Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3

Nature Metabolism volume 2, pages 620–634 (2020)Cite this article

Subjects

Abstract

Catecholamines stimulate the mobilization of stored triglycerides in adipocytes to provide fatty acids (FAs) for other tissues. However, a large proportion is taken back up and either oxidized or re-esterified. What controls the disposition of these FAs in adipocytes remains unknown. Here, we report that catecholamines redirect FAs for oxidation through the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Adipocyte STAT3 is phosphorylated upon activation of β-adrenergic receptors, and in turn suppresses FA re-esterification to promote FA oxidation. Adipocyte-specific Stat3 KO mice exhibit normal rates of lipolysis, but exhibit defective lipolysis-driven oxidative metabolism, resulting in reduced energy expenditure and increased adiposity when they are on a high-fat diet. This previously unappreciated, non-genomic role of STAT3 explains how sympathetic activation can increase both lipolysis and FA oxidation in adipocytes, revealing a new regulatory axis in metabolism.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: STAT3 is phosphorylated in response to β-adrenergic receptor activation in adipocytes.
Fig. 2: Localization and phosphorylation of STAT3 in catecholamine-stimulated adipocytes.
Fig. 3: Adipocyte STAT3 protects against diet-induced obesity.
Fig. 4: Loss of adipocyte STAT3 causes a defect in oxidative metabolism in vivo.
Fig. 5: Loss of adipocyte STAT3 causes a cell-autonomous defect in lipolysis-driven oxidative metabolism.
Fig. 6: The effect of STAT3 on adipocyte oxidative metabolism is non-genomic and non-mitochondrial.
Fig. 7: STAT3 suppresses FA re-esterification in adipocytes.
Fig. 8: Regulation of FA disposition by STAT3.

Data availability

The RNA-sequencing data reported in this paper have been deposited in the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database under accession code PRJNA557252. All additional data that support the findings of this study are available within the manuscript or supplement and from the corresponding author upon request.

References

  1. James, P. T., Leach, R., Kalamara, E. & Shayeghi, M. The worldwide obesity epidemic. Obes. Res. 9, 228S–233S (2001).

    Google Scholar 

  2. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech. Rep. Ser. 894, i–xii, 1–253 (2000).

  3. Swinburn, B. A. et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet 378, 804–814 (2011).

    PubMed  Google Scholar 

  4. Kennedy, E. P. Biosynthesis of complex lipids. Fed. Proc. 20, 934–940 (1961).

    CAS  PubMed  Google Scholar 

  5. Weiss, S. B., Kennedy, E. P. & Kiyasu, J. Y. The enzymatic synthesis of triglycerides. J. Biol. Chem. 235, 40–44 (1960).

    CAS  PubMed  Google Scholar 

  6. Wendel, A. A., Lewin, T. M. & Coleman, R. A. Glycerol-3-phosphate acyltransferases: rate limiting enzymes of triacylglycerol biosynthesis. Biochim. Biophys. Acta 1791, 501–506 (2009).

    CAS  PubMed  Google Scholar 

  7. Gimeno, R. E. & Cao, J. Thematic review series: glycerolipids. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity. J. Lipid Res. 49, 2079–2088 (2008).

    CAS  PubMed  Google Scholar 

  8. Wilfling, F. et al. Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev. Cell 24, 384–399 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang, H. et al. Seipin is required for converting nascent to mature lipid droplets. eLife 5, e.16582 (2016).

    Google Scholar 

  10. Pagac, M. et al. SEIPIN regulates lipid droplet expansion and adipocyte development by modulating the activity of glycerol-3-phosphate acyltransferase. Cell Rep. 17, 1546–1559 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Cao, J., Li, J. L., Li, D., Tobin, J. F. & Gimeno, R. E. Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase, a key enzyme in de novo triacylglycerol synthesis. Proc. Natl Acad. Sci. USA 103, 19695–19700 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen, Y. Q. et al. AGPAT6 is a novel microsomal glycerol-3-phosphate acyltransferase. J. Biol. Chem. 283, 10048–10057 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Nagle, C. A. et al. Identification of a novel sn-glycerol-3-phosphate acyltransferase isoform, GPAT4, as the enzyme deficient in Agpat6 –/– mice. J. Lipid Res. 49, 823–831 (2008).

    CAS  PubMed  Google Scholar 

  14. Monroy, G., Kelker, H. C. & Pullman, M. E. Partial purification and properties of an acyl coenzyme A:sn-glycerol 3-phosphate acyltransferase from rat liver mitochondria. J. Biol. Chem. 248, 2845–2852 (1973).

    CAS  PubMed  Google Scholar 

  15. Yet, S. F., Lee, S., Hahm, Y. T. & Sul, H. S. Expression and identification of p90 as the murine mitochondrial glycerol-3-phosphate acyltransferase. Biochemistry 32, 9486–9491 (1993).

    CAS  PubMed  Google Scholar 

  16. Ganesh Bhat, B. et al. Rat sn-glycerol-3-phosphate acyltransferase: molecular cloning and characterization of the cDNA and expressed protein. Biochim. Biophys. Acta 1439, 415–423 (1999).

    CAS  PubMed  Google Scholar 

  17. Harada, N. et al. Molecular cloning of a murine glycerol-3-phosphate acyltransferase-like protein 1 (xGPAT1). Mol. Cell Biochem. 297, 41–51 (2007).

    CAS  PubMed  Google Scholar 

  18. Shan, D. et al. GPAT3 and GPAT4 are regulated by insulin-stimulated phosphorylation and play distinct roles in adipogenesis. J. Lipid Res. 51, 1971–1981 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cao, J. et al. Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity. Am. J. Physiol. Endocrinol. Metab. 306, E1176–E1187 (2014).

    CAS  PubMed  Google Scholar 

  20. Wendel, A. A., Cooper, D. E., Ilkayeva, O. R., Muoio, D. M. & Coleman, R. A. Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation. J. Biol. Chem. 288, 27299–27306 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cooper, D. E., Grevengoed, T. J., Klett, E. L. & Coleman, R. A. Glycerol-3-phosphate acyltransferase Isoform-4 (GPAT4) limits oxidation of exogenous fatty acids in brown adipocytes. J. Biol. Chem. 290, 15112–15120 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Agarwal, A. K. et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat. Genet. 31, 21–23 (2002).

    CAS  PubMed  Google Scholar 

  23. Akinci, B., Meral, R. & Oral, E. A. Phenotypic and genetic characteristics of lipodystrophy: pathophysiology, metabolic abnormalities, and comorbidities. Curr. Diab. Rep. 18, 143 (2018).

    PubMed  Google Scholar 

  24. Garg, A. & Misra, A. Lipodystrophies: rare disorders causing metabolic syndrome. Endocrinol. Metab. Clin. North. Am. 33, 305–331 (2004).

    CAS  PubMed  Google Scholar 

  25. Alberti, K. G., Zimmet, P., Shaw, J. & Group, I. D. F. E. T. F. C. The metabolic syndrome—a new worldwide definition. Lancet 366, 1059–1062 (2005).

    PubMed  Google Scholar 

  26. Eckel, R. H., Grundy, S. M. & Zimmet, P. Z. The metabolic syndrome. Lancet 365, 1415–1428 (2005).

    CAS  PubMed  Google Scholar 

  27. White, J. E. & Engel, F. L. A lipolytic action of epinephrine and norepinephrine on rat adipose tissue in vitro. Proc. Soc. Exp. Biol. Med. 99, 375–378 (1958).

    CAS  PubMed  Google Scholar 

  28. Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).

    CAS  PubMed  Google Scholar 

  29. Bartness, T. J. & Song, C. K. Thematic review series: adipocyte biology. Sympathetic and sensory innervation of white adipose tissue. J. Lipid Res. 48, 1655–1672 (2007).

    CAS  PubMed  Google Scholar 

  30. Youngstrom, T. G. & Bartness, T. J. Catecholaminergic innervation of white adipose tissue in Siberian hamsters. Am. J. Physiol. 268, R744–R751 (1995).

    CAS  PubMed  Google Scholar 

  31. Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H. S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lafontan, M. & Langin, D. Lipolysis and lipid mobilization in human adipose tissue. Prog. Lipid Res. 48, 275–297 (2009).

    CAS  PubMed  Google Scholar 

  33. Jocken, J. W. & Blaak, E. E. Catecholamine-induced lipolysis in adipose tissue and skeletal muscle in obesity. Physiol. Behav. 94, 219–230 (2008).

    CAS  PubMed  Google Scholar 

  34. Czech, M. P., Tencerova, M., Pedersen, D. J. & Aouadi, M. Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 56, 949–964 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Haemmerle, G. et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312, 734–737 (2006).

    CAS  PubMed  Google Scholar 

  36. Zimmermann, R. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383–1386 (2004).

    CAS  PubMed  Google Scholar 

  37. Vaughan, M. The production and release of glycerol by adipose tissue incubated in vitro. J. Biol. Chem. 237, 3354–3358 (1962).

    CAS  PubMed  Google Scholar 

  38. Jensen, M. D., Ekberg, K. & Landau, B. R. Lipid metabolism during fasting. Am. J. Physiol. Endocrinol. Metab. 281, E789–E793 (2001).

