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Transcriptional control of energy metabolism by nuclear receptors

Nature Reviews Molecular Cell Biology volume 23, pages 750–770 (2022)Cite this article

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Abstract

Transcriptional regulation of catabolic pathways is a central mechanism by which cells respond to physiological cues to generate the energy required for anabolic pathways, transport of molecules and mechanical work. Nuclear receptors are members of a superfamily of transcription factors that transduce hormonal, nutrient, metabolite and redox signals into specific metabolic gene programmes, and thus hold a major status as regulators of cellular energy generation. Nuclear receptors also regulate the expression of genes involved in cellular processes that are implicated in energy production, including mitochondrial biogenesis and autophagy. Recent advances in genome-wide approaches have considerably expanded the repertoire of both nuclear receptors and metabolic genes under their direct transcriptional control. To fine-tune the expression of their target genes, nuclear receptors must act cooperatively with other transcription factors and coregulator proteins, integrate signals from key metabolic sensory systems such as the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complexes and synchronize their activities with the biological clock. Therefore, nuclear receptors must function as more than molecular switches for small lipophilic ligands — as initially ascribed — but rather must be capable of orchestrating a large ensemble of input signals. Therefore, a primary role for several nuclear receptors is to serve as the focal point of transcriptional hubs in energy metabolism: their molecular task is to receive and transduce multiple systemic and intracellular metabolic signals to maintain energy homeostasis from individual cells to the whole organism.

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Fig. 1: The nuclear receptor superfamily.
Fig. 2: Basics of nuclear receptor action.
Fig. 3: Regulatory metabolic crosstalk.
Fig. 4: Cellular energy metabolic pathways transcriptionally controlled by nuclear receptors.
Fig. 5: Relative contribution of nuclear receptors to the transcriptional regulation of metabolic genes.
Fig. 6: Nuclear receptor-dependent metabolic regulatory hubs.

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References

  1. Judge, A. & Dodd, M. S. Metabolism. Essays Biochem. 64, 607–647 (2020). This work is a comprehensive review of the biochemical pathways involved in energy metabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pavlova, N. N., Zhu, J. & Thompson, C. B. The hallmarks of cancer metabolism: still emerging. Cell Metab. 34, 355–377 (2022).

    Article  CAS  PubMed  Google Scholar 

  3. Giguère, V., Yang, N., Segui, P. & Evans, R. M. Identification of a new class of steroid hormone receptors. Nature 331, 91–94 (1988). This article describes the identification of the first orphan nuclear receptor, predicting the existence of previously unknown hormone and small lipophilic compound response systems.

    Article  PubMed  Google Scholar 

  4. Wang, L. H. et al. Coup transcription factor is a member of the steroid-receptor superfamily. Nature 340, 163–166 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Giguère, V. Orphan nuclear receptors: from gene to function. Endocr. Rev. 20, 689–725 (1999).

    PubMed  Google Scholar 

  6. Mullican, S. E., Dispirito, J. R. & Lazar, M. A. The orphan nuclear receptors at their 25-year reunion. J. Mol. Endocrinol. 51, T115–T140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Markov, G. V. & Laudet, V. Origin and evolution of the ligand-binding ability of nuclear receptors. Mol. Cell. Endocrinol. 334, 21–30 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Sural, S. & Hobert, O. Nematode nuclear receptors as integrators of sensory information. Curr. Biol. 31, 4361–4366 e4362 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Robinson-Rechavi, M., Escriva Garcia, H. & Laudet, V. The nuclear receptor superfamily. J. Cell Sci. 116, 585–586 (2003).

    Article  PubMed  Google Scholar 

  10. Robinson-Rechavi, M., Maina, C. V., Gissendanner, C. R., Laudet, V. & Sluder, A. Explosive lineage-specific expansion of the orphan nuclear receptor HNF4 in nematodes. J. Mol. Evol. 60, 577–586 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Bodofsky, S., Koitz, F. & Wightman, B. Conserved and exapted functions of nuclear receptors in animal development. Nucl. Receptor Res. 4, 101305 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wisely, G. B. et al. Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids. Structure 10, 1225–1234 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Van Gilst, M. R., Hadjivassiliou, H., Jolly, A. & Yamamoto, K. R. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS Biol. 3, e53 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Palanker, L., Tennessen, J. M., Lam, G. & Thummel, C. S. Drosophila HNF4 regulates lipid mobilization and β-oxidation. Cell Metab. 9, 228–239 (2009). This genetic and metabolic study in Drosophila defines the ancestral function of HNF4 as a key regulator of lipid mobilization and β-oxidation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tennessen, J. M., Baker, K. D., Lam, G., Evans, J. & Thummel, C. S. The Drosophila estrogen-related receptor directs a metabolic switch that supports developmental growth. Cell Metab. 13, 139–148 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pathare, P. P., Lin, A., Bornfeldt, K. E., Taubert, S. & Van Gilst, M. R. Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLoS Genet. 8, e1002645 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Storelli, G., Nam, H. J., Simcox, J., Villanueva, C. J. & Thummel, C. S. Drosophila HNF4 directs a switch in lipid metabolism that supports the transition to adulthood. Dev. Cell 48, 200–214 e206 (2019).

    Article  CAS  PubMed  Google Scholar 

  18. Beebe, K. et al. Drosophila estrogen-related receptor directs a transcriptional switch that supports adult glycolysis and lipogenesis. Genes Dev. 34, 701–714 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Voss, T. C. & Hager, G. L. Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat. Rev. Genet. 15, 69–81 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Boyle, A. P. et al. High-resolution mapping and characterization of open chromatin across the genome. Cell 132, 311–322 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Buenrostro, J. D., Wu, B., Chang, H. Y. & Greenleaf, W. J. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109, 21 29 21–21 29 29 (2015).

