title: GADD45γ regulates the thermogenic capacity of brown adipose tissue.
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 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.
authors: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; and.
authors: Marin L
authors: ML
authors: Gantner
authors: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; and.
authors: Bethany C
authors: BC
authors: Hazen
authors: Stowers Institute for Medical Research, Kansas City, MO 64110.
authors: Juliana
authors: J
authors: Conkright
authors: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; and kralli@scripps.edu.
authors: Anastasia
authors: A
authors: Kralli
mesh_terms: D000064:Acclimatization / Q000235:genetics / Q000502:physiology; D002001:Adipose Tissue, Brown / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003080:Cold Temperature; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D000071256:Uncoupling Protein 1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000071256:Uncoupling Protein 1; D048051:p38 Mitogen-Activated Protein Kinases; C098925:Esrrb protein, mouse; C490916:Esrrg protein, mouse; C121373:Gadd45g protein, mouse; D000097642:GADD45 Proteins; C485290:Ppargc1a protein, mouse; C000604372:Ucp1 protein, mouse
keywords: adrenergic response; norepinephrine signaling; nuclear receptors; transcriptional regulation