The Drosophila Estrogen-Related Receptor Directs a Metabolic Switch that Supports Developmental Growth

Tennessen, Jason M.; Baker, Keith D.; Lam, Geanette; Evans, Jason M.; Thummel, Carl S.

doi:10.1016/j.cmet.2011.01.005

Cited by 242 publications

(222 citation statements)

References 48 publications

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“…Ultimately, a key result of ERRα expression and activity appears to be to promote stability or translation of glycolytic proteins and the flux of pyruvate into acetyl-CoA and the TCA cycle, possibly through regulation of DLAT and PDK1 expression. An inability to properly direct glucose to mitochondrial metabolism would lead to decreased lipid synthesis and cell growth, similar to what has been described in ERR-deficient Drosophila (22).…”

Section: Resultsmentioning

confidence: 95%

“…The orphan nuclear hormone receptor, estrogen-related receptor-α (ERRα), is associated with poor prognosis (16,17) and tumor growth in breast cancer (18,19). ERRα is also known to regulate cell metabolism (20,21) and Drosophila ERR can promote gene expression to drive carbohydrate metabolism associated with proliferating cells in larval development (22). In immunity, ERRα −/− mice exhibit increased susceptibility to Listeria monocytogenes infection (23).…”

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confidence: 99%

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Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Michalek¹,

Gerriets²,

Nichols³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

196

189

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Stimulation of resting CD4 + T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabolic programs to support subset specification, survival, and function. Here, we describe that the orphan nuclear receptor estrogen-related receptor-α (ERRα) regulates metabolic pathways critical for Teff. Resting CD4 + T cells expressed low levels of ERRα protein that increased on activation. ERRα deficiency reduced activated T-cell numbers in vivo and cytokine production in vitro but did not seem to modulate immunity through inhibition of activating signals or viability. Rather, ERRα broadly affected metabolic gene expression and glucose metabolism essential for Teff. In particular, up-regulation of Glut1 protein, glucose uptake, and mitochondrial processes were suppressed in activated ERRα −/− T cells and T cells treated with two chemically independent ERRα inhibitors or by shRNAi. Acute ERRα inhibition also blocked T-cell growth and proliferation. This defect appeared as a result of inadequate glucose metabolism, because provision of lipids, but not increased glucose uptake or pyruvate, rescued ATP levels and cell division. Additionally, we have shown that Treg requires lipid oxidation, whereas Teff uses glucose metabolism, and lipid addition selectively restored Tregbut not Teff-generation after acute ERRα inhibition. Furthermore, in vivo inhibition of ERRα reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERRα is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity. glycolysis | fatty acid | oxidative metabolism | mammalian target of rapamycin | AMPK

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Section: Resultsmentioning

confidence: 95%

mentioning

confidence: 99%

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Michalek¹,

Gerriets²,

Nichols³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

196

189

View full text Add to dashboard Cite

show abstract

“…A ChIP-Chip analysis 30 and a recent ChIP-seq study of mouse liver 29 demonstrated that ERRa is involved in the regulation of genes involved in energy metabolism, including glycolysis, the TCA cycle, oxidative phosphorylation and lipid metabolism. Moreover, Drosophila ERR was also shown to regulate glycolytic gene expression in mid-embryogenesis 46 . Accordingly, with a focus on glycolytic genes, we compared the ChIP-seq data sets for Ad4BP/SF-1 and ERRa.…”

Section: Discussionmentioning

confidence: 99%

“…The production of VMH-specific Ad4BP/SF-1-deficient mice that could survive postnatally allowed for experiments that linked the loss of Ad4BP/SF-1 with high-fat diet-induced obesity and impaired thermogenesis 46 . Although the precise mechanisms underlying these connections remain to be delineated, it might be noteworthy that the expression of genes participating in metabolic regulation, for example, the leptin receptor, was downregulated in VMH-specific Ad4BP/SF-1 null animals.…”

Section: Discussionmentioning

confidence: 99%

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

et al. 2014

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Genetic deficiencies in transcription factors can lead to the loss of certain types of cells and tissue. The steroidogenic tissue-specific nuclear receptor Ad4BP/SF-1 (NR5A1) is one such gene, because mice in which this gene is disrupted fail to develop the adrenal gland and gonads. However, the specific role of Ad4BP/SF-1 in these biological events remains unclear. Here we use chromatin immunoprecipitation sequencing to show that nearly all genes in the glycolytic pathway are regulated by Ad4BP/SF-1. Suppression of Ad4BP/SF-1 by small interfering RNA reduces production of the energy carriers ATP and nicotinamide adenine dinucleotide phosphate, as well as lowers expression of genes involved in glucose metabolism. Together, these observations may explain tissue dysgenesis as a result of Ad4BP/SF-1 gene disruption in vivo. Considering the function of estrogen-related receptor a, the present study raises the possibility that certain types of nuclear receptors regulate sets of genes involved in metabolic pathways to generate energy carriers.

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“…Circulating and stored carbohydrate levels were measured via a modified method from the original (Tennessen et al 2011) (see Supplementary Materials and methods). Lipid measurements were performed as described previously (Williams et al 2014b).…”

Section: Trehalose Glucose and Lipid Analysismentioning

confidence: 99%

The Drosophila ortholog of TMEM18 regulates insulin and glucagon-like signaling

Wiemerslage

Gohel

Maestri

et al. 2016

Journal of Endocrinology

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Transmembrane protein 18 (TMEM18) is an ill-described, obesity-related gene, but few studies have explored its molecular function. We found single-nucleotide polymorphism data, suggesting that TMEM18 may be involved in the regulation/physiology of metabolic syndrome based on associations with insulin, homeostatic model assessment-β (HOMAβ), triglycerides, and blood sugar. We then found an ortholog in the Drosophila genome, knocked down Drosophila Tmem18 specifically in insulin-producing cells, and tested for its effects on metabolic function. Our results suggest that TMEM18 affects substrate levels through insulin and glucagon signaling, and its downregulation induces a metabolic state resembling type 2 diabetes. This work is the first to experimentally describe the metabolic consequences of TMEM18 knockdown, and further supports its association with obesity. 233-243TMEM18 regulates insulin and glucagon l wiemerslage and others

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The Drosophila Estrogen-Related Receptor Directs a Metabolic Switch that Supports Developmental Growth

Cited by 242 publications

References 48 publications

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

The Drosophila ortholog of TMEM18 regulates insulin and glucagon-like signaling

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