title: Mitochondrial T3 receptor p43 regulates insulin secretion and glucose homeostasis.
abstract: Thyroid hormone is a major determinant of energy expenditure and a key regulator of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine receptor (p43) that acts as a mitochondrial transcription factor of the organelle genome, which leads, in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Here we generated mice specifically lacking p43 to address its physiological influence. We found that p43 is required for normal glucose homeostasis. The p43(-/-) mice had a major defect in insulin secretion both in vivo and in isolated pancreatic islets and a loss of glucose-stimulated insulin secretion. Moreover, a high-fat/high-sucrose diet elicited more severe glucose intolerance than that recorded in normal animals. In addition, we observed in p43(-/-) mice both a decrease in pancreatic islet density and in the activity of complexes of the respiratory chain in isolated pancreatic islets. These dysfunctions were associated with a down-regulation of the expression of the glucose transporter Glut2 and of Kir6.2, a key component of the K(ATP) channel. Our findings establish that p43 is an important regulator of glucose homeostasis and pancreatic β-cell function and provide evidence for the first time of a physiological role for a mitochondrial endocrine receptor.
authors.affiliation: UMR866 Dynamique Musculaire et Métabolisme, Université Montpellier 1, Montpellier, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Blanchet
authors.forename: Christelle
authors.initials: C
authors.lastname: Bertrand
authors.forename: Jean Sébastien
authors.initials: JS
authors.lastname: Annicotte
authors.forename: Audrey
authors.initials: A
authors.lastname: Schlernitzauer
authors.forename: Laurence
authors.initials: L
authors.lastname: Pessemesse
authors.forename: Jonathan
authors.initials: J
authors.lastname: Levin
authors.forename: Gilles
authors.initials: G
authors.lastname: Fouret
authors.forename: Christine
authors.initials: C
authors.lastname: Feillet-Coudray
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bonafos
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
authors.forename: Gérard
authors.initials: G
authors.lastname: Cabello
authors.forename: Chantal
authors.initials: C
authors.lastname: Wrutniak-Cabello
authors.forename: François
authors.initials: F
authors.lastname: Casas
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001831:Body Temperature / Q000502:physiology; D002460:Cell Line; D004041:Dietary Fats / Q000494:pharmacology; D019422:Dietary Sucrose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007035:Hypothermia / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D019422:Dietary Sucrose; D007328:Insulin; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones