title: Thyroid hormone promotes postnatal rat pancreatic β-cell development and glucose-responsive insulin secretion through MAFA.
abstract: Neonatal β cells do not secrete glucose-responsive insulin and are considered immature. We previously showed the transcription factor MAFA is key for the functional maturation of β cells, but the physiological regulators of this process are unknown. Here we show that postnatal rat β cells express thyroid hormone (TH) receptor isoforms and deiodinases in an age-dependent pattern as glucose responsiveness develops. In vivo neonatal triiodothyronine supplementation and TH inhibition, respectively, accelerated and delayed metabolic development. In vitro exposure of immature islets to triiodothyronine enhanced the expression of Mafa, the secretion of glucose-responsive insulin, and the proportion of responsive cells, all of which are effects that were abolished in the presence of dominant-negative Mafa. Using chromatin immunoprecipitation and electrophoretic mobility shift assay, we show that TH has a direct receptor-ligand interaction with the Mafa promoter and, using a luciferase reporter, that this interaction was functional. Thus, TH can be considered a physiological regulator of functional maturation of β cells via its induction of Mafa.
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguayo-Mazzucato
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Zavacki
authors.forename: Alejandra
authors.initials: A
authors.lastname: Marinelarena
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.forename: Ilham
authors.initials: I
authors.lastname: El Khattabi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Marsili
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000032:analysis*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D046509:Tissue Culture Techniques; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C495609:Maf protein, rat; D020033:Protein Isoforms; D051257:Proto-Oncogene Proteins c-maf; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D014284:Triiodothyronine; D007453:Iodide Peroxidase