LSD1 Interacts with Zfp516 to Promote UCP1 Transcription and Brown Fat Program

Sambeat, Audrey; Gulyaeva, Olga; Dempersmier, Jon; Tharp, Kevin M.; Stahl, Andreas; Paul, Sarah M.; Sul, Hei Sook

doi:10.1016/j.celrep.2016.05.019

Cited by 88 publications

(81 citation statements)

References 28 publications

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“…While we were preparing this article, the same group published another paper suggesting that LSD1 is responsible for the H3K9 demethylation activity associated with ZFP516 (Sambeat et al 2016). They further showed that BAT-specific LSD1 knockout mice displayed an obese phenotype similar to what we observed with the AdLKO mice and suggested that the reduced UCP1 expression might be one of the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 65%

Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation

et al. 2016

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Brown adipocytes display phenotypic plasticity, as they can switch between the active states of fatty acid oxidation and energy dissipation versus a more dormant state. Cold exposure or β-adrenergic stimulation favors the active thermogenic state, whereas sympathetic denervation or glucocorticoid administration promotes more lipid accumulation. Our understanding of the molecular mechanisms underlying these switches is incomplete. Here we found that LSD1 (lysine-specific demethylase 1), a histone demethylase, regulates brown adipocyte metabolism in two ways. On the one hand, LSD1 associates with PRDM16 to repress expression of white fat-selective genes. On the other hand, LSD1 represses HSD11B1 (hydroxysteroid 11-β-dehydrogenase isozyme 1), a key glucocorticoid-activating enzyme, independently from PRDM16. Adipose-specific ablation of LSD1 impaired mitochondrial fatty acid oxidation capacity of the brown adipose tissue, reduced whole-body energy expenditure, and increased fat deposition, which can be significantly alleviated by simultaneously deleting HSD11B1. These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis.

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Section: Discussionmentioning

confidence: 65%

Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation

et al. 2016

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“…Cold exposure stimulates expression of Zfp516 in BAT that binds to Prdm16 and stimulates UCP1 transcription (64, 267). In agreement with these findings, adipocyte-specific overexpression of Zfp516 increases brown adipogenesis in mice (64).…”

Section: Genetic and Epigenetic Regulation Of Brown And Beige Fat Thementioning

confidence: 99%

Brown and Beige Adipose Tissues in Health and Disease

Rui

2017

Comprehensive Physiology

146

113

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Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal muscle. Beige fat develops postnatally and is highly inducible. Beige fat recruitment is mediated by multiple mechanisms, including de novo beige adipogenesis and white-to-brown adipocyte transdifferentiaiton. Beige precursors reside around vasculatures, and proliferate and differentiate into beige adipocytes. PDGFRα+Ebf2+ precursors are restricted to beige lineage cells, while another PDGFRα+ subset gives rise to beige adipocytes, white adipocytes, or fibrogenic cells. White adipocytes can be reprogramed and transdifferentiated into beige adipocytes. Brown and beige adipocytes display many similar properties, including multilocular lipid droplets, dense mitochondria, and expression of UCP1. UCP1-mediated thermogenesis is a hallmark of brown/beige adipocytes, albeit UCP1-independent thermogenesis also occurs. Development, maintenance, and activation of BAT/beige fat are guided by genetic and epigenetic programs. Numerous transcriptional factors and coactivators act coordinately to promote BAT/beige fat thermogenesis. Epigenetic reprograming also influences expression of brown/beige adipocyte-selective genes. BAT/beige fat is regulated by neuronal, hormonal, and immune mechanisms. Hypothalamic thermal circuits define the temperature setpoint that guides BAT/beige fat activity. Metabolic hormones, paracrine/autocrine factors, and various immune cells also play a critical role in regulating BAT/beige fat functions. BAT and beige fat defend temperature homeostasis, and regulate body weight and glucose and lipid metabolism. Obesity is associated with brown/beige fat deficiency, and reactivation of brown/beige fat provides metabolic health benefits in some patients. Pharmacological activation of BAT/beige fat may hold promise for combating metabolic diseases.

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“…74 The HDAC inhibitor program of Novartis that led to the approval of panobinostat for the treatment of multiple myeloma, originated from a campaign that was looking for compounds that induce the overexpression of p21. 75 Several promoters have also been found to be regulated by LSD1, e.g., BAT gene promoters 76 or the mouse PGC-1a promoter. 78 The challenge with histone modifying enzyme is the incorporation of the transgene into the nucleosome.…”

Section: Reporter Gene Assaysmentioning

confidence: 99%

Cellular analysis of the action of epigenetic drugs and probes

et al. 2017

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Small molecule drugs and probes are important tools in drug discovery, pharmacology, and cell biology. This is of course also true for epigenetic inhibitors. Important examples for the use of established epigenetic inhibitors are the study of the mechanistic role of a certain target in a cellular setting or the modulation of a certain phenotype in an approach that aims toward therapeutic application. Alternatively, cellular testing may aim at the validation of a new epigenetic inhibitor in drug discovery approaches. Cellular and eventually animal models provide powerful tools for these different approaches but certain caveats have to be recognized and taken into account. This involves both the selectivity of the pharmacological tool as well as the specificity and the robustness of the cellular system. In this article, we present an overview of different methods that are used to profile and screen for epigenetic agents and comment on their limitations. We describe not only diverse successful case studies of screening approaches using different assay formats, but also some problematic cases, critically discussing selected applications of these systems.

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LSD1 Interacts with Zfp516 to Promote UCP1 Transcription and Brown Fat Program

Cited by 88 publications

References 28 publications

Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation

Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation

Brown and Beige Adipose Tissues in Health and Disease

Cellular analysis of the action of epigenetic drugs and probes

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