    Article  PubMed  Google Scholar 

  22. Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Carroll, J. S. et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122, 33–43 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Laganière, J. et al. Location analysis of estrogen receptor α target promoters reveals that FOXA1 defines a domain of the estrogen response. Proc. Natl Acad. Sci. USA 102, 11651–11656 (2005). This study, together with Carroll et al. (2005), shows the requirement of the pioneer factor FOXA1 for a nuclear receptor binding to enhancers and promoters in the genome.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kain, J. et al. Pioneer factor Foxa2 enables ligand-dependent activation of type II nuclear receptors FXR and LXRα. Mol. Metab. 53, 101291 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sahu, B. et al. FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res. 73, 1570–1580 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Jin, H. J., Zhao, J. C., Wu, L., Kim, J. & Yu, J. Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program. Nat. Commun. 5, 3972 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Reizel, Y. et al. Collapse of the hepatic gene regulatory network in the absence of FoxA factors. Genes Dev. 34, 1039–1050 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Horisawa, K. et al. The dynamics of transcriptional activation by hepatic reprogramming factors. Mol. Cell 79, 660–676 e668 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Voss, T. C. et al. Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 146, 544–554 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Swinstead, E. E. et al. Steroid receptors reprogram FoxA1 occupancy through dynamic chromatin transitions. Cell 165, 593–605 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Adachi, K. et al. Esrrb unlocks silenced enhancers for reprogramming to naive pluripotency. Cell Stem Cell 23, 266–275 e266 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Madsen, M. S., Siersbaek, R., Boergesen, M., Nielsen, R. & Mandrup, S. Peroxisome proliferator-activated receptor γ and C/EBPα synergistically activate key metabolic adipocyte genes by assisted loading. Mol. Cell. Biol. 34, 939–954 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ratman, D. et al. Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα. Nucleic Acids Res. 44, 10539–10553 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Biddie, S. C. et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Perissi, V., Aggarwal, A., Glass, C. K., Rose, D. W. & Rosenfeld, M. G. A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. Cell 116, 511–526 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Shabtai, Y. et al. A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver. Genes Dev. 35, 367–378 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Robertson, G. et al. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat. Methods 4, 651–657 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Cohen, D. M. & Steger, D. J. Nuclear receptor function through genomics: lessons from the glucocorticoid receptor. Trends Endocrinol. Metab. 28, 531–540 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Siersbaek, R. et al. Dynamic rewiring of promoter-anchored chromatin loops during adipocyte differentiation. Mol. Cell 66, 420–435 e425 (2017). This elegant work using a variety of genomics approaches demonstrates that rewiring of promoter-anchored loops is coupled to changes in the activity of the connected promoters and enhancers occupied by a cluster of metabolic transcription factors and nuclear receptors.

    Article  CAS  PubMed  Google Scholar 

  41. Lefterova, M. I. et al. Cell-specific determinants of peroxisome proliferator-activated receptor γ function in adipocytes and macrophage. Mol. Cell. Biol. 30, 2078–2089 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hu, W. et al. Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids. Cell Metab. 33, 1592–1609 e1597 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Deblois, G. et al. ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer. Nat. Commun. 7, 12156 (2016). This work reveals a molecular mechanism by which nuclear receptor-induced metabolic reprogramming promotes survival of drug-resistant cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Qin, Y., Grimm, S. A., Roberts, J. D., Chrysovergis, K. & Wade, P. A. Alterations in promoter interaction landscape and transcriptional network underlying metabolic adaptation to diet. Nat. Commun. 11, 962 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fang, B. & Lazar, M. A. Dissecting the Rev-erbα cistrome and the mechanisms controlling circadian transcription in liver. Cold Spring Harb. Symp. Quant. Biol. 80, 233–238 (2015).

    Article  PubMed  Google Scholar 

  46. Xia, H., Dufour, C. R. & Giguère, V. ERRα as a bridge between transcription and function: role in liver metabolism and disease. Front. Endocrinol. 10, 206 (2019).

    Article  Google Scholar 

  47. Soccio, R. E. et al. Genetic variation determines PPARγ function and anti-diabetic drug response In vivo. Cell 162, 33–44 (2015). This tour-de-force work combining mouse genetics and genome-wide association studies in human shows that genetic variation in PPARγ genomic occupancy determines metabolic disease risk and drug response, providing a proof of concept for personalized medicine related to nuclear receptor genomic occupancy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hah, N. et al. A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell 145, 622–634 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Step, S. E. et al. Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancer. Genes Dev. 28, 1018–1028 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Goldstein, I. & Hager, G. L. Transcriptional and chromatin regulation during fasting- the genomic era. Trends Endocrinol. Metab. 26, 699–710 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Grontved, L. et al. C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. EMBO J. 32, 1568–1583 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Langlais, D., Couture, C., Balsalobre, A. & Drouin, J. The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome. Mol. Cell 47, 38–49 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Vockley, C. M. et al. Direct GR binding sites potentiate clusters of TF binding across the human genome. Cell 166, 1269–1281 e1219 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Giudici, M., Goni, S., Fan, R. & Treuter, E. Nuclear receptor coregulators in metabolism and disease. Handb. Exp. Pharmacol. 233, 95–135 (2016).

    Article  CAS  PubMed  Google Scholar 

  57. Zhang, Y. et al. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348, 1488–1492 (2015). This work shows that REV-ERBα uses distinct mechanisms, direct binding and tethering, to recognize its target genes in the genome and thus differentially regulates biological clock and metabolic genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Murayama, Y. et al. Glucocorticoid receptor suppresses gene expression of Rev-erbα (Nr1d1) through interaction with the CLOCK complex. FEBS Lett. 593, 423–432 (2019).

