RESUMEN
TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.
Asunto(s)
Proteínas de la Membrana/genética , Obesidad/genética , Células 3T3-L1 , Adipocitos/metabolismo , Adipogénesis/genética , Tejido Adiposo/metabolismo , Animales , Diferenciación Celular/genética , Línea Celular , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Resistencia a la Insulina/genética , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , PPAR gamma/metabolismo , Transducción de Señal , Pez CebraRESUMEN
Accumulation of fat mass in obesity may result from hypertrophy and/or hyperplasia and is frequently associated with adipose tissue (AT) dysfunction in adults. Here we assessed early alterations in AT biology and function by comprehensive experimental and clinical characterization of 171 AT samples from lean and obese children aged 0 to 18 years. We show an increase in adipocyte size and number in obese compared with lean children beginning in early childhood. These alterations in AT composition in obese children were accompanied by decreased basal lipolytic activity and significantly enhanced stromal vascular cell proliferation in vitro, potentially underlying the hypertrophy and hyperplasia seen in obese children, respectively. Furthermore, macrophage infiltration, including the formation of crown-like structures, was increased in AT of obese children from 6 years on and was associated with higher hs-CRP serum levels. Clinically, adipocyte hypertrophy was not only associated with leptin serum levels but was highly and independently correlated with HOMA-IR as a marker of insulin resistance in children. In summary, we show that adipocyte hypertrophy is linked to increased inflammation in AT in obese children, thereby providing evidence that obesity-associated AT dysfunction develops in early childhood and is related to insulin resistance.
Asunto(s)
Tejido Adiposo/fisiopatología , Inflamación/fisiopatología , Resistencia a la Insulina/fisiología , Obesidad/fisiopatología , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Adolescente , Glucemia , Diferenciación Celular , Proliferación Celular/fisiología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Inflamación/metabolismo , Insulina/sangre , Leptina/sangre , Macrófagos/metabolismo , Masculino , Obesidad/metabolismoRESUMEN
Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-ß is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-ß signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-ß signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-ß receptor Tgfbr3, also called betaglycan. Tgfbr3 was demonstrated to be a "switch" that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-ß to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung Tgfbr3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-ß signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions.
