Biomaterial Database

Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. 2017

Matthew J Emmett, and Hee-Woong Lim, and Jennifer Jager, and Hannah J Richter, and Marine Adlanmerini, and Lindsey C Peed, and Erika R Briggs, and David J Steger, and Tao Ma, and Carrie A Sims, and Joseph A Baur, and Liming Pei, and Kyoung-Jae Won, and Patrick Seale, and Zachary Gerhart-Hines, and Mitchell A Lazar

Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D008928	Mitochondria	Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed)	Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D010085	Oxidative Phosphorylation	Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds.	Phosphorylation, Oxidative,Oxidative Phosphorylations,Phosphorylations, Oxidative
D011960	Receptors, Estrogen	Cytoplasmic proteins that bind estrogens and migrate to the nucleus where they regulate DNA transcription. Evaluation of the state of estrogen receptors in breast cancer patients has become clinically important.	Estrogen Receptor,Estrogen Receptors,Estrogen Nuclear Receptor,Estrogen Receptor Type I,Estrogen Receptor Type II,Estrogen Receptors Type I,Estrogen Receptors Type II,Receptor, Estrogen Nuclear,Receptors, Estrogen, Type I,Receptors, Estrogen, Type II,Nuclear Receptor, Estrogen,Receptor, Estrogen
D002001	Adipose Tissue, Brown	A thermogenic form of adipose tissue composed of BROWN ADIPOCYTES. It is found in newborns of many species including humans, and in hibernating mammals. Brown fat is richly vascularized, innervated, and densely packed with MITOCHONDRIA which can generate heat directly from the stored lipids.	Brown Fat,Hibernating Gland,Brown Adipose Tissue,Fat, Brown,Tissue, Brown Adipose
D003080	Cold Temperature	An absence of warmth or heat or a temperature notably below an accustomed norm.	Cold,Cold Temperatures,Temperature, Cold,Temperatures, Cold
D004742	Enhancer Elements, Genetic	Cis-acting DNA sequences which can increase transcription of genes. Enhancers can usually function in either orientation and at various distances from a promoter.	Enhancer Elements,Enhancer Sequences,Element, Enhancer,Element, Genetic Enhancer,Elements, Enhancer,Elements, Genetic Enhancer,Enhancer Element,Enhancer Element, Genetic,Enhancer Sequence,Genetic Enhancer Element,Genetic Enhancer Elements,Sequence, Enhancer,Sequences, Enhancer
D005786	Gene Expression Regulation	Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.	Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006358	Hot Temperature	Presence of warmth or heat or a temperature notably higher than an accustomed norm.	Heat,Hot Temperatures,Temperature, Hot,Temperatures, Hot
D006655	Histone Deacetylases	Deacetylases that remove N-acetyl groups from amino side chains of the amino acids of HISTONES. The enzyme family can be divided into at least three structurally-defined subclasses. Class I and class II deacetylases utilize a zinc-dependent mechanism. The sirtuin histone deacetylases belong to class III and are NAD-dependent enzymes.	Class I Histone Deacetylases,Class II Histone Deacetylases,HDAC Proteins,Histone Deacetylase,Histone Deacetylase Complexes,Complexes, Histone Deacetylase,Deacetylase Complexes, Histone,Deacetylase, Histone,Deacetylases, Histone