Highlights
- •Pref-1 expression level is inversely correlated with UCP1 level in mouse iWAT.
- •Cold or CL316,243-induced thermogenic activity is blunted by Pref-1 treatment.
- •CL316,243-induced thermogenic activity is augmented by Pref-1 knock-down.
- •Adrenergic stimuli modulate TACE activity and Pref-1 cleavage.
- •Pref-1 is a novel regulator of adipose tissue browning.
Abstract
Background
Increasing adaptive thermogenesis in adipose tissue may be a potential therapeutic
target for overcoming obesity and obesity-related disorders. Preadipocyte factor 1
(Pref-1), a preadipocyte secreted protein, plays an inhibitory role in adipogenic
differentiation. However, the role of Pref-1 in adipose tissue browning remains unknown.
We investigated whether Pref-1 regulates thermogenic program and beige fat biogenesis.
Methods
Pref-1 expression levels were examined in inguinal white adipose tissue (iWAT) and
differentiated 3T3-L1 adipocytes in thermogenic conditions induced by cold exposure
or a beta-adrenergic stimulus (CL316,243). Overexpression and knockdown studies were
performed both in vivo and in vitro to clarify the role of Pref-1 in iWAT browning.
Results
Cold exposure or CL316,243 induced a thermogenic program in adipose tissue of C57BL/6N
mice and in 3T3-L1 adipocytes. Notably, Pref-1 levels were down-regulated in iWAT
and adipocytes under these conditions. Overexpressing Pref-1 showed reduced thermogenic
gene expressions in response to CL316,243 treatment, whereas depletion of Pref-1 augmented
thermogenic program in 3T3-L1 adipocytes. Correspondingly, treating C57BL/6N mice
with Pref-1 resulted in reduced expression of thermogenic and beige fat markers, a
reduced rate of oxygen consumption, blunting of UCP1 expression and beige fat formation
in iWAT in response to cold exposure or CL316,243 injection compared to the untreated
mice. The opposite phenotype was observed in mice with inducible fat-specific knock-out
of Pref-1. Mechanistically, these effects were regulated by modulation of TNF-α-converting
enzyme activity and Pref-1 cleavage.
Conclusion
Our findings establish a novel role of Pref-1 that regulates adaptive thermogenesis.
This offers a unique target for improving energy homeostasis and treating obesity.
Abbreviations:
BAT (brown adipose tissue), BMP (bone morphogenetic protein), Dlk1 (Delta-like protein 1), eWAT (epididymal white adipose tissue), FCCP (trifluoromethoxy carbonylcyanide phenylhydrazone), GTT (glucose tolerance test), IBMX (3-isobutyl-1-methylzanthine), ITT (insulin tolerance test), iWAT (inguinal white adipose tissue), OCR (oxygen consumption rate), PBS (phosphate-buffered saline), Pref-1 (Preadipocyte factor 1), RT (room temperature), SVF (stromal vascular fraction), TACE (TNF-α-converting enzyme), WAT (white adipose tissue)Keywords
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Article info
Publication history
Published online: October 23, 2019
Accepted:
September 11,
2019
Received:
July 26,
2019
Identification
Copyright
© 2019 Elsevier Inc. All rights reserved.
