GADD45γ regulates the thermogenic capacity of brown adipose tissue

Significance Brown adipose tissue (BAT) specializes in converting stored chemical energy into heat. When activated in response to cold, BAT increases the body’s metabolic rate and promotes fat loss. The recent identification of BAT in humans makes activation of this tissue an attractive target for counteracting obesity. However, our understanding of the intracellular pathways that regulate the response to cold is limited. Here, we identify a previously unknown regulator of BAT activation, growth arrest and DNA-damage-inducible protein 45 γ, which is induced in response to cold and works via the MAPK p38 and the transcription factor estrogen-related receptor γ to enhance the expression of genes important for thermogenesis. Our findings may provide new avenues for the stimulation of energy expenditure. 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 ERRβ 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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