    Article  CAS  PubMed  Google Scholar 

  59. Boergesen, M. et al. Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor α in mouse liver reveals extensive sharing of binding sites. Mol. Cell. Biol. 32, 852–867 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Siersbaek, R. et al. Molecular architecture of transcription factor hotspots in early adipogenesis. Cell Rep. 7, 1434–1442 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Grontved, L. et al. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling. Nat. Commun. 6, 7048 (2015).

    Article  PubMed  Google Scholar 

  62. Dasgupta, S., Lonard, D. M. & O’Malley, B. W. Nuclear receptor coactivators: master regulators of human health and disease. Annu. Rev. Med. 65, 279–292 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Mouchiroud, L., Eichner, L. J., Shaw, R. J. & Auwerx, J. Transcriptional coregulators: fine-tuning metabolism. Cell Metab. 20, 26–40 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Vainshtein, A., Tryon, L. D., Pauly, M. & Hood, D. A. Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am. J. Physiol. Cell Physiol. 308, C710–C719 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Gidlund, E. K. et al. Rapidly elevated levels of PGC-1α-β protein in human skeletal muscle after exercise: exploring regulatory factors in a randomized controlled trial. J. Appl. Physiol. 119, 374–384 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005). This article shows that NAD+-dependent induction of SIRT1 deacetylates PGC1α at specific lysine residues and leads to the induction of gluconeogenic genes and hepatic glucose output, thus identifying a molecular mechanism whereby sirtuins function in glucose homeostasis.

    Article  CAS  PubMed  Google Scholar 

  68. Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Coste, A. et al. The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α. Proc. Natl Acad. Sci. USA 105, 17187–17192 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schreiber, S. N., Knutti, D., Brogli, K., Uhlmann, T. & Kralli, A. The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor α (ERRα). J. Biol. Chem. 278, 9013–9018 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Laganiere, J. et al. A polymorphic autoregulatory hormone response element in the human estrogen-related receptor α (ERRα) promoter dictates peroxisome proliferator-activated receptor γ coactivator-1α control of ERRα expression. J. Biol. Chem. 279, 18504–18510 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Mootha, V. K. et al. ERRα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc. Natl Acad. Sci. USA 101, 6570–6575 (2004). The results in this article demonstrate that, together, ERRα and PGC1α control the expression of OXPHOS pathway gene expression, suggesting that modulation of ERRα transcriptional activity may ameliorate insulin resistance in individuals with type 2 diabetes mellitus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gaillard, S. et al. Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs. Mol. Cell 24, 797–803 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Chen, W., Yang, Q. & Roeder, R. G. Dynamic interactions and cooperative functions of PGC-1α and MED1 in TRα-mediated activation of the brown-fat-specific UCP-1 gene. Mol. Cell 35, 755–768 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhou, J. et al. MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism. Autophag 17, 4043–4061 (2021).

    Article  CAS  Google Scholar 

  76. Ito, K. et al. Critical roles of transcriptional coactivator MED1 in the formation and function of mouse adipose tissues. Genes Dev. 35, 729–748 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Stashi, E. et al. SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm. Cell Rep. 6, 633–645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tachmatzidi, E. C., Galanopoulou, O. & Talianidis, I. Transcription control of liver development. Cells 10, 2026 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Charest-Marcotte, A. et al. The homeobox protein Prox1 is a negative modulator of ERRα/PGC-1α bioenergetic functions. Genes Dev. 24, 537–542 (2010). This article identifies PROX1 as an important coregulator of the PGC1α–ERRα complex involved in the transcriptional regulation of genes encoding components of the OXPHOS, TCA cycle and ETC pathways. This vast cluster of functionally linked energy metabolism genes is referred to in this study as the ‘ERRα bioenergetic regulon’.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Dufour, C. R. et al. Genomic convergence among ERRα, Prox1 and Bmal1 in the control of metabolic clock outputs. PLoS Genet. 7, e1002143 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Song, K. H., Li, T. & Chiang, J. Y. A Prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4α that regulates the cholesterol 7α-hydroxylase gene. J. Biol. Chem. 281, 10081–10088 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Qin, J. et al. Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-α-hydroxylase gene. Mol. Endocrinol. 18, 2424–2439 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Stein, S. et al. SUMOylation-dependent LRH-1/PROX1 interaction promotes atherosclerosis by decreasing hepatic reverse cholesterol transport. Cell Metab. 20, 603–613 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Steffensen, K. R. et al. Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue. EMBO Rep. 5, 613–619 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Armour, S. M. et al. An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides. Nat. Commun. 8, 549 (2017). This article shows the importance of specific combinations of nuclear receptors and coregulators in the fine-tuning of metabolism.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Goto, T. et al. Liver-specific Prox1 inactivation causes hepatic injury and glucose intolerance in mice. FEBS Lett. 591, 624–635 (2017).

    Article  CAS  PubMed  Google Scholar 

  87. Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lecompte, S. et al. Genetic and molecular insights into the role of PROX1 in glucose metabolism. Diabetes 62, 1738–1745 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Liang, N., Jakobsson, T., Fan, R. & Treuter, E. The nuclear receptor-co-repressor complex in control of liver metabolism and disease. Front. Endocrinol. 10, 411 (2019).

    Article  Google Scholar 

  90. Perez-Schindler, J. et al. The corepressor NCoR1 antagonizes PGC-1α and estrogen-related receptor α in the regulation of skeletal muscle function and oxidative metabolism. Mol. Cell. Biol. 32, 4913–4924 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jo, Y. S. et al. Phosphorylation of the nuclear receptor corepressor 1 by protein kinase B switches its corepressor targets in the liver in mice. Hepatology 62, 1606–1618 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018).

