Abstract
The development of thermogenic adipocytes concurs with mitochondrial biogenesis, an iron-dependent pathway. Iron regulatory proteins (IRP) 1 and 2 are RNA-binding proteins that regulate intracellular iron homeostasis. IRPs bind to the iron-response element (IRE) of their target mRNAs, balancing iron uptake and deposition at the posttranscriptional levels. However, IRP/IRE-dependent iron regulation in adipocytes is largely unknown. We hypothesized that iron demands are higher in brown/beige adipocytes than white adipocytes to maintain the thermogenic mitochondrial capacity. To test this hypothesis, we investigated the IRP/IRE regulatory system in different depots of adipose tissue. Our results revealed that 1) IRP/IRE interaction was increased in proportional to the thermogenic function of the adipose depot, 2) adipose iron content was increased in adipose tissue browning upon β3-adrenoceptor stimulation, while decreased in thermoneutral conditions, and 3) modulation of iron content was linked with mitochondrial biogenesis. Moreover, the iron requirement was higher in HIB1B brown adipocytes than 3T3-L1 white adipocytes during differentiation. The reduction of the labile iron pool (LIP) suppressed the differentiation of brown/beige adipocytes and mitochondrial biogenesis. Using the 59Fe-Tf, we also demonstrated that thermogenic stimuli triggered cell-autonomous iron uptake and mitochondrial compartmentalization as well as enhanced mitochondrial respiration. Collectively, our work demonstrated that IRP/IRE signaling and subsequent adaptation in iron metabolism are a critical determinant for the thermogenic function of adipocytes.
Highlights
Addition to these morphological features, the brownish color of adipose tissue provides an immediate clue to distinguish the thermogenic capacity of the adipose depots
Based on the high metabolic rate of brown fat, we first hypothesized that iron demands and iron regulatory proteins (IRP)/ironresponse element (IRE) interaction would be higher in brown adipose tissue than white adipose tissue
To investigate IRP/IRE binding, we performed an electrophoretic mobility shift assay (EMSA) using an IRDye700-labeled IRE probe with the cytosolic fractions prepared from epididymal, inguinal white adipose tissue, and interscapular brown fat that represent visceral, subcutaneous fat and classical brown fat, respectively
Summary
Addition to these morphological features, the brownish color of adipose tissue provides an immediate clue to distinguish the thermogenic capacity of the adipose depots. Nonheme iron found in the iron–sulfur cluster (Fe-S) proteins plays a crucial role in the redox reaction of electron transfer in mitochondria These studies suggest that iron demands for brown/beige adipocytes are higher than that of white adipocytes, little information is available regarding the iron regulatory mechanisms that discern white, beige, and brown adipocytes. One of the key characteristics to discern thermogenic cell progenitors from white adipocyte precursors is the transcriptional capacity accumulating iron and protecting oxidative stress [5]. We aimed to investigate the differential regulation of iron metabolism in white, brown, and beige adipogenesis by using the depot-specific adipose tissue as well as defined cell models of white, beige, and brown adipocytes. Our results demonstrate that enhanced IRP/IRE interaction and the subsequent iron influx into the mitochondria are essential for the differentiation of thermogenic brown and beige adipocytes
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