Inter-organ cross-talk in metabolic syndrome

Abstract

Maintenance of systemic homeostasis and the response to nutritional and environmental challenges require the coordination of multiple organs and tissues. To respond to various metabolic demands, higher organisms have developed a system of inter-organ communication through which one tissue can affect metabolic pathways in a distant tissue. Dysregulation of these lines of communication contributes to human pathologies, including obesity, diabetes, liver disease and atherosclerosis. In recent years, technical advances such as data-driven bioinformatics, proteomics and lipidomics have enabled efforts to understand the complexity of systemic metabolic cross-talk and its underlying mechanisms. Here, we provide an overview of inter-organ signals and their roles in metabolic control, and highlight recent discoveries in the field. We review peptide, small-molecule and lipid mediators secreted by metabolic tissues, as well as the role of the central nervous system in orchestrating peripheral metabolic functions. Finally, we discuss the contributions of inter-organ signalling networks to the features of metabolic syndrome.

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Fig. 1: Liver-secreted factors.
Fig. 2: Adipose-secreted factors.
Fig. 3: Muscle-secreted factors.
Fig. 4: Gut- and endocrine-secreted factors.
Fig. 5: Secreted factors and the vasculature.

References

  1. 1.

    Aguilar, M., Bhuket, T., Torres, S., Liu, B. & Wong, R. J. Prevalence of the metabolic syndrome in the United States, 2003-2012. J. Am. Med. Assoc. 313, 1973–1974 (2015).

    CAS  Google Scholar 

  2. 2.

    Afshin, A., Reitsma, M. B. & Murray, C. J. L. Health effects of overweight and obesity in 195 countries. N. Engl. J. Med. 377, 1496–1497 (2017).

    PubMed  Google Scholar 

  3. 3.

    Ogden, C. L., Carroll, M. D., Kit, B. K. & Flegal, K. M. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010. J. Am. Med. Assoc. 307, 483–490 (2012).

    Google Scholar 

  4. 4.

    Gregg, E. W. & Shaw, J. E. Global health effects of overweight and obesity. N. Engl. J. Med. 377, 80–81 (2017).

    PubMed  Google Scholar 

  5. 5.

    Saklayen, M. G. The global epidemic of the metabolic syndrome. Curr. Hypertens. Rep. 20, 12 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Ogurtsova, K. et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract. 128, 40–50 (2017).

    CAS  PubMed  Google Scholar 

  7. 7.

    Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 3, 866–875 (2015).

    PubMed Central  Google Scholar 

  8. 8.

    Ryan, D. H. & Diabetes Prevention Program Research Group. Diet and exercise in the prevention of diabetes. Int. J. Clin. Pract. Suppl., 28–35 (2003).

  9. 9.

    Yoo, H. J. & Choi, K. M. Hepatokines as a link between obesity and cardiovascular diseases. Diabetes Metab. J. 39, 10–15 (2015).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Browning, J. D. & Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147–152 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Bellentani, S. et al. Risk factors for alcoholic liver disease. Addict. Biol. 5, 261–268 (2000).

    CAS  PubMed  Google Scholar 

  12. 12.

    Ding, E. L. et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N. Engl. J. Med. 361, 1152–1163 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ding, L., Wendl, M. C., Koboldt, D. C. & Mardis, E. R. Analysis of next-generation genomic data in cancer: accomplishments and challenges. Hum. Mol. Genet. 19, R188–R196 (2010). R2.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Li, C. Y. et al. Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure. Gut 59, 817–826 (2010).

    CAS  PubMed  Google Scholar 

  15. 15.

    Wu, H. T. et al. The role of hepassocin in the development of non-alcoholic fatty liver disease. J. Hepatol. 59, 1065–1072 (2013).

    CAS  PubMed  Google Scholar 

  16. 16.

    Wang, Y. et al. Angiopoietin-like protein 4 improves glucose tolerance and insulin resistance but induces liver steatosis in high-fat-diet mice. Mol. Med. Rep. 14, 3293–3300 (2016).

    CAS  PubMed  Google Scholar 

  17. 17.

    Koo, B. K. et al. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease. Liver Int. 38, 695–705 (2018).

    CAS  PubMed  Google Scholar 

  18. 18.

    Kim, K. H. et al. Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice. Sci. Rep. 8, 6789 (2018).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Dijk, W. et al. Angiopoietin-like 4 promotes intracellular degradation of lipoprotein lipase in adipocytes. J. Lipid Res. 57, 1670–1683 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Kutlu, O. et al. Serum adropin levels are reduced in adult patients with non-alcoholic fatty liver disease. Med. Princ. Pract. 28, 463–469 (2019).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Gao, S. et al. Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistance. Mol. Metab. 4, 310–324 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Meex, R. C. et al. Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab. 22, 1078–1089 (2015).

    CAS  PubMed  Google Scholar 

  23. 23.

    Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).

    CAS  PubMed  Google Scholar 

  24. 24.

    Mukhopadhyay, S. & Bhattacharya, S. Plasma fetuin-A triggers inflammatory changes in macrophages and adipocytes by acting as an adaptor protein between NEFA and TLR-4. Diabetologia 59, 859–860 (2016).

    PubMed  Google Scholar 

  25. 25.

    Misu, H. et al. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab. 12, 483–495 (2010).

    CAS  PubMed  Google Scholar 

  26. 26.

