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Brown adipose tissue epigenetics

Audrey Sambeat, Olga Gulyaeva, Jon Dempersmier, Hei Sook Sul
In contrast to white adipose tissue (WAT), which stores energy in the form of triglycerides, brown adipose tissue (BAT) dissipates energy by producing heat to maintain body temperature by burning glucose and fatty acids in a process called adaptive thermogenesis. The presence of an inducible thermogenic adipose tissue, and its beneficial effects for maintaining body weight and glucose and lipid homeostasis, has raised intense interest in understanding the regulation of thermogenesis. Elucidating the regulatory mechanisms underlying the thermogenic adipose program may provide excellent targets for therapeutics against obesity and diabetes...
September 27, 2016: Trends in Endocrinology and Metabolism: TEM
Yan Chen, Jeesun Kim, Ruipeng Zhang, Xiaoqin Yang, Yong Zhang, Jianwu Fang, Zhui Chen, Lin Teng, Xiaowei Chen, Hui Ge, Peter Atadja, En Li, Taiping Chen, Wei Qi
Adipose tissue plays important roles in animals. White fat stores energy in lipids, while brown fat is responsible for nonshivering thermogenesis through UCP1-mediated energy dissipation. Although epigenetic mechanisms modulate differentiation in multiple lineages, the epigenetic regulation of brown adipocyte differentiation is poorly understood. By screening a collection of epigenetic compounds, we found that Lysine-Specific Demethylase 1 (LSD1) inhibitors repress brown adipocyte differentiation. RNAi-mediated Lsd1 knockdown causes a similar effect, which can be rescued by expression of wild-type but not catalytic-inactive LSD1...
September 9, 2016: Cell Chemical Biology
Qiyuan Yang, Xingwei Liang, Xiaofei Sun, Lupei Zhang, Xing Fu, Carl J Rogers, Anna Berim, Shuming Zhang, Songbo Wang, Bo Wang, Marc Foretz, Benoit Viollet, David R Gang, Buel D Rodgers, Mei-Jun Zhu, Min Du
Promoting brown adipose tissue (BAT) development is an attractive strategy for the treatment of obesity, as activated BAT dissipates energy through thermogenesis; however, the mechanisms controlling BAT formation are not fully understood. We hypothesized that as a master regulator of energy metabolism, AMP-activated protein kinase (AMPK) may play a direct role in the process and found that AMPKα1 (PRKAA1) ablation reduced Prdm16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of α-ketoglutarate (αKG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the Prdm16 promoter...
October 11, 2016: Cell Metabolism
Jean Z Lin, Stephen R Farmer
In this issue of Genes & Development, Zeng and colleagues (pp. 1822-1836) identify lysine-specific demethylase 1 (LSD1) as a pivotal regulator of whole-body energy expenditure by controlling the oxidative and thermogenic activity of brown adipose tissue (BAT). They show that LSD1 interacts with PRDM16 to repress select white adipose tissue (WAT) genes but also represses hydroxysteroid 11-β-dehydrogenase 1 (HSD11B1) independently of PRDM16 to prevent production of glucocorticoids that impair BAT functions. Their study provides important insight into epigenetic mechanisms regulating the function of BAT...
August 15, 2016: Genes & Development
Olivier Goupille, Tipparat Penglong, Zahra Kadri, Marine Granger-Locatelli, Suthat Fucharoen, Leila Maouche-Chrétien, Stéphane Prost, Philippe Leboulch, Stany Chrétien
The bromodomain and extraterminal (BET) domain family proteins are epigenetic modulators involved in the reading of acetylated lysine residues. The first BET protein inhibitor to be identified, (+)-JQ1, a thienotriazolo-1, 4-diazapine, binds selectively to the acetyl lysine-binding pocket of BET proteins. We evaluated the impact on adipogenesis of this druggable targeting of chromatin epigenetic readers, by investigating the physiological consequences of epigenetic modifications through targeting proteins binding to chromatin...
April 15, 2016: Biochemical and Biophysical Research Communications
Matthew Van De Pette, Simon J Tunster, Grainne I McNamara, Tatyana Shelkovnikova, Steven Millership, Lindsay Benson, Stuart Peirson, Mark Christian, Antonio Vidal-Puig, Rosalind M John
The accurate diagnosis and clinical management of the growth restriction disorder Silver Russell Syndrome (SRS) has confounded researchers and clinicians for many years due to the myriad of genetic and epigenetic alterations reported in these patients and the lack of suitable animal models to test the contribution of specific gene alterations. Some genetic alterations suggest a role for increased dosage of the imprinted CYCLIN DEPENDENT KINASE INHIBITOR 1C (CDKN1C) gene, often mutated in IMAGe Syndrome and Beckwith-Wiedemann Syndrome (BWS)...
