Abstract
The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) is widely considered a central transcriptional regulator of adaptive thermogenesis in brown adipose tissue (BAT). However,mice lacking PGC-1α specifically in adipose tissue have only mild thermogenic defects, suggesting the presence of additional regulators. Using the activity of estrogen-related receptors (ERRs), downstream effectors of PGC-1α, as read-out in a high-throughput genome-wide cDNA screen, we identify here growth arrest and DNA-damage-inducible protein 45 γ (GADD45γ) as a cold-induced activator of uncoupling protein 1 (UCP1) and oxidative capacity in BAT. Mice lacking Gadd45γ have defects in Ucp1 induction and the thermogenic response to cold. GADD45γ works by activating MAPK p38, which is a potent activator of ERRâ and ERRγ transcriptional function. GADD45γ activates ERRγ independently of PGC-1 coactivators, yet synergizes with PGC-1α to induce the thermogenic program. Our findings elucidate a previously unidentified GADD45γ/p38/ ERRγ pathway that regulates BAT thermogenesis and may enable new approaches for the stimulation of energy expenditure. Our study also implicates GADD45 proteins as general metabolic regulators.
Original language | English (US) |
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Pages (from-to) | 11870-11875 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 111 |
Issue number | 32 |
DOIs | |
State | Published - Aug 12 2014 |
Externally published | Yes |
Keywords
- Adrenergic response
- Norepinephrine signaling
- Nuclear receptors
- Transcriptional regulation
ASJC Scopus subject areas
- General