    CAS  PubMed  Google Scholar 

  39. Ballard, F. J., Hanson, R. W. & Leveille, G. A. Phosphoenolpyruvate carboxykinase and the synthesis of glyceride-glycerol from pyruvate in adipose tissue. J. Biol. Chem. 242, 2746–2750 (1967).

    CAS  PubMed  Google Scholar 

  40. Reshef, L., Hanson, R. W. & Ballard, F. J. A possible physiological role for glyceroneogenesis in rat adipose tissue. J. Biol. Chem. 245, 5979–5984 (1970).

    CAS  PubMed  Google Scholar 

  41. Gorin, E., Tal-Or, Z. & Shafrir, E. Glyceroneogenesis in adipose tissue of fasted, diabetic and triamcinolone treated rats. Eur. J. Biochem. 8, 370–375 (1969).

    CAS  PubMed  Google Scholar 

  42. Elia, M., Zed, C., Neale, G. & Livesey, G. The energy cost of triglyceride-fatty acid recycling in nonobese subjects after an overnight fast and four days of starvation. Metabolism 36, 251–255 (1987).

    CAS  PubMed  Google Scholar 

  43. Reshef, L. et al. Glyceroneogenesis and the triglyceride/fatty acid cycle. J. Biol. Chem. 278, 30413–30416 (2003).

    CAS  PubMed  Google Scholar 

  44. Edens, N. K., Leibel, R. L. & Hirsch, J. Mechanism of free fatty acid re-esterification in human adipocytes in vitro. J. Lipid Res. 31, 1423–1431 (1990).

    CAS  PubMed  Google Scholar 

  45. Vaughan, M. & Steinberg, D. Effect of hormones on lipolysis and esterification of free fatty acids during incubation of adipose tissue in vitro. J. Lipid Res. 4, 193–199 (1963).

    CAS  PubMed  Google Scholar 

  46. Brooks, B., Arch, J. R. & Newsholme, E. A. Effects of hormones on the rate of the triacylglycerol/fatty acid substrate cycle in adipocytes and epididymal fat pads. FEBS Lett. 146, 327–330 (1982).

    CAS  PubMed  Google Scholar 

  47. Bjorntorp, P., Karlsson, M. & Hovden, A. Quantitative aspects of lipolysis and reesterification in human adipose tissue in vitro. Acta Med. Scand. 185, 89–97 (1969).

    CAS  PubMed  Google Scholar 

  48. Carnicero, H. H. Changes in the metabolism of long chain fatty acids during adipose differentiation of 3T3 L1 cells. J. Biol. Chem. 259, 3844–3850 (1984).

    CAS  PubMed  Google Scholar 

  49. Yehuda-Shnaidman, E., Buehrer, B., Pi, J., Kumar, N. & Collins, S. Acute stimulation of white adipocyte respiration by PKA-induced lipolysis. Diabetes 59, 2474–2483 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Goldstein, D. S., Eisenhofer, G. & Kopin, I. J. Sources and significance of plasma levels of catechols and their metabolites in humans. J. Pharmacol. Exp. Ther. 305, 800–811 (2003).

    CAS  PubMed  Google Scholar 

  51. Cannon, W. B. & de la Paz, D. Emotional stimulation of adrenal secretion. Am. J. Physiol. 28, 64–70 (1911).

    CAS  Google Scholar 

  52. Ahmadian, M., Wang, Y. & Sul, H. S. Lipolysis in adipocytes. Int. J. Biochem. Cell Biol. 42, 555–559 (2010).

    CAS  PubMed  Google Scholar 

  53. Scheurink, A. J. et al. Sympathoadrenal influence on glucose, FFA, and insulin levels in exercising rats. Am. J. Physiol. 256, R161–R168 (1989).

    CAS  PubMed  Google Scholar 

  54. Egan, J. J. et al. Mechanism of hormone-stimulated lipolysis in adipocytes: translocation of hormone-sensitive lipase to the lipid storage droplet. Proc. Natl Acad. Sci. USA 89, 8537–8541 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Steinberg, D. Hormonal control of lipolysis in adipose tissue. Adv. Exp. Med. Biol. 26, 77–88 (1972).

    CAS  PubMed  Google Scholar 

  56. Garton, A. J., Campbell, D. G., Cohen, P. & Yeaman, S. J. Primary structure of the site on bovine hormone-sensitive lipase phosphorylated by cyclic AMP-dependent protein kinase. FEBS Lett. 229, 68–72 (1988).

    CAS  PubMed  Google Scholar 

  57. Anthonsen, M. W., Ronnstrand, L., Wernstedt, C., Degerman, E. & Holm, C. Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. J. Biol. Chem. 273, 215–221 (1998).

