title: Regulation of Brown and White Adipocyte Transcriptome by the Transcriptional Coactivator NT-PGC-1α.
abstract: The β3-adrenergic receptor (AR) signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β3-AR signaling highly induces the expression of transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, which in turn activate the transcription program of adaptive thermogenesis by co-activating a number of transcription factors. We previously reported that NT-PGC-1α is able to increase mitochondrial number and activity in cultured brown adipocytes by promoting the expression of mitochondrial and thermogenic genes. In the present study, we performed genome-wide profiling of NT-PGC-1α-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1α. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1α-responsive genes identified several metabolic pathways including glycolysis and fatty acid synthesis. In order to validate the identified genes in vivo, we utilized the FL-PGC-1α-/- mouse that is deficient in full-length PGC-1α (FL-PGC-1α) but expresses a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α254). The β3-AR-induced increase of NT-PGC-1α254 in FL-PGC-1α-/- brown and white adipose tissue was closely associated with elevated expression of genes involved in thermogenesis, mitochondrial oxidative metabolism, glycolysis and fatty acid synthesis. Increased adipose tissue thermogenesis by β3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1α-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1α regulates mitochondrial genes involved in thermogenesis and oxidative metabolism in brown and white adipocytes and further suggest that NT-PGC-1α regulates a broad spectrum of genes to meet cellular needs for adaptive thermogenesis.
authors.affiliation: Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Vivian E
authors.initials: VE
authors.lastname: Fernand
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Henagan
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Jeho
authors.initials: J
authors.lastname: Shin
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Huypens
authors.affiliation: Genomics Core, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Newman
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gettys
authors.affiliation: Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Ji Suk
authors.identifier: http://orcid.org/0000-0002-0706-1960
authors.initials: JS
authors.lastname: Chang
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D004734:Energy Metabolism / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D022702:Receptors, Adrenergic, beta-3; D015534:Trans-Activators