    Article  CAS  PubMed  Google Scholar 

  93. Lien, F. et al. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J. Clin. Invest. 124, 1037–1051 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chopra, A. R. et al. Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption. Cell Metab. 13, 35–43 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hong, Y. H., Varanasi, U. S., Yang, W. & Leff, T. AMP-activated protein kinase regulates HNF4α transcriptional activity by inhibiting dimer formation and decreasing protein stability. J. Biol. Chem. 278, 27495–27501 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Ding, J. et al. AMPK phosphorylates PPARδ to mediate its stabilization, inhibit glucose and glutamine uptake and colon tumor growth. J. Biol. Chem. 297, 100954 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Audet-Walsh, E. et al. The PGC-1α/ERRα axis represses one-carbon metabolism and promotes sensitivity to anti-folate therapy in breast cancer. Cell Rep. 14, 920–931 (2016).

    Article  CAS  PubMed  Google Scholar 

  98. Yan, M. et al. Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα. Genes Dev. 30, 1034–1046 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Possik, E. et al. Folliculin regulates AMPK-dependent autophagy and metabolic stress survival. PLoS Genet. 10, e1004273 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Gonzalez, A. & Hall, M. N. Nutrient sensing and TOR signaling in yeast and mammals. EMBO J. 36, 397–408 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Szwed, A., Kim, E. & Jacinto, E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol. Rev. 101, 1371–1426 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Giguère, V. Canonical signaling and nuclear activity of mTOR: a teamwork effort to regulate metabolism and cell growth. FEBS J. 285, 1572–1588 (2018).

    Article  PubMed  Google Scholar 

  103. Shimizu, N. et al. Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. Cell Metab. 13, 170–182 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Chaveroux, C. et al. Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced non-alcoholic fatty liver. Cell Metab. 17, 586–598 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Audet-Walsh, E. et al. Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer. Genes Dev. 31, 1228–1242 (2017). Chaveroux et al. (2013) and Audet-Walsh et al. (Genes Dev., 2017) are two publications revealing that nuclear mTOR occupies specific sites in the genome and works in concert with nuclear receptors to regulate the expression of metabolic genes in both normal and cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Kim, K., Pyo, S. & Um, S. H. S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor α activity in the liver. Hepatology 55, 1727–1737 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Reinke, H. & Asher, G. Crosstalk between metabolism and circadian clocks. Nat. Rev. Mol. Cell Biol. 20, 227–241 (2019).

    Article  CAS  PubMed  Google Scholar 

  109. Panda, S. Circadian physiology of metabolism. Science 354, 1008–1015 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kim, Y. H. & Lazar, M. A. Transcriptional control of circadian rhythms and metabolism: a matter of time and space. Endocr. Rev. 41, 707–732 (2020).

    Article  PubMed Central  Google Scholar 

  111. Zhao, X. et al. Nuclear receptors rock around the clock. EMBO Rep. 15, 518–528 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Nader, N., Chrousos, G. P. & Kino, T. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J. 23, 1572–1583 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Grimaldi, B. et al. PER2 controls lipid metabolism by direct regulation of PPARγ. Cell Metab. 12, 509–520 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011). This article demonstrates that two core components of the biological clock, CRY1 and CRY2, interact with GR in a ligand-dependent fashion to alter the transcriptional response to glucocorticoid and regulate metabolic homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Jordan, S. D. et al. CRY1/2 selectively repress PPARδ and limit exercise capacity. Cell Metab. 26, 243–255 e246 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Thorens, B. & Mueckler, M. Glucose transporters in the 21st century. Am. J. Physiol. Endocrinol. Metab. 298, E141–E145 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Leto, D. & Saltiel, A. R. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat. Rev. Mol. Cell Biol. 13, 383–396 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Oosterveer, M. H. et al. LRH-1-dependent glucose sensing determines intermediary metabolism in liver. J. Clin. Invest. 122, 2817–2826 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Baba, T. et al. Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1. Nat. Commun. 5, 3634 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Wende, A. R., Huss, J. M., Schaeffer, P. J., Giguère, V. & Kelly, D. P. PGC-1α coactivates PDK4 gene expression via the orphan nuclear receptor ERRα: a mechanism for transcriptional control of muscle glucose metabolism. Mol. Cell. Biol. 25, 10684–10694 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhang, Y. et al. Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression. J. Biol. Chem. 281, 39897–39906 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Niu, B. et al. In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets. Nucleic Acids Res. 46, 8385–8403 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Connaughton, S. et al. Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin. Mol. Cell. Endocrinol. 315, 159–167 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Nielsen, R. et al. Genome-wide profiling of PPARγ:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev. 22, 2953–2967 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hunter, A. L. et al. Adipocyte NR1D1 dictates adipose tissue expansion during obesity. eLife 10, e63324 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Gan, Z. et al. The nuclear receptor PPARβ/δ programs muscle glucose metabolism in cooperation with AMPK and MEF2. Genes Dev. 25, 2619–2630 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Park, S. et al. ERRα-regulated lactate metabolism contributes to resistance to targeted therapies in breast cancer. Cell Rep. 15, 323–335 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fan, W. & Evans, R. PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr. Opin. Cell Biol. 33, 49–54 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Sladek, R., Bader, J.-A. & Giguère, V. The orphan nuclear receptor estrogen-related receptor α is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol. Cell. Biol. 17, 5400–5409 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Vega, R. B. & Kelly, D. P. A role for estrogen-related receptor α in the control of mitochondrial fatty acid β-oxidation during brown adipocyte differentiation. J. Biol. Chem. 272, 31693–31699 (1997).