    CAS  PubMed  Google Scholar 

  58. Sztalryd, C. et al. Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation. J. Cell Biol. 161, 1093–1103 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Miyoshi, H. et al. Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms. J. Biol. Chem. 281, 15837–15844 (2006).

    CAS  PubMed  Google Scholar 

  60. Brasaemle, D. L. Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis. J. Lipid Res. 48, 2547–2559 (2007).

    CAS  PubMed  Google Scholar 

  61. Carmen, G. Y. & Victor, S. M. Signalling mechanisms regulating lipolysis. Cell Signal 18, 401–408 (2006).

    CAS  PubMed  Google Scholar 

  62. Mohamed-Ali, V. et al. β-Adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies. J. Clin. Endocrinol. Metab. 86, 5864–5869 (2001).

    CAS  PubMed  Google Scholar 

  63. Tchivileva, I. E. et al. Signaling pathways mediating β3-adrenergic receptor-induced production of interleukin-6 in adipocytes. Mol. Immunol. 46, 2256–2266 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Yin, F. et al. Noncanonical cAMP pathway and p38 MAPK mediate β2-adrenergic receptor-induced IL-6 production in neonatal mouse cardiac fibroblasts. J. Mol. Cell Cardiol. 40, 384–393 (2006).

    CAS  PubMed  Google Scholar 

  65. Reilly, S. M. et al. A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis. Nat. Commun. 6, 6047 (2015).

    CAS  PubMed  Google Scholar 

  66. Saini, A. et al. Interleukin-6 in combination with the interleukin-6 receptor stimulates glucose uptake in resting human skeletal muscle independently of insulin action. Diabetes Obes. Metab. 16, 931–936 (2014).

  67. Carey, A. L. et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688–2697 (2006).

    CAS  PubMed  Google Scholar 

  68. Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).

    CAS  PubMed  Google Scholar 

  69. Mauer, J. et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15, 423–430 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Braune, J. et al. IL-6 regulates M2 polarization and local proliferation of adipose tissue macrophages in obesity. J. Immunol. 198, 2927–2934 (2017).

    CAS  PubMed  Google Scholar 

  71. Kern, P. A., Ranganathan, S., Li, C., Wood, L. & Ranganathan, G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 280, E745–E751 (2001).

    CAS  PubMed  Google Scholar 

  72. Bastard, J. P. et al. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J. Clin. Endocrinol. Metab. 87, 2084–2089 (2002).

    CAS  PubMed  Google Scholar 

  73. Pradhan, A. D., Manson, J. E., Rifai, N., Buring, J. E. & Ridker, P. M. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286, 327–334 (2001).

    CAS  PubMed  Google Scholar 

  74. Rotter, V., Nagaev, I. & Smith, U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J. Biol. Chem. 278, 45777–45784 (2003).

    CAS  PubMed  Google Scholar 

  75. van Hall, G. et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J. Clin. Endocrinol. Metab. 88, 3005–3010 (2003).

    PubMed  Google Scholar 

  76. Path, G. et al. Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function. J. Clin. Endocrinol. Metab. 86, 2281–2288 (2001).

    CAS  PubMed  Google Scholar 

  77. Ji, C. et al. IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytes. J. Bioenerg. Biomembr. 43, 367–375 (2011).

    CAS  PubMed  Google Scholar 

  78. Nahmias, C. et al. Molecular characterization of the mouse beta 3-adrenergic receptor: relationship with the atypical receptor of adipocytes. EMBO J. 10, 3721–3727 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    CAS  PubMed  Google Scholar 

  80. Krief, S. et al. Tissue distribution of beta 3-adrenergic receptor mRNA in man. J. Clin. Invest. 91, 344–349 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Guschin, D. et al. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 14, 1421–1429 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Schindler, C., Levy, D. E. & Decker, T. JAK–STAT signaling: from interferons to cytokines. J. Biol. Chem. 282, 20059–20063 (2007).

    CAS  PubMed  Google Scholar 

  83. Wegrzyn, J. et al. Function of mitochondrial Stat3 in cellular respiration. Science 323, 793–797 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Gough, D. J. et al. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324, 1713–1716 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang, Q. et al. Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J. Biol. Chem. 288, 31280–31288 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Wen, Z., Zhong, Z. & Darnell, J. E. Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241–250 (1995).

    CAS  PubMed  Google Scholar 

  87. Aznar, S. et al. Simultaneous tyrosine and serine phosphorylation of STAT3 transcription factor is involved in Rho A GTPase oncogenic transformation. Mol. Biol. Cell 12, 3282–3294 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Heinrich, P. C., Behrmann, I., Muller-Newen, G., Schaper, F. & Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J. 334(Pt 2), 297–314 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Chrencik, J. E. et al. Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J. Mol. Biol. 400, 413–433 (2010).

