Abstract
Thyroid hormones, including 3,5,3′-triiodothyronine (T3), cause a wide spectrum of genomic effects on cellular metabolism and bioenergetic regulation in various tissues. The non-genomic actions of T3 have been reported but are not yet completely understood. Acute T3 treatment significantly enhanced basal, maximal, ATP-linked, and proton-leak oxygen consumption rates (OCRs) of primary differentiated mouse brown adipocytes accompanied with increased protein abundances of uncoupling protein 1 (UCP1) and mitochondrial Ca2+ uniporter (MCU). T3 treatment depolarized the resting mitochondrial membrane potential (Ψm) but augmented oligomycin-induced hyperpolarization in brown adipocytes. Protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were activated by T3, leading to the inhibition of autophagic degradation. Rapamycin, as an mTOR inhibitor, blocked T3-induced autophagic suppression and UCP1 upregulation. T3 increases intracellular Ca2+ concentration ([Ca2+]i) in brown adipocytes. Most of the T3 effects, including mTOR activation, UCP1 upregulation, and OCR increase, were abrogated by intracellular Ca2+ chelation with BAPTA-AM. Calmodulin inhibition with W7 or knockdown of MCU dampened T3-induced mitochondrial activation. Furthermore, edelfosine, a phospholipase C (PLC) inhibitor, prevented T3 from acting on [Ca2+]i, UCP1 abundance, Ψm, and OCR. We suggest that short-term exposure of T3 induces UCP1 upregulation and mitochondrial activation due to PLC-mediated [Ca2+]i elevation in brown adipocytes.
Highlights
IntroductionThyroid hormones (TH), including thyroxine (T4 ) and its more active form 3,5,30 triiodothyronine (T3 ), have been widely accepted and applied in clinical practices because of their wide spectrum of effects on the regulation of cellular metabolism, cell structure, and membrane transport [7]
Recent studies suggest the oxygen consumption rates (OCRs) measurement using an activator of lipolysis and bovine serum albumin (BSA) in order to estimate the capacity of uncoupling protein 1 (UCP1)-dependent proton leak [21]
We found that the alterations in autophagy-regulating signals associated with [Ca2+ ]i -bound CaM led to the upregulation of mitochondrial protein abundance
Summary
Thyroid hormones (TH), including thyroxine (T4 ) and its more active form 3,5,30 triiodothyronine (T3 ), have been widely accepted and applied in clinical practices because of their wide spectrum of effects on the regulation of cellular metabolism, cell structure, and membrane transport [7] These effects are traditionally thought to depend on the transcriptional modulation of specific genes after binding on the hormonal responsive elements in promoters by intranuclear complexes of TH and thyroid receptor (TR) as homodimers or, most popularly, as heterodimers with retinoid X receptor (RXR) [7]. The binding of TH-TR complexes to target genes increases the expression of either functional protein, causing alterations in cell metabolism, or structural proteins, which are responsible for cell growth This process usually takes time, from several hours to several days. 30 min, we propose a novel molecular mechanism of T3 for enhancing mitochondria activities in brown adipocytes in a transcription-independent manner
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