    Article  CAS  PubMed  Google Scholar 

  131. Maehara, K. et al. Functional interference between estrogen-related receptor α and peroxisome proliferator-activated receptor α/9-cis-retinoic acid receptor α heterodimer complex in the nuclear receptor response element-1 of the medium chain acyl-coenzyme A dehydrogenase gene. J. Mol. Endocrinol. 31, 47–60 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Gulick, T., Cresci, S., Caira, T., Moore, D. D. & Kelly, D. P. The peroxisome proliferator activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc. Natl Acad. Sci. USA 91, 11012–11016 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Alaynick, W. A. et al. ERRγ directs and maintains the transition to oxidative metabolism in the post-natal heart. Cell Metab. 6, 16–24 (2007).

    Article  Google Scholar 

  134. Huss, J. M., Torra, I. P., Staels, B., Giguère, V. & Kelly, D. P. Estrogen-related receptor α directs peroxisome proliferator-activated receptor α signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol. Cell. Biol. 24, 9079–9091 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Seth, A. et al. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab. 6, 236–245 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dufour, C. R. et al. Genome-wide orchestration of cardiac functions by orphan nucler receptors ERRα and γ. Cell Metab. 5, 345–356 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Ribet, C. et al. Peroxisome proliferator-activated receptor-α control of lipid and glucose metabolism in human white adipocytes. Endocrinology 151, 123–133 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. McMullen, P. D. et al. A map of the PPARα transcription regulatory network for primary human hepatocytes. Chem. Biol. Interact. 209, 14–24 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. He, Y. et al. The role of retinoic acid in hepatic lipid homeostasis defined by genomic binding and transcriptome profiling. BMC Genomics 14, 575 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tanaka, T. et al. Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl Acad. Sci. USA 100, 15924–15929 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Chen, L. et al. HNF4 regulates fatty acid oxidation and Is required for renewal of intestinal stem cells in mice. Gastroenterology 158, 985–999 e989 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Rodriguez, J. C., Ortiz, J. A., Hegardt, F. G. & Haro, D. Chicken ovalbumin upstream-promoter transcription factor (COUP-TF) could act as a transcriptional activator or repressor of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene. Biochem. J. 326, 587–592 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Nakamura, K., Moore, R., Negishi, M. & Sueyoshi, T. Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J. Biol. Chem. 282, 9768–9776 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Chen, F. et al. Metabolomic approaches reveal the role of CAR in energy metabolism. J. Proteome Res. 18, 239–251 (2019).

    CAS  PubMed  Google Scholar 

  145. Rodriguez, J. C., Ortiz, J. A., Hegardt, F. G. & Haro, D. The hepatocyte nuclear factor 4 (HNF-4) represses the mitochondrial HMG-CoA synthase gene. Biochem. Biophys. Res. Commun. 242, 692–696 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Rodriguez, J. C., Gil-Gomez, G., Hegardt, F. G. & Haro, D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J. Biol. Chem. 269, 18767–18772 (1994).

    Article  CAS  PubMed  Google Scholar 

  147. Loft, A. et al. A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis. Cell Metab. 34, 473–486 e479 (2022).

    Article  CAS  PubMed  Google Scholar 

  148. Svensson, K., Albert, V., Cardel, B., Salatino, S. & Handschin, C. Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. FASEB J. 30, 1976–1986 (2016).

    Article  CAS  PubMed  Google Scholar 

  149. Dhillon, P. et al. The nuclear receptor ESRRA protects from kidney disease by coupling metabolism and differentiation. Cell Metab. 33, 379–394 e378 (2021).

    Article  CAS  PubMed  Google Scholar 

  150. Tran, A. et al. Estrogen-related receptor α (ERRα) is a key regulator of intestinal homeostasis and protects against colitis. Sci. Rep. 11, 15073 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sjogren, R. J. O. et al. Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes. Diabetologia 64, 2077–2091 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Contreras, A. V. et al. PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis. Genes Nutr. 10, 452 (2015).

    Article  PubMed  Google Scholar 

  153. Tobon-Cornejo, S. et al. PPARα/RXRα downregulates amino acid catabolism in the liver via interaction with HNF4α promoting its proteasomal degradation. Metabolism 116, 154705 (2021).

    Article  CAS  PubMed  Google Scholar 

  154. Wu, S. P. et al. Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nat. Commun. 6, 8245 (2015).

    Article  PubMed  Google Scholar 

  155. Singh, B. K. et al. Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function. Sci. Signal. 11, eaam5855 (2018).

    Article  PubMed  Google Scholar 

  156. Koenis, D. S. et al. Nuclear receptor Nur77 limits the macrophage inflammatory response through transcriptional reprogramming of mitochondrial metabolism. Cell Rep. 24, 2127–2140 e2127 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Giguère, V. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr. Rev. 29, 677–696 (2008).

    Article  PubMed  Google Scholar 

  158. Eichner, L. J. & Giguère, V. Estrogen related receptors (ERRs): a new dawn in transcriptional control of mitochondrial gene networks. Mitochondrion 11, 544–552 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Sonoda, J. et al. Nuclear receptor ERRα and coactivator PGC-1β are effectors of IFN-γ induced host defense. Genes Dev. 21, 1909–1920 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Villena, J. A. et al. Orphan nuclear receptor estrogen-related receptor α is essential for adaptive thermogenesis. Proc. Natl Acad. Sci. USA 104, 1418–1423 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Eichner, L. J. et al. miR-378* mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway. Cell Metab. 12, 352–361 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Narkar, V. A. et al. Exercise and PGC-1α-independent synchronization of type I muscle metabolism and vasculature by ERRγ. Cell Metab. 13, 283–293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Rangwala, S. M. et al. Estrogen-related receptor γ is a key regulator of muscle mitochondrial activity and oxidative capacity. J. Biol. Chem. 285, 22619–22629 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Cho, Y., Hazen, B. C., Russell, A. P. & Kralli, A. Peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1)- and estrogen-related receptor (ERR)-induced regulator in muscle 1 (Perm1) is a tissue-specific regulator of oxidative capacity in skeletal muscle cells. J. Biol. Chem. 288, 25207–25218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Hong, E.-J., Levasseur, M.-P., Dufour, C. R., Perry, M.-C. & Giguère, V. Loss of estrogen-related receptor α promotes hepatocellular carcinogenesis development via metabolic and inflammatory disturbances. Proc. Natl Acad. Sci. USA 110, 17975–17980 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Pei, L. et al. Dependence of hippocampal function on ERRγ-regulated mitochondrial metabolism. Cell Metab. 21, 628–636 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Audet-Walsh, E. et al. Androgen-dependent repression of ERRγ reprograms metabolism in prostate cancer. Cancer Res. 77, 378–389 (2017).

    Article  CAS  PubMed  Google Scholar 

  168. Gantner, M. L., Hazen, B. C., Eury, E., Brown, E. L. & Kralli, A. Complementary roles of estrogen-related receptors in brown adipocyte thermogenic function. Endocrinology 157, 4770–4781 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Fan, W. et al. PPARδ promotes running endurance by preserving glucose. Cell Metab. 25, 1186–1193 e1184 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Fan, W. et al. ERRγ promotes angiogenesis, mitochondrial biogenesis, and oxidative remodeling in PGC1α/β-deficient muscle. Cell Rep. 22, 2521–2529 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Vega, R. B. & Kelly, D. P. Cardiac nuclear receptors: architects of mitochondrial structure and function. J. Clin. Invest. 127, 1155–1164 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Wang, T. et al. Estrogen-related receptor α (ERRα) and ERRγ are essential coordinators of cardiac metabolism and function. Mol. Cell. Biol. 35, 1281–1298 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Dyar, K. A. et al. Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock. PLoS Biol. 16, e2005886 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  174. DeNicola, G. M. & Cantley, L. C. Cancer’s fuel choice: new flavors for a picky eater. Mol. Cell 60, 514–523 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Vazquez, F. et al. PGC-1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23, 287–301 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. LeBleu, V. S. et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16, 992–1003 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Srivastava, N. et al. Inhibition of cancer cell proliferation by PPARγ is mediated by a metabolic switch that increases reactive oxygen species levels. Cell Metab. 20, 650–661 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Park, S. et al. Inhibition of ERRα prevents mitochondrial pyruvate uptake exposing NADPH-generating pathways as targetable vulnerabilities in breast cancer. Cell Rep. 27, 3587–3601 e3584 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Sies, H. et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-022-00456-z (2022).

    Article  PubMed  Google Scholar 

  181. Scholtes, C. & Giguère, V. Transcriptional regulation of ROS homeostasis by the ERR subfamily of nuclear receptors. Antioxid. (Basel) 10, 437 (2021).

    Article  CAS  Google Scholar 

  182. Vernier, M. et al. Estrogen-related receptors are targetable ROS sensors. Genes Dev. 34, 544–559 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Brown, E. L. et al. Estrogen-related receptors mediate the adaptive response of brown adipose tissue to adrenergic stimulation. iScience 2, 221–237 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Nie, Y. & Wong, C. Suppressing the activity of ERRα in 3T3-L1 adipocytes reduces mitochondrial biogenesis but enhances glycolysis and basal glucose uptake. J. Cell. Mol. Med. 13, 3051–3060 (2009).

    Article  PubMed  Google Scholar 

  185. Schreiber, S. N. et al. The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis. Proc. Natl Acad. Sci. USA 101, 6472–6477 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Chen, X. et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106–1117 (2008).

    Article  CAS  PubMed  Google Scholar 

  187. Koh, J. H. et al. PPARβ Is essential for maintaining normal levels of PGC-1α and mitochondria and for the increase in muscle mitochondria induced by exercise. Cell Metab. 25, 1176–1185 e1175 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Mattingly, K. A. et al. Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis. Mol. Endocrinol. 22, 609–622 (2008).

    Article  CAS  PubMed  Google Scholar 

  189. Li, L. et al. The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism. Cell Metab. 9, 77–87 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Giacomello, M., Pyakurel, A., Glytsou, C. & Scorrano, L. The cell biology of mitochondrial membrane dynamics. Nat. Rev. Mol. Cell Biol. 21, 204–224 (2020).

    Article  CAS  PubMed  Google Scholar 

  191. Choudhary, V. et al. Novel role of androgens in mitochondrial fission and apoptosis. Mol. Cancer Res. 9, 1067–1077 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Kim, H. J. et al. Liver-specific deletion of RORα aggravates diet-induced nonalcoholic steatohepatitis by inducing mitochondrial dysfunction. Sci. Rep. 7, 16041 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Li, Y. et al. Peroxisome proliferator-activated receptor δ regulates mitofusin 2 expression in the heart. J. Mol. Cell. Cardiol. 46, 876–882 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Cartoni, R. et al. Mitofusins 1/2 and ERRα expression are increased in human skeletal muscle after physical exercise. J. Physiol. 567, 349–358 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Soriano, F. X. et al. Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-γ coactivator-1α, estrogen-related receptor-α, and mitofusin 2. Diabetes 55, 1783–1791 (2006).

    Article  CAS  PubMed  Google Scholar 

  196. Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).