    CAS  PubMed  Google Scholar 

  90. Taura, M. et al. TLR3 induction by anticancer drugs potentiates poly I:C-induced tumor cell apoptosis. Cancer Sci. 101, 1610–1617 (2010).

    CAS  PubMed  Google Scholar 

  91. Chijiwa, T. et al. Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J. Biol. Chem. 265, 5267–5272 (1990). .

  92. Liu, A. M. et al. Activation of STAT3 by G alpha(s) distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase. J. Biol. Chem. 281, 35812–35825 (2006).

    CAS  PubMed  Google Scholar 

  93. Songyang, Z. et al. Use of an oriented peptide library to determine the optimal substrates of protein kinases. Curr. Biol. 4, 973–982 (1994).

    CAS  PubMed  Google Scholar 

  94. Chung, J., Uchida, E., Grammer, T. C. & Blenis, J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol. Cell Biol. 17, 6508–6516 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Lo, R. K., Cheung, H. & Wong, Y. H. Constitutively active Gα16 stimulates STAT3 via a c-Src/JAK- and ERK-dependent mechanism. J. Biol. Chem. 278, 52154–52165 (2003).

    CAS  PubMed  Google Scholar 

  96. Lo, R. K. & Wong, Y. H. Signal transducer and activator of transcription 3 activation by the delta-opioid receptor via Gα14 involves multiple intermediates. Mol. Pharmacol. 65, 1427–1439 (2004).

    CAS  PubMed  Google Scholar 

  97. Fung, M. M., Rohwer, F. & McGuire, K. L. IL-2 activation of a PI3K-dependent STAT3 serine phosphorylation pathway in primary human T cells. Cell Signal 15, 625–636 (2003).

    CAS  PubMed  Google Scholar 

  98. Ng, J. & Cantrell, D. STAT3 is a serine kinase target in T lymphocytes. Interleukin 2 and T cell antigen receptor signals converge upon serine 727. J. Biol. Chem. 272, 24542–24549 (1997).

    CAS  PubMed  Google Scholar 

  99. Su, L., Rickert, R. C. & David, M. Rapid STAT phosphorylation via the B cell receptor. Modulatory role of CD19. J. Biol. Chem. 274, 31770–31774 (1999).

    CAS  PubMed  Google Scholar 

  100. Turkson, J. et al. Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol. Cell Biol. 19, 7519–7528 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Stephens, J. M., Lumpkin, S. J. & Fishman, J. B. Activation of signal transducers and activators of transcription 1 and 3 by leukemia inhibitory factor, oncostatin-M, and interferon-gamma in adipocytes. J. Biol. Chem. 273, 31408–31416 (1998).

    CAS  PubMed  Google Scholar 

  102. Moule, S. K. & Denton, R. M. The activation of p38 MAPK by the beta-adrenergic agonist isoproterenol in rat epididymal fat cells. FEBS Lett. 439, 287–290 (1998).

    CAS  PubMed  Google Scholar 

  103. Cao, W., Medvedev, A. V., Daniel, K. W. & Collins, S. β-Adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase. J. Biol. Chem. 276, 27077–27082 (2001).

    CAS  PubMed  Google Scholar 

  104. Cuenda, A. et al. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 364, 229–233 (1995).

    CAS  PubMed  Google Scholar 

  105. Wesselborg, S., Bauer, M. K., Vogt, M., Schmitz, M. L. & Schulze-Osthoff, K. Activation of transcription factor NF-κB and p38 mitogen-activated protein kinase is mediated by distinct and separate stress effector pathways. J. Biol. Chem. 272, 12422–12429 (1997).

    CAS  PubMed  Google Scholar 

  106. Davis, R. J. & Martin, B. R. The effect of beta-adrenergic agonists on the membrane potential of fat-cell mitochondria in situ. Biochem. J. 206, 611–618 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhang, K., Guo, W., Yang, Y. & Wu, J. JAK2/STAT3 pathway is involved in the early stage of adipogenesis through regulating C/EBPbeta transcription. J. Cell Biochem. 112, 488–497 (2011).

    CAS  PubMed  Google Scholar 

  108. Wang, D. et al. Signal transducer and activator of transcription 3 (STAT3) regulates adipocyte differentiation via peroxisome-proliferator-activated receptor gamma (PPARγ). Biol. Cell 102, 1–12 (2010).

    CAS  Google Scholar 

  109. Richard, A. J. & Stephens, J. M. The role of JAK–STAT signaling in adipose tissue function. Biochim. Biophys. Acta 1842, 431–439 (2014).

