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Second messenger signaling mechanisms of the brown adipocyte thermogenic program: an integrative perspective.
Shi F, Collins S
(2017) Horm Mol Biol Clin Investig 31:
MeSH Terms: Adipocytes, Beige, Adipocytes, Brown, Animals, Cyclic AMP-Dependent Protein Kinases, Cyclic GMP-Dependent Protein Kinases, Energy Metabolism, Gene Expression Regulation, Humans, Intracellular Space, Mechanistic Target of Rapamycin Complex 1, MicroRNAs, Natriuretic Agents, RNA, Long Noncoding, Receptors, Adrenergic, beta, Second Messenger Systems, Signal Transduction, Thermogenesis, Uncoupling Protein 1
Show Abstract · Added September 26, 2018
β-adrenergic receptors (βARs) are well established for conveying the signal from catecholamines to adipocytes. Acting through the second messenger cyclic adenosine monophosphate (cAMP) they stimulate lipolysis and also increase the activity of brown adipocytes and the 'browning' of adipocytes within white fat depots (so-called 'brite' or 'beige' adipocytes). Brown adipose tissue mitochondria are enriched with uncoupling protein 1 (UCP1), which is a regulated proton channel that allows the dissipation of chemical energy in the form of heat. The discovery of functional brown adipocytes in humans and inducible brown-like ('beige' or 'brite') adipocytes in rodents have suggested that recruitment and activation of these thermogenic adipocytes could be a promising strategy to increase energy expenditure for obesity therapy. More recently, the cardiac natriuretic peptides and their second messenger cyclic guanosine monophosphate (cGMP) have gained attention as a parallel signaling pathway in adipocytes, with some unique features. In this review, we begin with some important historical work that touches upon the regulation of brown adipocyte development and physiology. We then provide a synopsis of some recent advances in the signaling cascades from β-adrenergic agonists and natriuretic peptides to drive thermogenic gene expression in the adipocytes and how these two pathways converge at a number of unexpected points. Finally, moving from the physiologic hormonal signaling, we discuss yet another level of control downstream of these signals: the growing appreciation of the emerging roles of non-coding RNAs as important regulators of brown adipocyte formation and function. In this review, we discuss new developments in our understanding of the signaling mechanisms and factors including new secreted proteins and novel non-coding RNAs that control the function as well as the plasticity of the brown/beige adipose tissue as it responds to the energy needs and environmental conditions of the organism.
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MeSH Terms
β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors.
Roberts LD, Boström P, O'Sullivan JF, Schinzel RT, Lewis GD, Dejam A, Lee YK, Palma MJ, Calhoun S, Georgiadi A, Chen MH, Ramachandran VS, Larson MG, Bouchard C, Rankinen T, Souza AL, Clish CB, Wang TJ, Estall JL, Soukas AA, Cowan CA, Spiegelman BM, Gerszten RE
(2014) Cell Metab 19: 96-108
MeSH Terms: Adipocytes, Brown, Adipocytes, White, Adipose Tissue, Brown, Adipose Tissue, White, Aminoisobutyric Acids, Animals, Cardiovascular Diseases, Cell Differentiation, Exercise, Gene Expression Regulation, Glucose Tolerance Test, Humans, Induced Pluripotent Stem Cells, Liver, Metabolic Diseases, Mice, Organ Specificity, Oxidation-Reduction, PPAR alpha, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phenotype, Physical Conditioning, Animal, Risk Factors, Transcription Factors, Transcription, Genetic, Weight Gain
Show Abstract · Added February 28, 2014
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
Copyright © 2014 Elsevier Inc. All rights reserved.
1 Communities
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26 MeSH Terms
p62 links β-adrenergic input to mitochondrial function and thermogenesis.
Müller TD, Lee SJ, Jastroch M, Kabra D, Stemmer K, Aichler M, Abplanalp B, Ananthakrishnan G, Bhardwaj N, Collins S, Divanovic S, Endele M, Finan B, Gao Y, Habegger KM, Hembree J, Heppner KM, Hofmann S, Holland J, Küchler D, Kutschke M, Krishna R, Lehti M, Oelkrug R, Ottaway N, Perez-Tilve D, Raver C, Walch AK, Schriever SC, Speakman J, Tseng YH, Diaz-Meco M, Pfluger PT, Moscat J, Tschöp MH
(2013) J Clin Invest 123: 469-78
MeSH Terms: Adaptor Proteins, Signal Transducing, Adipocytes, Brown, Adipose Tissue, Brown, Animals, Cells, Cultured, Heat-Shock Proteins, MAP Kinase Signaling System, Mice, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Organ Specificity, Sequestosome-1 Protein, Thermogenesis, Transcription Factors, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added July 22, 2020
The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to β-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1α, DIO2, NRF1, CYTC, COX2, ATP5β, and UCP1. p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.
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De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age, adipose depot, and gender specific.
