Abstract
Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at -258 to -250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues.
Highlights
Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses
To test whether modulators of cAMP levels were able to induce HSF1, we treated brown differentiated SVF cells derived from subcutaneous white adipose depots (scWAT) with forskolin and observed an increase in HSF1 mRNA and protein levels compared with vehicle-treated cells (Fig. 2A)
These results suggest that HSF1 mRNA is regulated in response to modulators of cAMP levels in thermogenic adipocytes
Summary
In addition to brown fat cells, beige adipocytes, which are present in subcutaneous white adipose depots (scWAT), have been shown to regulate the thermogenic processes and overall contribute to energy expenditure [3,4,5,6,7]. We measured in parallel UCP1 and demonstrated that its levels are induced concomitantly to those of HSF1, confirming that the cells underwent brown-like differentiation (Fig. 1, C and D) These results demonstrate that HSF1 mRNA is selectively elevated in mature thermogenic tissues in vivo and in differentiated brown-like adipocytes in vitro. HSF1 expression in thermogenic fat cells revealed that HSF1 is regulated by the activating transcription factor 3 (ATF3), which, in turn, is induced in response to thermogenic stimuli. Our studies provide novel evidence that HSF1 mRNA levels are rapidly up-regulated in response to thermogenic cues and identify for the first time the stress response transcription factor ATF3 as a critical new regulator of HSF1 levels in response to thermogenic signals
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