    CAS  PubMed  Google Scholar 

  110. Eguchi, J. et al. Transcriptional control of adipose lipid handling by IRF4. Cell Metab. 13, 249–259 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Lee, K. Y. et al. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes 62, 864–874 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Cernkovich, E. R., Deng, J., Bond, M. C., Combs, T. P. & Harp, J. B. Adipose-specific disruption of signal transducer and activator of transcription 3 increases body weight and adiposity. Endocrinology 149, 1581–1590 (2008).

    CAS  PubMed  Google Scholar 

  113. Atgie, C., Faintrenie, G., Carpene, C., Bukowiecki, L. J. & Geloen, A. Effects of chronic treatment with noradrenaline or a specific β3-adrenergic agonist, CL 316 243, on energy expenditure and epididymal adipocyte lipolytic activity in rat. Comp. Biochem. Physiol. A: Mol. Integr. Physiol. 119, 629–636 (1998).

    CAS  Google Scholar 

  114. Weyer, C., Tataranni, P. A., Snitker, S., Danforth, E. Jr. & Ravussin, E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective β3-adrenoceptor agonist in humans. Diabetes 47, 1555–1561 (1998).

    CAS  PubMed  Google Scholar 

  115. Fisher, M. H. et al. A selective human β3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys. J. Clin. Invest. 101, 2387–2393 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Carbognin, E., Betto, R. M., Soriano, M. E., Smith, A. G. & Martello, G. Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency. EMBO J. 35, 618–634 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang, W. et al. Critical roles of STAT3 in β-adrenergic functions in the heart. Circulation 133, 48–61 (2016).

    PubMed  Google Scholar 

  118. Demaria, M. et al. A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction. Aging (Albany NY) 2, 823–842 (2010).

    CAS  Google Scholar 

  119. Wang, T. et al. JAK/STAT3-regulated fatty acid beta-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 27, 136–150 (2018).

    CAS  PubMed  Google Scholar 

  120. Wydysh, E. A., Medghalchi, S. M., Vadlamudi, A. & Townsend, C. A. Design and synthesis of small molecule glycerol 3-phosphate acyltransferase inhibitors. J. Med. Chem. 52, 3317–3327 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Levy, D. E., Kessler, D. S., Pine, R. & Darnell, J. E. Jr. Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Dev 3, 1362–1371 (1989).

    CAS  PubMed  Google Scholar 

  122. Wang, S. et al. Cloning and functional characterization of a novel mitochondrial N-ethylmaleimide-sensitive glycerol-3-phosphate acyltransferase (GPAT2). Arch. Biochem. Biophys. 465, 347–358 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Babaei, R. et al. Jak–TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis. Sci. Signal 11, eaai7838 (2018).

    PubMed  Google Scholar 

  124. Khatun, I. et al. Characterization of a novel intestinal glycerol-3-phosphate acyltransferase pathway and its role in lipid homeostasis. J. Biol. Chem. 291, 2602–2615 (2016).

    CAS  PubMed  Google Scholar 

  125. Kuhajda, F. P. et al. Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R116–R130 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. McFadden, J. W. et al. Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation. PLoS ONE 9, e115642 (2014).

    PubMed  PubMed Central  Google Scholar 

  127. Franckhauser, S. et al. Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance. Diabetes 51, 624–630 (2002).

    CAS  PubMed  Google Scholar 

  128. Macias, E., Rao, D., Carbajal, S., Kiguchi, K. & DiGiovanni, J. Stat3 binds to mtDNA and regulates mitochondrial gene expression in keratinocytes. J. Invest. Dermatol. 134, 1971–1980 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Avalle, L. et al. STAT3 localizes to the ER, acting as a gatekeeper for ER-mitochondrion Ca(2+) fluxes and apoptotic responses. Cell Death Differ. 26, 932–942 (2019).

    CAS  PubMed  Google Scholar 

  130. MacDougald, O. A. Methods in Enzymology. Methods of adipose tissue biology, part B. Preface. Methods Enzymol. 538, xv (2014).

    PubMed  Google Scholar 

  131. Divakaruni, A. S., Paradyse, A., Ferrick, D. A., Murphy, A. N. & Jastroch, M. Analysis and interpretation of microplate-based oxygen consumption and pH data. Methods Enzymol. 547, 309–354 (2014).

    CAS  PubMed  Google Scholar 

  132. Rogers, G. W. et al. High throughput microplate respiratory measurements using minimal quantities of isolated mitochondria. PLoS ONE 6, e21746 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Divakaruni, A. S. et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc. Natl Acad. Sci. USA 110, 5422–5427 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Divakaruni, A. S., Rogers, G. W. & Murphy, A. N. Measuring mitochondrial function in permeabilized cells using the seahorse XF analyzer or a clark-type oxygen electrode. Curr. Protoc. Toxicol. 60, 25 22 21–16 (2014).

