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GADD45¿ regulates the thermogenic capacity of brown adipose tissue.

Authors: Gantner, Marin L  Hazen, Bethany C  Conkright, Juliana  Kralli, Anastasia 
Citation: Gantner ML, etal., Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11870-5. doi: 10.1073/pnas.1406638111. Epub 2014 Jul 28.
Pubmed: (View Article at PubMed) PMID:25071184
DOI: Full-text: DOI:10.1073/pnas.1406638111

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 ERRß 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.

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RGD Object Information
RGD ID: 13673821
Created: 2018-06-23
Species: All species
Last Modified: 2018-06-23
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.