March 2016: PLoS Genetics
Dongning Pan, Lei Huang, Lihua J Zhu, Tie Zou, Jianhong Ou, William Zhou, Yong-Xu Wang
Progression from brown preadipocytes to adipocytes engages two transcriptional programs: the expression of adipogenic genes common to both brown fat (BAT) and white fat (WAT), and the expression of BAT-selective genes. However, the dynamics of chromatin states and epigenetic enzymes involved remain poorly understood. Here we show that BAT development is selectively marked and guided by repressive H3K27me3 and is executed by its demethylase Jmjd3. We find that a significant subset of BAT-selective genes, but not common fat genes or WAT-selective genes, are demarcated by H3K27me3 in both brown and white preadipocytes...
December 7, 2015: Developmental Cell
Thomas Tsiloulis, Matthew J Watt
Adipose tissue is a major regulator of metabolism in health and disease. The prominent roles of adipose tissue are to sequester fatty acids in times of energy excess and to release fatty acids via the process of lipolysis during times of high-energy demand, such as exercise. The fatty acids released during lipolysis are utilized by skeletal muscle to produce adenosine triphosphate to prevent fatigue during prolonged exercise. Lipolysis is controlled by a complex interplay between neuro-humoral regulators, intracellular signaling networks, phosphorylation events involving protein kinase A, translocation of proteins within the cell, and protein-protein interactions...
2015: Progress in Molecular Biology and Translational Science
Lin Zha, Fenfen Li, Rui Wu, Liana Artinian, Vincent Rehder, Liqing Yu, Houjie Liang, Bingzhong Xue, Hang Shi
Brown adipocytes function to dissipate energy as heat through adaptive thermogenesis. Understanding the molecular mechanisms underlying the brown fat thermogenic program may provide insights for the development of therapeutic approaches in the treatment of obesity. Most studies investigating the mechanisms underlying brown fat development focus on genetic mechanisms; little is known about the epigenetic mechanisms in this process. We have discovered that ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), a histone demethylase for di- or tri-methylated histone 3 lysine 27 (H3K27me2/3), plays a potential role in regulating brown adipocyte thermogenic program...
October 9, 2015: Journal of Biological Chemistry
Xiao Li, Jinquan Wang, Zheng Jiang, Feng Guo, Paul D Soloway, Ruqian Zhao
The positive regulatory domain containing 16 (PRDM16) is commonly regarded as a "switch" controlling the transdifferentiation of myoblasts to brown adipocytes. The N-positive regulatory (PR) domain, which is highly homologous to SET domain, is a characteristic structure for the PRDM family. Many SET domain containing proteins and several PRDM members have been found to possess histone methyltransferase activity, yet the role of PRDM16 and its PR domain in the epigenetic regulation of myogenic and adipogenic genes during myoblasts/adipocytes transdifferentiation remains unexplored...
October 10, 2015: Gene
Jun Wu, Heejin Jun, Joseph R McDermott
Thermogenic fat cells that convert chemical energy into heat are present in both mice and humans. Recent years have witnessed great advances in our understanding of the regulation of these adipocytes and an increased appreciation of the potential these cells have to counteract obesity. We summarize recent efforts to understand the formation of these fat cells and critically review genetic models and other experimental tools currently available to further investigate the development and activation of both classical brown and inducible beige fat cells...
May 2015: Trends in Genetics: TIG
Yulia Biggar, Kenneth B Storey
Hibernation is crucial to winter survival for many small mammals and is characterized by prolonged periods of torpor during which strong global controls are applied to suppress energy-expensive cellular processes. We hypothesized that one strategy of energy conservation is a global reduction in gene transcription imparted by reversible modifications to DNA and to proteins involved in chromatin packing. Transcriptional regulation during hibernation was examined over euthermic control groups and five stages of the torpor/arousal cycle in brown adipose tissue of thirteen-lined ground squirrels (Ictidomys tridecemlineatus)...
October 2014: Cryobiology
Ji-Eun Lee, Kai Ge
The nuclear receptor PPARγ is a master regulator of adipogenesis. PPARγ is highly expressed in adipose tissues and its expression is markedly induced during adipogenesis. In this review, we describe the current knowledge, as well as future directions, on transcriptional and epigenetic regulation of PPARγ expression during adipogenesis. Investigating the molecular mechanisms that control PPARγ expression during adipogenesis is critical for understanding the development of white and brown adipose tissues, as well as pathological conditions such as obesity and diabetes...