    Google Scholar 

  135. Trapnell, C. et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7, 562–578 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank members of the Saltiel laboratory for helpful discussions. We thank M. R. Mackey and D. Boassa at the NCMIR Core Facility for performing electron microscopy, and B. Vanderfeesten for blinded analysis of lipid droplet volume. This work was supported by US National Institutes of Health grants 1K01DK105075-01A1 and R03DK118195 to S.M.R., R01NS087611 to A.N.M, R01DK117551 and R01DK076906 to A.R.S., K99HL143277 to P.Z., P30DK063491 to A.R.S., S.M.R., P30 2P30CA023100-28 to the Microscopy core at UCSD Moores Cancer Center, P30NS047101 to the UCSD School of Medicine Microscopy Core, and P41 GM103412 to the NCMIR Core Facility. This work was also supported by American Diabetes Association grant 1-19-JDF-012 to S.M.R. and 1-18-PDF-094 to C.W.H. Finally, the authors dedicate this work to the memory of our inspirational friend and colleague Maryam Ahmadian.

Author information

Author notes

  1. BreAnne Poirier

    Present address: Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

  2. Anne N. Murphy

    Present address: Cytokinetics, South San Francisco, CA, USA

  3. Deceased: Maryam Ahmadian.

Authors and Affiliations

  1. Division of Metabolism and Endocrinology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA

    Shannon M. Reilly, Chao-Wei Hung, Maryam Ahmadian, Peng Zhao, Omer Keinan, Andrew V. Gomez, Julia H. DeLuca, Benyamin Dadpey, Donald Lu, Jessica Zaid & Alan R. Saltiel

  2. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Shannon M. Reilly, Peng Zhao, BreAnne Poirier, Xiaoling Peng & Alan R. Saltiel

  3. Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, CA, USA

    Maryam Ahmadian, Ruth T. Yu, Michael Downes, Christopher Liddle & Ronald M. Evans

  4. Department of Pharmacology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA

    Anne N. Murphy & Alan R. Saltiel

Authors
  1. Shannon M. Reilly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chao-Wei Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maryam Ahmadian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Omer Keinan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew V. Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julia H. DeLuca
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Benyamin Dadpey
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Donald Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jessica Zaid
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. BreAnne Poirier
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiaoling Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ruth T. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michael Downes
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Christopher Liddle
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ronald M. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Anne N. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Alan R. Saltiel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, S.M.R., ARS; Methodology, S.M.R., C.W.H., M.A., O.K., B.D., X.P., A.N.M.; Formal Analysis, S.M.R., C.W.H., B.D., R.T.Y., M.D., C.L.; Investigation, S.M.R., C.W.H., M.A., P.Z., O.K., A.V.G., J.H.D., B.D., D.L., J.Z., B.P., X.P., R.T.Y., M.D., C.L., A.N.M.; Visualization, S.M.R., C.W.H. J.H.D.; Supervision, S.M.R., R.M.E., A.N.M., A.R.S.; Writing original draft, S.M.R.; Writing reviewing and editing, S.M.R., M.A., J.Z., A.R.S.

Corresponding authors

Correspondence to Shannon M. Reilly or Alan R. Saltiel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Primary Handling Editor: Christoph Schmitt.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Catecholamine signaling in white and brown adipose tissue.

Western blot analysis of WT and SAKO mice fed a HFD for 12 weeks, then treated with 1 mg/kg CL-316,243 or vehicle control for indicated time before sacrifice and tissue collection. a, Epididymal white adipose tissue. b, Inguinal white adipose tissue. Outlier detected with Grubs outlier test removed. c, Brown adipose tissue. Blots are representative of results from three independent experiments.

Extended Data Fig. 2 Fractionation of 3T3-L1 differentiated adipocytes.

Relative levels of β-tubulin (cytosol marker), H3 (nuclear marker), Calnexin (ER/membrane marker), TOM20 (mitochondrial marker) and Perilipin1 (lipid droplet marker) in fractionated samples from time course analysis in Fig. 2a. Cytosol, nucleus, membrane and mitochondria run on the same gel. These experiments were repeated independently four times with similar results.

Extended Data Fig. 3 Metabolic phenotype of SAKO mice on a normal diet (ND).

a, Left panel: Western blot of mature adipocytes isolated from 12-week old WT and SAKO mice. Right panel: Quantification of STAT3 protein relative to RalA loading control. Individual data points plotted ± SEM (n = 3 iWAT, 2 eWAT). b, Body weight of 12-week old ND fed WT and SAKO mice. Individual data points plotted ± SEM (n = 6 per genotype). c, Oxygen consumption rate in ND fed WT and SAKO mice at 16-weeks of age. Data are represented as mean ± SEM (n = 16). d, Adipocyte size distribution from ND-fed 12-week old WT and SAKO eWAT (n = 2 WT and 3 SAKO). e, Adipocyte size distribution from ND-fed 12-week old WT and SAKO iWAT (n = 2 WT and 3 SAKO). f, Body composition of ND fed WT and SAKO mice at 12 weeks of age. Individual data points plotted ± SEM (n = 6 WT and 4 SAKO).

