Examinando por Autor "Vidal-Puig, Antonio"

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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.
Mitochondrial Fusion Is Increased by the Nuclear Coactivator PGC-1ß
(PLoS ONE, 2008-10-31) Liesa, Marc; Borda-d'Água, Bárbara; Medina-Gómez, Gema; Lelliott, Christopher J.; Paz, José Carlos; Rojo-Álvarez, José Luis; Palacín, Manuel; Vidal-Puig, Antonio; Zorzano, Antonio
There is no evidence to date on whether transcriptional regulators are able to shift the balance between mitochondrial fusion and fission events through selective control of gene expression. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1beta is associated with a selective reduction in Mitofusin 2 (Mfn2) expression, a mitochondrial fusion protein. This decrease in Mfn2 is specific since expression of the remaining components of mitochondrial fusion and fission machinery were not affected. Furthermore, PGC-1beta increases mitochondrial fusion and elongates mitochondrial tubules. This PGC-1beta-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells. Finally, we show that PGC-1beta increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor alpha (ERRalpha). CONCLUSIONS/SIGNIFICANCE: Taken together, our data reveal a novel mechanism by which mammalian cells control mitochondrial fusion. In addition, we describe a novel role of PGC-1beta in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2.
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.