2014: Cell & Bioscience
F Sheedfar, M Vermeer, V Pazienza, J Villarroya, F Rappa, F Cappello, G Mazzoccoli, F Villarroya, H van der Molen, M H Hofker, D P Koonen, M Vinciguerra
BACKGROUND/OBJECTIVES: In the context of obesity, epigenetic mechanisms regulate cell-specific chromatin plasticity, perpetuating gene expression responses to nutrient excess. MacroH2A1, a variant of histone H2A, emerged as a key chromatin regulator sensing small nutrients during cell proliferation and differentiation. Mice genetically ablated for macroH2A1 (knockout (KO)) do not show overt phenotypes under a standard diet. Our objective was to analyse the in vivo role of macroH2A1 in response to nutritional excess...
February 2015: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Alice F Tarantal, Lars Berglund
A marked increase in the frequency of obesity at the population level has resulted in an increasing number of obese women entering pregnancy. The increasing realization of the importance of the fetal environment in relation to chronic disease across the lifespan has focused attention on the role of maternal obesity in fetal development. Previous studies have demonstrated that obesity during adolescence and adulthood can be traced back to fetal and early childhood exposures. This review focuses on factors that contribute to early developmental events, such as epigenetic modifications, the potential for an increase in inflammatory burden, early developmental programming changes such as the variable development of white versus brown adipose tissue, and alterations in organ ontogeny...
April 2014: Nutrients
Michael E Symonds, Helen Budge, Alexis C Frazier-Wood
Obesity can have multifactorial causes that may change with development and are not simply attributable to one's genetic constitution. To date, expensive and laborious genome-wide association studies have only ascribed a small contribution of genetic variants to obesity. The emergence of the field of epigenetics now offers a new paradigm with which to study excess fat mass. Currently, however, there are no compelling epigenetic studies to explain the role of epigenetics in obesity, especially from a developmental perspective...
2013: Human Heredity
Andreu Palou, M Luisa Bonet
Obesity is the main nutritional problem and one of the most important health problems in developed societies. Central to the challenge of obesity prevention and management is a thoroughly understanding of its determinants. Multiple socio-cultural, socio-economic, behavioural and biological factors--often interrelated and many of them still unknown or poorly understood--can contribute to the establishment and perpetuation of obese phenotypes. Here, we address current research challenges regarding basic aspects of obesity and emerging science for its control, including brown adipose tissue thermogenesis and browning of white fat as possible therapeutic targets for obesity, the influence of the microbioma, and genetics, epigenetics, nutrigenomics and nutrigenetics of obesity...
September 2013: Nutrición Hospitalaria: Organo Oficial de la Sociedad Española de Nutrición Parenteral y Enteral
Lifeng Wang, Shiliyang Xu, Ji-Eun Lee, Anne Baldridge, Sean Grullon, Weiqun Peng, Kai Ge
PPARγ promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control expression of these positive and negative master regulators of adipogenesis remain incompletely understood. By genome-wide histone methylation profiling in preadipocytes, we find that among gene loci encoding adipogenesis regulators, histone methyltransferase (HMT) G9a-mediated repressive epigenetic mark H3K9me2 is selectively enriched on the entire PPARγ locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPARγ...
January 9, 2013: EMBO Journal
Andrea Galmozzi, Nico Mitro, Alessandra Ferrari, Elise Gers, Federica Gilardi, Cristina Godio, Gaia Cermenati, Alice Gualerzi, Elena Donetti, Dante Rotili, Sergio Valente, Uliano Guerrini, Donatella Caruso, Antonello Mai, Enrique Saez, Emma De Fabiani, Maurizio Crestani
Chromatin modifications are sensitive to environmental and nutritional stimuli. Abnormalities in epigenetic regulation are associated with metabolic disorders such as obesity and diabetes that are often linked with defects in oxidative metabolism. Here, we evaluated the potential of class-specific synthetic inhibitors of histone deacetylases (HDACs), central chromatin-remodeling enzymes, to ameliorate metabolic dysfunction. Cultured myotubes and primary brown adipocytes treated with a class I-specific HDAC inhibitor showed higher expression of Pgc-1α, increased mitochondrial biogenesis, and augmented oxygen consumption...
March 2013: Diabetes
Michael E Symonds, Sylvain Sebert, Helen Budge
The prevalence of obesity continues to increase particularly in developed countries. To establish the primary mechanisms involved, relevant animal models which track the developmental pathway to obesity are required. This need is emphasized by the substantial rise in the number of overweight and obese children, of which a majority will remain obese through adulthood. The past half century has been accompanied with unprecedented transitions in our lifestyle. Each of these changes substantially contributes to enhancing our capacity to store energy into adipose tissues...
2011: Frontiers in Genetics
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