Extended Data Fig. 4 Histology from HFD-fed WT and SAKO mice.

From top to bottom, eWAT (scale bar = 100 μm), iWAT (scale bar = 100 μm), BAT (scale bar = 50 μm), and liver (scale bar = 100 μm). Results are representative of results from three independent experiments.

Extended Data Fig. 5 Effect of CL-316,243 on metabolism.

a, Oxygen consumption and b, RER before and after intraperitoneal injection with 1 mg/kg CL-316,243. Individual data points plotted ± SEM (n = 6 per treatment). * p value = 0.002 (VO2) and <0.0001 (RER) CL versus baseline (two-tailed paired t-test).

Extended Data Fig. 6 Mitochondria bioenergetics profiles.

a-e, Isolated mitochondria. Vertical lines indicate addition of oligomycin (2 μM), and FCCP (two sequential additions of 3 μM). a, 4 mM ADP + 5 mM pyruvate + 1 mM malate, b, 40 μM palmitoyl-carnitine + 1 mM malate, c, 5 mM succinate + 2 μM rotenone, d, 5 mM glycerol 3-phosphate + 2 μM rotenone 700 nM CaCl2, e, 20 mM ascorb-ate + 200 μM Tetramethyl-p-Phenylenediamine. f-j, Permeabilized PPDIVs. Vertical lines indicate addition of oligomycin (2 μM), and FCCP (two sequential additions of 2 μM). f, 40 μM palmitoylcarnitine + 1 mM malate, g, 4 mM ADP + 5 mM pyruvate + 1 mM malate, h, 5 mM succinate + 2 μM rotenone, i, 5 mM glycerol 3 phosphate + 2 μM rotenone 700 nM CaCl2, j, 20 mM ascorbate + 200 μM Tetramethyl-p-Phenylenediamine. Data are represented as mean ± SEM (n = 8 per genotype).

Extended Data Fig. 7 STAT3/GPAT3 interaction.

a, Western blot analysis of fractionated 3T3-L1 adipocytes treated with 10 μM CL-316,243 or vehicle control for 60 min. b-d and f, Western blot analysis of input, flow through and immunoprecipitation using Myc-antibody coated beads (b, c) or Flag-antibody coated beads (d, f) of HEK293T cell lysates overexpressing Flag-tagged STAT3 and/or Myc-tagged GPAT3/GPAT4. Blots are representative of three independent replicates. Dark exposure (D.E.). e, Western blot analysis of input and immunoprecipitation using GPAT3 antibody in 3T3-L1 differentiated adipocytes treated with 10 μM CL-316,243 or vehicle control for 15 min. f, Western blot analysis of input, flow through and immunoprecipitation using Flag antibody coated beads of HEK293T cell lysates overexpressing Flag-tagged STAT3 (WT/S727A/S727D) and/or Myc-tagged GPAT3. Blots are representative of three independent replicates. Arrow indicates expected size of Ser727 phosphorylated STAT3; the band observed in the IP samples is a larger non-specific band. g, Western blot analysis of input, flow through, and immunoprecipitation using Flag antibody coated beads from 3T3-L1 differentiated adipocytes with lentiviral overexpression of flag-tagged STAT3 (WT/Y705F/S727A) and/or Myc-tagged GPAT3, cells treated with 10 μM CL-316,243 or vehicle control for 60 min before harvest and IP. These experiments were repeated independently twice with similar results.

Supplementary information

Supplementary Information

Supplementary Table 1

Reporting Summary

Supplementary Data

MS data from STAT3 and IgG co-immunoprecipitation in 3T3-L1 adipocytes

Supplementary Video

Time course of lipid droplet depletion (visualized by BODIPY staining) in WT and SAKO PPDIVs treated with CL-316,243.

Source data

Source Data Fig. 2

Unprocessed western blots

Source Data Fig. 4

Unprocessed western blots

Source Data Fig. 5

Unprocessed western blots. Phosphorylated HSL and p38 from the same membrane, while total HSL and p38 from a second membrane

Source Data Fig. 8

Unprocessed western blots. GPAT3 and STAT3 blots from the same membrane. Two GPAT3 exposures from the same membrane.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reilly, S.M., Hung, CW., Ahmadian, M. et al. Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3. Nat Metab 2, 620–634 (2020). https://doi.org/10.1038/s42255-020-0217-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-020-0217-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing