Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).
Stanford, K.I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).
Berbée, J.F. et al. Brown fat activation reduces hypercholesterolemia and protects from atherosclerosis development. Nat. Commun. 6, 6356 (2015).
Bartelt, A. et al. Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport. Nat. Commun. 8, 15010 (2017).
Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).
Kajimura, S., Spiegelman, B.M. & Seale, P. Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559 (2015).
Gnad, T. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516, 395–399 (2014).
Rothwell, N.J. & Stock, M.J. A role for brown adipose tissue in diet-induced thermogenesis. Nature 281, 31–35 (1979).
Feldmann, H.M., Golozoubova, V., Cannon, B. & Nedergaard, J. Ucp1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 9, 203–209 (2009).
Shimizu, I. et al. Vascular rarefaction mediates whitening of brown fat in obesity. J. Clin. Invest. 124, 2099–2112 (2014).
Cypess, A.M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).
Travers, K.J. et al. Functional and genomic analyses reveal an essential coordination between the unfolded-protein response and ER-associated degradation. Cell 101, 249–258 (2000).
Friedlander, R., Jarosch, E., Urban, J., Volkwein, C. & Sommer, T. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat. Cell Biol. 2, 379–384 (2000).
Goldberg, A.L. Protein degradation and protection against misfolded or damaged proteins. Nature 426, 895–899 (2003).
Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded-protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).
Hotamisligil, G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900–917 (2010).
Yang, L. et al. METABOLISM. S-nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 349, 500–506 (2015).
Otoda, T. et al. Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver. Diabetes 62, 811–824 (2013).
Wikstrom, J.D. et al. Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. EMBO J. 33, 418–436 (2014).
Arruda, A.P. et al. Chronic enrichment of hepatic endoplasmic reticulum–mitochondria contact leads to mitochondrial dysfunction in obesity. Nat. Med. 20, 1427–1435 (2014).
Gregor, M.F. et al. The role of adipocyte XBP1 in metabolic regulation during lactation. Cell Rep. 3, 1430–1439 (2013).
Wang, W. & Chan, J.Y. Nrf1 is targeted to the endoplasmic reticulum membrane by an N-terminal transmembrane domain. Inhibition of nuclear translocation and transacting function. J. Biol. Chem. 281, 19676–19687 (2006).
Cannon, B. & Nedergaard, J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J. Exp. Biol. 214, 242–253 (2011).
Adams, J. et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 59, 2615–2622 (1999).
Sha, Z. & Goldberg, A.L. Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97. Curr. Biol. 24, 1573–1583 (2014).
Arastu-Kapur, S. et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin. Cancer Res. 17, 2734–2743 (2011).
Fu, S. et al. Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded-protein response with antidiabetic activity. Sci. Transl. Med. 7, 292ra98 (2015).
Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action and type 2 diabetes. Science 306, 457–461 (2004).
Steffen, J., Seeger, M., Koch, A. & Krüger, E. Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol. Cell 40, 147–158 (2010).
Radhakrishnan, S.K. et al. Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol. Cell 38, 17–28 (2010).
Kahn, N.W., Rea, S.L., Moyle, S., Kell, A. & Johnson, T.E. Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans. Biochem. J. 409, 205–213 (2008).
Xue, R. et al. Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes. Nat. Med. 21, 760–768 (2015).
Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 (2014).
Peirce, V., —, S. & Vidal-Puig, A. The different shades of fat. Nature 510, 76–83 (2014).
Rosen, E.D. & Spiegelman, B.M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).
Bruns, O.T. et al. Next-generation in vivo optical imaging with shortwave infrared quantum dots. Nat. Biomed. Eng. 1 (2017).
Hershko, A. & Ciechanover, A. The ubiquitin system for protein degradation. Annu. Rev. Biochem. 61, 761–807 (1992).
Kulathu, Y. & Komander, D. Atypical ubiquitylation—the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat. Rev. Mol. Cell Biol. 13, 508–523 (2012).
Kim, W. et al. Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol. Cell 44, 325–340 (2011).
Wagner, S.A. et al. A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol. Cell Proteomics 10, M111.013284 (2011).
Mootha, V.K. et al. Integrated analysis of protein composition, tissue diversity and gene regulation in mouse mitochondria. Cell 115, 629–640 (2003).
Clarke, K.J. et al. A role for ubiquitinylation and the cytosolic proteasome in turnover of mitochondrial uncoupling protein 1 (UCP1). Biochim. Biophys. Acta 1817, 1759–1767 (2012).
Mootha, V.K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).
Kamburov, A. et al. ConsensusPathDB: toward a more complete picture of cell biology. Nucleic Acids Res. 39, D712–D717 (2011).
Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).
Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).
Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor–α: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
Kim, J.Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).
Li, J. et al. Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia–reperfusion injury in mice. J. Clin. Invest. 121, 3689–3700 (2011).
Zhang, Y. et al. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513, 440–443 (2014).
Lee, C.S., Ho, D.V. & Chan, J.Y. Nuclear factor–erythroid-2-related factor 1 regulates expression of proteasome genes in hepatocytes and protects against endoplasmic reticulum stress and steatosis in mice. FEBS J. 280, 3609–3620 (2013).
Wahl, S. et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 541, 81–86 (2017).
Zhang, Y. & Xiang, Y. Molecular and cellular basis for the unique functioning of Nrf1, an indispensable transcription factor for maintaining cell homoeostasis and organ integrity. Biochem. J. 473, 961–1000 (2016).
Widenmaier, S.B. et al. NRF1 is an ER membrane sensor that is central to cholesterol homeostasis. Cell 171, 1094–1109 (2017).
Tsujita, T. et al. Discovery of an NRF1-specific inducer from a large-scale chemical library using a direct NRF1–protein monitoring system. Genes Cells 20, 563–577 (2015).
Li, F., Gao, B., Dong, H., Shi, J. & Fang, D. Icariin induces synoviolin expression through NFE2L1 to protect neurons from ER-stress-induced apoptosis. PLoS One 10, e0119955 (2015).
Kong, X. et al. IRF4 is a key thermogenic transcriptional partner of PGC-1α. Cell 158, 69–83 (2014).
Tschöp, M.H. et al. A guide to analysis of mouse energy metabolism. Nat. Methods 9, 57–63 (2011).
Cypess, A.M. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat. Med. 19, 635–639 (2013).
Rodbell, M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J. Biol. Chem. 239, 375–380 (1964).
Brand, M.D. & Nicholls, D.G. Assessing mitochondrial dysfunction in cells. Biochem. J. 435, 297–312 (2011).
Cannon, B. & Nedergaard, J. Studies of thermogenesis and mitochondrial function in adipose tissues. Methods Mol. Biol. 456, 109–121 (2008).
Orr, A.L., Quinlan, C.L., Perevoshchikova, I.V. & Brand, M.D. A refined analysis of superoxide production by mitochondrial sn-glycerol 3-phosphate dehydrogenase. J. Biol. Chem. 287, 42921–42935 (2012).
Haemmerle, G. et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312, 734–737 (2006).
Luo, J. et al. A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat. Protoc. 2, 1236–1247 (2007).