D), and renal dysplasia (R) caused by genetic variants of the GATA3 gene. We present the case of a 38-year-old Japanese man with HDR syndrome who exhibited hypoparathyroidism, sensorineural deafness, renal dysfunction, severe symptomatic hypocalcemia with Chvostek's and Trousseau's signs, and QT prolongation on electrocardiography. He had a family history of deafness and hypocalcemia. Genetic testing revealed a novel GATA3 gene variant at exon 2 (c.48delC), which induces a frameshift resulting in termination at codon 178, causing HDR syndrome. We summarized 45 Japanese cases of HDR syndrome with regard to the mode of onset (familial or sporadic) and the age at diagnosis. In addition, we summarized all previous cases of HDR syndrome with GATA3 gene variants. Mapping of previously reported genetic variants in HDR syndrome revealed that most missense variants were observed at exons 4 and 5 regions in the GATA3 gene. These two regions contain zinc finger domains, demonstrating their functional importance in GATA3 transcription. This review of literature provides a useful reference for diagnosing HDR syndrome and predicting the related future manifestations.
RESUMO
OBJECTIVE: Promoting thermogenesis in adipose tissue has been a promising strategy against obesity and related metabolic complications. We aimed to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism. METHODS: To identify compounds that directly promote thermogenesis from a structurally diverse set of 4800 compounds, we utilized a cell-based platform for high-throughput screening that induces uncoupling protein 1 (Ucp1) expression in adipocytes. RESULTS: We identified one candidate compound that activates UCP1. Additional characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with negligible cytotoxicity. In a subsequent diet-induced obesity model, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure. Mechanistic studies have revealed that this compound increases mitochondrial biogenesis by elevating maximal respiration, which is partly mediated by the protein kinase A (PKA)-p38 mitogen-activated protein kinase (MAPK) signaling pathway. A further comprehensive genetic analysis of adipocytes treated with these compounds identified two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627). CONCLUSIONS: The identified compound can serve as a potential therapeutic drug for the treatment of obesity and its related metabolic disorders. Furthermore, our newly clarified thermogenic genes play an important role in UCP1-dependent thermogenesis in adipocytes.
Assuntos
Resistência à Insulina , Obesidade , Proteína Desacopladora 1 , Animais , Camundongos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Metabolismo Energético , Obesidade/complicações , Obesidade/tratamento farmacológico , Termogênese/fisiologia , Proteína Desacopladora 1/antagonistas & inibidoresRESUMO
The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.
Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Resistência à Insulina , Humanos , Sobrepeso , Leptina , Inibidor 1 de Ativador de Plasminogênio , Estudos Transversais , Obesidade/complicaçõesRESUMO
A high-sensitive x-ray computed tomography (CT) system is useful for decreasing absorbed dose for patients, and we performed preliminary experiments for first-generation photon-counting CT using a high-sensitive single detector. X-ray photons are detected using an LSO [Lu2(SiO4)O] single crystal scintillator and a multipixel photon counter (MPPC). The photocurrent from the MPPC is amplified by a current-voltage amplifier and an integrator, and the event pulse is sent to a high-speed comparator. Logical pulses are then produced by the comparator and are counted by a counter card. Tomography is accomplished by repeated linear scans and rotations of an object, and projection curves of the object are obtained by the linear scan. The count rate decreased with increase in lower level voltage of the comparator Vl, and the maximum count rate was 265 kcps at a Vl of 0.4 V. The exposure time for obtaining a tomogram was 10 minutes at a scan step of 0.5 mm and a rotation step of 1.0°. The image contrast of gadolinium medium slightly varied with change in Vl. We carried out low-dose-rate photon-counting CT at a tube current of 100 µA and a tube voltage of 100 kV. The energy-dispersive effect of the CT image was confirmed by selecting Vl. The absorbed dose for objects can be reduced using the linear detector consisting of plural LSO-MPPC detectors.