Examinando por Autor "Medina-Gomez, Gema"

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Central nicotine induces browning through hypothalamic κ opioid receptor
(Nature, 2019) Seoane-Collazo, Patricia; Liñares-Pose, Laura; Rial-Pensado, Eva; Romero-Picó, Amparo; Moreno-Navarrete, José María; Martínez-Sánchez, Noelia; Garrido-Gil, Pablo; Iglesias-Rey, Ramón; Morgan, Donald A.; Tomasini, Naoki; Andrew Malone, Samuel; Senra, Ana; Folgueira, Cintia; Medina-Gomez, Gema; Sobrino, Tomás; Labandeira-García, José L.; Nogueiras, Rubén; Domingos, Ana I.; Fernández Real, José Manuel; Rahmouni, Kamal; Diéguez, Carlos; López, Miguel
Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.
Long-term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity
(2019-06) Corrales, Patricia; Vivas, Yurena; Izquierdo-Lahuerta, Adriana; Hornillo, Daniel; Seoane-Collazo, Patricia; Velasco, Ismael; Torres, Lucia; López, Yamila; Martínez, Carmen; López, Miguel; Ros, Manuel; Obregon, María Jesús; Medina-Gomez, Gema
Age‐related increased adiposity is an important contributory factor in the development of insulin resistance (IR) and is associated with metabolic defects. Caloric restriction (CR) is known to induce weight loss and to decrease adiposity while preventing metabolic risk factors. Here, we show that moderate 20% CR delays early deleterious effects of aging on white and brown adipose tissue (WAT and BAT, respectively) function and improves peripheral IR. To elucidate the role of CR in delaying early signs of aging, young (3 months), middle‐aged (12 months), and old (20 months) mice fed al libitum and middle‐aged and old mice subjected to early‐onset CR were used. We show that impaired plasticity of subcutaneous WAT (scWAT) contributes to IR, which is already evident in middle‐aged mice. Moreover, alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction in middle‐aged animals. Both defects in WAT and BAT/beige cells are ameliorated by CR. Accordingly, CR attenuated the age‐related decline in scWAT function and decreased the extent of fibro‐inflammation. Furthermore, CR promoted scWAT browning. In brief, our study identifies the contribution of scWAT impairment to age‐associated metabolic dysfunction and identifies browning in response to food restriction, as a potential therapeutic strategy to prevent the adverse metabolic effects in middle‐aged animals.
Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function
(PUBLIC LIBRARY SCIENCE, 2020-10-15) Hammerle, Constanze M.; Sandovici, Ionel; Brierley, Gemma V.; Smith, Nicola M.; Zimmer, Warren E.; Zvetkova, lona; Prosser, Haydn M.; Sekita, Yoichi; Lam, Brian Y. H.; Ma, Marcella; Cooper, Wendy N.; Vidal-Puig, Antonio; Ozanne, Susan E.; Medina-Gomez, Gema; Constancia, Miguel
The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.
Renoprotective role of bariatric surgery in patients with established chronic kidney disease
(Oxford University Press, 2020-12-20) Morales, Enrique; Porrini, Esteban; Martin-Taboada, Marina; Luis-Lima, Sergio; Vila-Bedmar, Rocıo; Gonzalez de Pablos, Ignacio; Gomez, Pilar; Rodriguez, Elias; Torres, Lucia; Lanzon, Borja; Rodriguez, Ana Elena; Maiz, Maria; Medina-Gomez, Gema; Praga, Manuel
Background. Bariatric surgery (BS) has been postulated as the most effective measure for weight reduction. Weight loss improves metabolic parameters and exerts changes in renal function that lead to the amelioration of absolute or relative glomerular hyperfiltration, a condition that may be renoprotective in the long term. However, few studies have demonstrated the influence of BS in patients with severe obesity and chronic kidney disease (CKD). Our objective was to analyse the evolution of renal function, adipose tissue–derived molecules and inflammatory parameters in patients with CKD after BS. Methods. This is an observational and prospective study. Thirty patients were screened and 12 were included between January 2016 and January 2018 with a 24-month follow-up. Glomerular filtration rate (GFR) was determined by plasma iohexol clearance. Adipokines, cytokines, circulating hormones and fibrotic parameters were evaluated before and 12 months after BS using the Bioplex system. Results. The mean age was 50.6 years and 58.3% were males. Seven patients had a body mass index >40 kg/m2 and 66.7% were diabetic. Twenty-four months following BS there was a significant decrease in body weight (36.4%). Proteinuria decreased by 63.7628.2%. Measured GFR significantly diminished from before surgery to Month 24 after surgery (94644 to 79644 mL/min, P ¼ 0.03). There was a significant decrease in adipocyte-derived molecules (leptin and vifastin) as well as in pro-inflammatory cytokines [interleukin (IL)-1b, tumour necrosis factor a, IL-6 and monocyte chemoattractant protein-1]
SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity
(Nature, 2019-05) Keiran, Noelia; Ceperuelo-Mallafré, Victoria; Calvo, Enrique; Hernández-Alvarez, María isabel; Ejarque, Miriam; Núñez-Roa, Catalina; Hormillo, Daniel; Maymó-Masip, Elsa; Rodriguez, M Mar; Fradera, Rosa; de la Rosa, Juan Vladimir; Jorba, Rosa; Megia, Ana; Zorzano, Antonio; Medina-Gomez, Gema; Serena, Carolina; Castrillo, Antonio; Vendrell, Joan; Fernández-Veledo, Sonia
Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney
(COMPANY BIOLOGISTS, 2021-09-01) Escasany, Elia; Lanzón, Borja; Garcia-Carrasco, Almudena; Izquierdo-Lahuerta, Adriuana; Torres, Lucia; Corrales, Patricia; Rodríguez Rodríguez, Ana Elena; Luis-Lima, Sergio; Martínez-Álvarez, Concepción; Ruperez, Francisco Javier; Ros, Manuel; Porrini, Esteban; Rydén, Mikael; Medina-Gomez, Gema
Glomerulosclerosis and tubulointerstitial fibrosis are pathological features of chronic kidney disease. Transforming growth factor β (TGFβ) is a key player in the development of fibrosis. However, of the three known TGFβ isoforms, only TGFβ1 has an established role in fibrosis, and the pathophysiological relevance of TGFβ2 and TGFβ3 is unknown. Because Tgfb3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfb3-knockout mice (Tgfb3+/-) and compared it with that of matched wild-type mice. Four-month-old Tgfb3+/- mice exhibited incipient renal fibrosis with epithelial-mesenchymal transition, in addition to glomerular basement membrane thickening and podocyte foot process effacement associated with albuminuria. Also evident was insulin resistance and oxidative stress at the renal level, together with aberrant renal lipid metabolism and mitochondrial function. Omics analysis revealed toxic species, such as diacylglycerides and ceramides, and dysregulated mitochondrial metabolism in Tgfb3+/- mice. Kidneys of Tgfb3+/- mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study indicates that renal TGFβ3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFβ1. This article has an associated First Person interview with the first author of the paper.
Transforming Growth Factor-β3 Regulates Adipocyte Number in Subcutaneous White Adipose Tissue
(CellPress, 2018-10-16) Petrus, Paul; Niklas, Mejhert; Corrales, Patricia; Lecoutre, Simon; Qian, Li; Maldonado, Estela; Kulyté, Agne; López, Yamila; Campbell, Mark; Acosta, Juan R; Laurencikiene, Jurga; Iyadh, Douagi; Gao, Hui; Martínez-Álvarez, Concepción; Hedén, Per; Spalding, Kirsty L; Vidal-Puig, Antonio; Medina-Gomez, Gema; Arner, Peter; Ryden, Mikael
White adipose tissue (WAT) mass is determined by adipocyte size and number. While adipocytes are continuously turned over, the mechanisms controlling fat cell number in WAT upon weight changes are unclear. Herein, prospective studies of human subcutaneous WAT demonstrate that weight gain increases both adipocyte size and number, but the latter remains unaltered after weight loss. Transcriptome analyses associate changes in adipocyte number with the expression of 79 genes. This gene set is enriched for growth factors, out of which one, transforming growth factor-β3 (TGFβ3), stimulates adipocyte progenitor proliferation, resulting in a higher number of cells undergoing differentiation in vitro. The relevance of these observations was corroborated in vivo where Tgfb3+/- mice, in comparison with wild-type littermates, display lower subcutaneous adipocyte progenitor proliferation, WAT hypertrophy, and glucose intolerance. TGFβ3 is therefore a regulator of subcutaneous adipocyte number and may link WAT morphology to glucose metabolism.