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 beta-cell function and provide evidence for the first time of a physiological role for a mitochondrial endocrine receptor.
Mitochondrial T3 receptor p43 regulates insulin secretion and glucose homeostasis
Blanchet, E.; Bertrand, C.; Annicotte, J. S.; Schlernitzauer, A.; Pessemesse, L.; Levin, J.; Fouret, G.; Feillet-Coudray, C.; Bonafos, B.; Fajas, L.; Cabello, G.; Wrutniak-Cabello, C.; Casas, F.
2012-01 / vol 26 / pages 40-50
1530-6860 (Electronic) 0892-6638 (Linking)
Humans; Animals; Mice; Male; Mice, Mutant Strains; Mice, Inbred C57BL; Cell Line; Blood Glucose/*metabolism; Body Temperature/physiology; Dietary Fats/pharmacology; Dietary Sucrose/pharmacology; Glucose Intolerance/genetics/*metabolism; Homeostasis/*physiology; Hypothermia/genetics/metabolism; Insulin-Secreting Cells/cytology/physiology/secretion; Insulin/blood/*secretion; Mitochondria/*metabolism; Myoblasts/cytology/physiology; Receptors, Thyroid Hormone/genetics/*metabolism; Thyroid Hormones/blood