    Article  CAS  PubMed  Google Scholar 

  197. Kitada, M. & Koya, D. Autophagy in metabolic disease and ageing. Nat. Rev. Endocrinol. 17, 647–661 (2021).

    Article  PubMed  Google Scholar 

  198. Kim, K. H. et al. Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice. Hepatology 66, 498–509 (2017).

    Article  CAS  PubMed  Google Scholar 

  199. Blessing, A. M. et al. Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression. Autophagy 13, 506–521 (2017).

    Article  CAS  PubMed  Google Scholar 

  200. Mylka, V. et al. The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages. Autophagy 14, 2049–2064 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Silwal, P., Paik, S., Jeon, S. M. & Jo, E. K. Nuclear receptors as autophagy-based antimicrobial therapeutics. Cells 9, 1979 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  202. Lee, D. H. et al. Mir214-3p and Hnf4α/Hnf4α reciprocally regulate Ulk1 expression and autophagy in nonalcoholic hepatic steatosis. Autophagy 17, 2415–2431 (2021).

    Article  CAS  PubMed  Google Scholar 

  203. Seok, S. et al. Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 516, 108–111 (2014). This study identifies FXR as a key physiological switch regulating autophagy via its repression of autophagy genes, resulting in FXR-dependent sustained nutrient regulation of autophagy during feeding–fasting cycles in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Byun, S. et al. A postprandial FGF19-SHP-LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy. EMBO J. 36, 1755–1769 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Sinha, R. A. et al. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J. Clin. Invest. 122, 2428–2438 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Zhou, J. et al. Thyroid hormone receptor α regulates autophagy, mitochondrial biogenesis, and fatty acid use in skeletal muscle. Endocrinology 162, bqab112 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Woldt, E. et al. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat. Med. 19, 1039–1046 (2013). This work reports that REV-ERBα deficiency induces skeletal muscle autophagy and plays a key role in regulating the oxidative capacity of the muscle and exercise endurance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Kim, S. Y. et al. ESRRA (estrogen-related receptor α) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense. Autophagy 14, 152–168 (2018).

    Article  CAS  PubMed  Google Scholar 

  209. Kim, S. et al. ESRRA (estrogen related receptor α) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota. Autophagy 17, 2856–2875 (2021).

    Article  CAS  PubMed  Google Scholar 

  210. Tavera-Mendoza, L. E. et al. Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells. Proc. Natl Acad. Sci. USA 114, E2186–E2194 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Patch, R. J. et al. Indazole-based ligands for estrogen-related receptor α as potential anti-diabetic agents. Eur. J. Med. Chem. 138, 830–853 (2017).

    Article  CAS  PubMed  Google Scholar 

  212. Patch, R. J. et al. Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents. J. Med. Chem. 54, 788–808 (2011).

    Article  CAS  PubMed  Google Scholar 

  213. Baar, K. et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. Federation Am. Societies Exp. Biol. 16, 1879–1886 (2002).

    Article  CAS  Google Scholar 

  214. Wilson, B. J., Tremblay, A. M., Deblois, G., Sylvain-Drolet, G. & Giguère, V. An acetylation switch modulates the transcriptional activity of estrogen-related recetpor α. Mol. Endocrinol. 24, 1349–1358 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Xia, H. et al. Insulin action and resistance is dependent on a GSK3β-FBXW7-ERRα transcriptional axis. Nat. Commun. 13, 2105 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Francque, S. M. et al. A randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH. N. Engl. J. Med. 385, 1547–1558 (2021).

    Article  CAS  PubMed  Google Scholar 

  217. Cariou, B., Charbonnel, B. & Staels, B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends Endocrinol. Metab. 23, 205–215 (2012).

    Article  CAS  PubMed  Google Scholar 

  218. Narkar, V. A. et al. AMPK and PPARδ agonists are exercise mimetic. Cell 134, 405–415 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Fan, W., Atkins, A. R., Yu, R. T., Downes, M. & Evans, R. M. Road to exercise mimetics: targeting nuclear receptors in skeletal muscle. J. Mol. Endocrinol. 51, T87–T100 (2013). Narkar et al. (2008) and Fan et al. (2013) demonstrate and discuss the possibility that orally active drugs targeting nuclear receptors and their coregulators can be used to enhance training adaptation or even to increase endurance without exercise.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptors superfamily. Cell 97, 161–163 (1999).

    Article  Google Scholar 

  221. Giguère, V. Editorial: what’s in a name, or the impact of misnomers in endocrine research. Mol. Endocrinol. 29, 789–790 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Giguère, V., Hollenberg, S. H., Rosenfeld, M. G. & Evans, R. M. Functional domains of the human glucocorticoid receptor. Cell 46, 645–652 (1986).

    Article  PubMed  Google Scholar 

  223. Chandra, V. et al. Structure of the intact PPAR-γ-RXR-α nuclear receptor complex on DNA. Nature 456, 350–356 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Giguère, V. et al. Isoform-specific amino-terminal domains dictate DNA-binding properties of RORα, a novel family of orphan nuclear receptors. Genes Dev. 8, 538–553 (1994).

    Article  PubMed  Google Scholar 

  225. Tremblay, A., Tremblay, G. B., Labrie, F. & Giguère, V. Ligand-independent recruitment of SRC-1 by estrogen receptor b through phosphorylation of activation function AF-1. Mol. Cell 3, 513–519 (1999).

    Article  CAS  PubMed  Google Scholar 

  226. Yu, X. et al. Structural insights of transcriptionally active, full-length androgen receptor coactivator complexes. Mol. Cell 79, 812–823 e814 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Beinsteiner, B. et al. A structural signature motif enlightens the origin and diversification of nuclear receptors. PLoS Genet. 17, e1009492 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Johnson, T. A., Paakinaho, V., Kim, S., Hager, G. L. & Presman, D. M. Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms. Nat. Commun. 12, 1987 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Presman, D. M. et al. DNA binding triggers tetramerization of the glucocorticoid receptor in live cells. Proc. Natl Acad. Sci. USA 113, 8236–8241 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors, RXR, and the Big Bang. Cell 157, 255–266 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Rivers, C. A. et al. Glucocorticoid receptor-tethered mineralocorticoid receptors increase glucocorticoid-induced transcriptional responses. Endocrinology 160, 1044–1056 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. De Bosscher, K., Desmet, S. J., Clarisse, D., Estebanez-Perpina, E. & Brunsveld, L. Nuclear receptor crosstalk - defining the mechanisms for therapeutic innovation. Nat. Rev. Endocrinol. 16, 363–377 (2020).

    Article  PubMed  Google Scholar 

  233. Chandra, V. et al. Multidomain integration in the structure of the HNF-4α nuclear receptor complex. Nature 495, 394–398 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Ellard, S. & Colclough, K. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1α (HNF1A) and 4α (HNF4A) in maturity-onset diabetes of the young. Hum. Mutat. 27, 854–869 (2006).

    Article  CAS  PubMed  Google Scholar 

  235. Tin, A. et al. Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. Nat. Genet. 51, 1459–1474 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Goodman Cancer Institute, McGill University, Montreal, QC, Canada

    Charlotte Scholtes & Vincent Giguère

  2. Department of Biochemistry, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada

    Vincent Giguère

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  1. Charlotte Scholtes
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  2. Vincent Giguère
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The authors contributed equally to all aspects of the article.

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Correspondence to Vincent Giguère.

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Glossary

Ketone bodies

Small, water-soluble circulating lipids produced by the adult liver that have an important role as an energy source during starvation, especially for the brain.

Catabolism

A series of chemical reactions involved in the degradation of complex macromolecules resulting in the production of energy and small molecules. Catabolic reactions are opposed by anabolic reactions, which consume energy, leading to the synthesis of complex macromolecules from small molecules.

Redox

Abbreviation for ‘reduction–oxidation’. Refers to a chemical reaction in which the oxidation states of atoms are changed. Oxidation is an increase in oxidation state, and reduction is a decrease in oxidation state. Redox homeostasis is the regulation of reactive oxygen species formation and removal inside the cell.

Autophagy

A lysosome-dependent catabolic process whereby cytoplasmic components are degraded and recycled. Autophagy plays an essential role in maintaining cellular energy homeostasis in response to intracellular stress.

DNase I hypersensitive site sequencing

A molecular biology technique used to identify the location of regulatory regions, based on the genome-wide sequencing of regions sensitive to cleavage by DNase I.

Assay for transposase-accessible chromatin using sequencing

A molecular biology technique used to assess genome-wide chromatin accessibility.

Pioneer factors

A class of transcription factors that can associate with compacted chromatin to facilitate the binding of additional transcription factors.

Maturity-onset diabetes of the young, type 1

A rare hereditary form of diabetes caused by a loss-of-function mutation in the HNF4A gene that usually develops in adolescence or early adulthood. It causes high blood glucose levels from reduced production of insulin.

Mediator complex

A multiprotein complex that mediates the interaction between transcription factors, coregulators and the general transcription machinery.

Chromatin immunoprecipitation followed by deep sequencing

(ChIP–seq). Molecular biology technique used to globally identify the binding sites of DNA-associated proteins in a genome.

High-throughput chromosome conformation capture

(Hi-C). A chromosome conformation capture technique used to analyse the spatial organization of chromatin in a cell. Hi-C quantifies the number of interactions between genomic loci that are adjacent in three-dimensional space but separated by lengthy DNA segments in the linear genome.

Global run-on followed by sequencing

A molecular biology technique used to identify the genes that are being actively transcribed. It provides a detailed catalogue of genes engaged in transcription with quantitative levels of expression.

Superenhancers

A group of enhancers located close to each other (less than 12 kb) in the genome and functionally linked together by the mediator complex.

Sirtuin

Evolutionarily conserved family of epigenetic regulators that modulate the activity of their targets by removing covalently attached acetyl groups. They are metabolic sensors sensitive to NAD+ levels that maintain physiological homeostasis.

General control non-depressible 5

(GCN5). Catalytic subunit of several histone acetyltransferase (HAT) complexes reported to play a range of different functions associated with transcription.

One-carbon metabolism

A group of reactions with a set of enzymes that have in common the transfer of one-carbon groups and that play a role in multiple physiological processes, such as biosynthesis, amino acid homeostasis or epigenetic maintenance.

Brown fat

A type of fat tissue very rich in mitochondria that plays a central role in regulating whole-body energy homeostasis and temperature by its capacity to dissipate macronutrient energy as heat.

Regulon

Group of several genes that are activated or inactivated in response to the same signal by the same regulatory protein.

Metabolic flexibility

The capacity to alter metabolism in response to exercise or available fuel. An organism displays metabolic flexibility if it is capable of metabolizing either carbohydrate or fat efficiently, depending on the availability of those fuels. Metabolic inflexibility is the inability to generate enough energy in response to physiological demands.

Slow twitch muscle type

One of the two main types of muscle fibres. This type contains more mitochondria and depends on aerobic respiration. Their role is sustained, smaller movements and postural control.

Reactive oxygen species

(ROS). Reactive molecules and free radicals or non-radicals derived from molecular oxygen.

Free radical

A chemical species unstable with unpaired electrons.

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Scholtes, C., Giguère, V. Transcriptional control of energy metabolism by nuclear receptors. Nat Rev Mol Cell Biol 23, 750–770 (2022). https://doi.org/10.1038/s41580-022-00486-7

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