Mineralocorticoid and glucocorticoid receptors inhibit UCP expression and function in brown adipocytes.
Uncoupling proteins (UCP), specific mitochondrial proton transporters that function by uncoupling oxidative metabolism from ATP synthesis, are involved in thermoregulation and control of energy expenditure. The hibernoma-derived T37i cells, which possess functional endogenous mineralocorticoid receptors (MR), can undergo differentiation into brown adipocytes. In differentiated T37i cells, UCP1 mRNA levels increased 10- to 20-fold after retinoic acid or beta-adrenergic treatment. Interestingly, UCP2 and UCP3 mRNA was also detected. Aldosterone treatment induced a drastic decrease in isoproterenol- and retinoic acid-stimulated UCP1 mRNA levels in a time- and dose-dependent manner (IC(50) approximately 1 nM aldosterone). This inhibition was unaffected by cycloheximide and did not modify UCP1 mRNA stability (half-life time = 5 h), indicating that it occurs at the transcriptional level. It involves both the MR and/or the glucocorticoid receptor (GR), depending on the retinoic or catecholamine induction pathway. Basal UCP3 expression was also significantly reduced by aldosterone, whereas UCP2 mRNA levels were not modified. Finally, as demonstrated by JC1 aggregate formation in living cells, aldosterone restored mitochondrial membrane potential abolished by isoproterenol or retinoic acid. Our results demonstrate that MR and GR inhibit expression of UCP1 and UCP3, thus participating in the control of energy expenditure.
INSERM U 478, Institut Fédératif de Recherche Cellules épithéliales IFR02, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75870 Paris, France.
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D017667:Adipocytes / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D007425:Intracellular Membranes / Q000502:physiology; D007473:Ion Channels; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; C000604372:Ucp1 protein, mouse; C000604393:Ucp3 protein, mouse; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D000450:Aldosterone