| First Author | Gantner ML | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 32 | Pages | 11870-5 |
| PubMed ID | 25071184 | Mgi Jnum | J:213702 |
| Mgi Id | MGI:5585653 | Doi | 10.1073/pnas.1406638111 |
| Citation | Gantner ML, et al. (2014) GADD45gamma regulates the thermogenic capacity of brown adipose tissue. Proc Natl Acad Sci U S A 111(32):11870-5 |
| abstractText | The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1alpha) is widely considered a central transcriptional regulator of adaptive thermogenesis in brown adipose tissue (BAT). However, mice lacking PGC-1alpha 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-1alpha, as read-out in a high-throughput genome-wide cDNA screen, we identify here growth arrest and DNA-damage-inducible protein 45 gamma (GADD45gamma) as a cold-induced activator of uncoupling protein 1 (UCP1) and oxidative capacity in BAT. Mice lacking Gadd45gamma have defects in Ucp1 induction and the thermogenic response to cold. GADD45gamma works by activating MAPK p38, which is a potent activator of ERRbeta and ERRgamma transcriptional function. GADD45gamma activates ERRgamma independently of PGC-1 coactivators, yet synergizes with PGC-1alpha to induce the thermogenic program. Our findings elucidate a previously unidentified GADD45gamma/p38/ERRgamma 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. |