Majka SM, Fox KE, Psilas JC, Helm KM, Childs CR, Acosta AS, Janssen RC, Friedman JE, Woessner BT, Shade TR, Varella-Garcia M, Klemm DJ
(2010) Proc Natl Acad Sci U S A 107: 14781-6
MeSH Terms: Adipocytes, Brown, Adipocytes, White, Adipose Tissue, Age Factors, Animals, Bone Marrow Cells, Cell Differentiation, Cell Lineage, Cells, Cultured, Cytogenetic Analysis, Female, Gene Expression Profiling, Male, Mesoderm, Mice, Models, Biological, Myeloid Cells, Oligonucleotide Array Sequence Analysis, Sex Factors
Show Abstract · Added August 4, 2015
It is generally assumed that white adipocytes arise from resident adipose tissue mesenchymal progenitor cells. We challenge this paradigm by defining a hematopoietic origin for both the de novo development of a subset of white adipocytes in adults and a previously uncharacterized adipose tissue resident mesenchymal progenitor population. Lineage and cytogenetic analysis revealed that bone marrow progenitor (BMP)-derived adipocytes and adipocyte progenitors arise from hematopoietic cells via the myeloid lineage in the absence of cell fusion. Global gene expression analysis indicated that the BMP-derived fat cells are bona fide adipocytes but differ from conventional white or brown adipocytes in decreased expression of genes involved in mitochondrial biogenesis and lipid oxidation, and increased inflammatory gene expression. The BMP-derived adipocytes accumulate with age, occur in higher numbers in visceral than in subcutaneous fat, and in female versus male mice. BMP-derived adipocytes may, therefore, account in part for adipose depot heterogeneity and detrimental changes in adipose metabolism and inflammation with aging and adiposity.
0 Communities
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19 MeSH Terms
ADD1/SREBP1c activates the PGC1-alpha promoter in brown adipocytes.
Hao Q, Hansen JB, Petersen RK, Hallenborg P, Jørgensen C, Cinti S, Larsen PJ, Steffensen KR, Wang H, Collins S, Wang J, Gustafsson JA, Madsen L, Kristiansen K
(2010) Biochim Biophys Acta 1801: 421-9
MeSH Terms: Adipocytes, Brown, Animals, Cell Differentiation, Cells, Cultured, Chromatin Immunoprecipitation, Electrophoretic Mobility Shift Assay, Electroporation, Liver X Receptors, Male, Mice, Mice, Inbred C57BL, Orphan Nuclear Receptors, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Promoter Regions, Genetic, RNA, Messenger, Regulatory Sequences, Nucleic Acid, Reverse Transcriptase Polymerase Chain Reaction, Sterol Regulatory Element Binding Protein 1, Trans-Activators, Transcription Factors
Show Abstract · Added July 22, 2020
Cold adaptation elicits a paradoxical simultaneous induction of fatty acid synthesis and beta-oxidation in brown adipose tissue. We show here that cold exposure coordinately induced liver X receptor alpha (LXRalpha), adipocyte determination and differentiation-dependent factor 1 (ADD1)/sterol regulatory element-binding protein-1c (SREBP1c) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1alpha) in brown and inguinal white adipose tissues, but not in epididymal white adipose tissue. Using in vitro models of white and brown adipocytes we demonstrate that beta-adrenergic stimulation induced expression of LXRalpha, ADD1/SREBP1c and PGC1alpha in cells with a brown-like adipose phenotype. We demonstrate that ADD1/SREBP1c is a powerful inducer of PGC1alpha expression via a conserved E box in the proximal promoter and that beta-adrenergic stimulation led to recruitment of ADD1/SREBP1c to this E box. The ability of ADD1/SREBP1c to activate the PGC1alpha promoter exhibited a striking cell type dependency, suggesting that additional cell type-restricted factors contribute to ADD1/SREBP1c-mediated activation. In conclusion, our data demonstrate a novel role of ADD1/SREBP1c as a regulator of PGC1alpha expression in brown adipose tissue.
2009 Elsevier B.V. All rights reserved.
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Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype.
Wang H, Zhang Y, Yehuda-Shnaidman E, Medvedev AV, Kumar N, Daniel KW, Robidoux J, Czech MP, Mangelsdorf DJ, Collins S
(2008) Mol Cell Biol 28: 2187-200
MeSH Terms: Adaptor Proteins, Signal Transducing, Adipocytes, Brown, Adrenergic beta-Agonists, Animals, Body Temperature, Cell Differentiation, Cells, Cultured, Colforsin, DNA-Binding Proteins, Enhancer Elements, Genetic, Ion Channels, Liver X Receptors, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Nuclear Proteins, Nuclear Receptor Interacting Protein 1, Orphan Nuclear Receptors, Oxygen Consumption, PPAR gamma, RNA, Small Interfering, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Transcription, Genetic, Uncoupling Protein 1
Show Abstract · Added July 22, 2020
The adipocyte integrates crucial information about metabolic needs in order to balance energy intake, storage, and expenditure. Whereas white adipose tissue stores energy, brown adipose tissue is a major site of energy dissipation through adaptive thermogenesis mediated by uncoupling protein 1 (UCP1) in mammals. In both white and brown adipose tissue, nuclear receptors and their coregulators, such as peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator 1alpha (PGC-1alpha), play key roles in regulating their development and metabolic functions. Here we show the unexpected role of liver X receptor alpha (LXRalpha) as a direct transcriptional inhibitor of beta-adrenergic receptor-mediated, cyclic AMP-dependent Ucp1 gene expression through its binding to the critical enhancer region of the Ucp1 promoter. The mechanism of inhibition involves the differential recruitment of the corepressor RIP140 to an LXRalpha binding site that overlaps with the PPARgamma/PGC-1alpha response element, resulting in the dismissal of PPARgamma. The ability of LXRalpha to dampen energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.
0 Communities
1 Members
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