    Choi, H. Y. et al. Increased selenoprotein P levels in subjects with visceral obesity and nonalcoholic fatty liver disease. Diabetes Metab. J. 37, 63–71 (2013).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Yang, Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005).

    CAS  PubMed  Google Scholar 

  28. 28.

    Moraes-Vieira, P. M. et al. RBP4 activates antigen-presenting cells, leading to adipose tissue inflammation and systemic insulin resistance. Cell Metab. 19, 512–526 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Kotnik, P., Fischer-Posovszky, P. & Wabitsch, M. RBP4: a controversial adipokine. Eur. J. Endocrinol. 165, 703–711 (2011).

    CAS  PubMed  Google Scholar 

  30. 30.

    Lan, F. et al. LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. Diabetes 63, 1649–1664 (2014).

    CAS  PubMed  Google Scholar 

  31. 31.

    Kliewer, S. A. & Mangelsdorf, D. J. A dozen years of discovery: insights into the physiology and pharmacology of FGF21. Cell Metab. 29, 246–253 (2019).

    CAS  PubMed  Google Scholar 

  32. 32.

    Staiger, H., Keuper, M., Berti, L., Hrabe de Angelis, M. & Häring, H. U. Fibroblast growth factor 21-metabolic role in mice and men. Endocr. Rev. 38, 468–488 (2017).

    PubMed  Google Scholar 

  33. 33.

    Bookout, A. L. et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. 19, (1147–1152 (2013).

    Google Scholar 

  34. 34.

    Owen, B. M. et al. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab. 20, 670–677 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Zhang, X. et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57, 1246–1253 (2008).

    CAS  PubMed  Google Scholar 

  36. 36.

    Zhang, Y. et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1, e00065 (2012).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Gaich, G. et al. The effects of LY2405319, an FGF21 analogue, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333–340 (2013).

    CAS  PubMed  Google Scholar 

  38. 38.

    Wei, W. et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc. Natl Acad. Sci. USA 109, 3143–3148 (2012).

    CAS  PubMed  Google Scholar 

  39. 39.

    Owen, B. M. et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat. Med. 19, 1153–1156 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005).

    CAS  PubMed  Google Scholar 

  41. 41.

    Potthoff, M. J. et al. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. Cell Metab. 13, 729–738 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Sinal, C. J. et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731–744 (2000).

    CAS  PubMed  Google Scholar 

  43. 43.

    Watanabe, M. et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 113, 1408–1418 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Zhang, Y. et al. Activation of the nuclear receptor FXR improves hyperglycaemia and hyperlipidemia in diabetic mice. Proc. Natl Acad. Sci. USA 103, 1006–1011 (2006).

    CAS  PubMed  Google Scholar 

  45. 45.

    Calkin, A. C. & Tontonoz, P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat. Rev. Mol. Cell Biol. 13, 213–224 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    van Nierop, F. S. et al. Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol. 5, 224–233 (2017).

    PubMed  Google Scholar 

  47. 47.

    Keitel, V. et al. The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia 58, 1794–1805 (2010).

    PubMed  Google Scholar 

  48. 48.

    Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006).

    CAS  PubMed  Google Scholar 

  49. 49.

    Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Simcox, J. et al. Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Cell Metab. 26, 509–522.e506 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Shah, R. V. et al. Visceral adiposity and the risk of metabolic syndrome across body mass index: the MESA Study. JACC Cardiovasc. Imaging 7, 1221–1235 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Cook, K. S. et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 237, 402–405 (1987).

    CAS  PubMed  Google Scholar 

  53. 53.

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    CAS  PubMed  Google Scholar 

  54. 54.

    Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Guo, K. et al. Disruption of peripheral leptin signalling in mice results in hyperleptinemia without associated metabolic abnormalities. Endocrinology 148, 3987–3997 (2007).

    CAS  PubMed  Google Scholar 

  56. 56.

    Flier, J. S. & Maratos-Flier, E. Leptin’s physiologic role: does the emperor of energy balance have no clothes? Cell Metab. 26, 24–26 (2017).

    CAS  PubMed  Google Scholar 

  57. 57.

    Minokoshi, Y. et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339–343 (2002).

    CAS  PubMed  Google Scholar 

  58. 58.

    Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).

    CAS  PubMed  Google Scholar 

  59. 59.

    Arita, Y. et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 79–83 (1999).

    CAS  PubMed  Google Scholar 

  60. 60.

    Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7, 941–946 (2001).

    CAS  PubMed  Google Scholar 

  61. 61.

    Qi, Y. et al. Adiponectin acts in the brain to decrease body weight. Nat. Med. 10, 524–529 (2004).

    CAS  PubMed  Google Scholar 

  62. 62.

    Wang, Z. V. & Scherer, P. E. Adiponectin, the past two decades. J. Mol. Cell Biol. 8, 93–100 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Combs, T. P., Berg, A. H., Obici, S., Scherer, P. E. & Rossetti, L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J. Clin. Invest. 108, 1875–1881 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Muoio, D. M., Dohm, G. L., Fiedorek, F. T. Jr., Tapscott, E. B. & Coleman, R. A. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 46, 1360–1363 (1997).

    CAS  PubMed  Google Scholar 

  65. 65.

    Auguet, T. et al. Upregulation of lipocalin 2 in adipose tissues of severely obese women: positive relationship with proinflammatory cytokines. Obesity (Silver Spring) 19, 2295–2300 (2011).

    CAS  Google Scholar 

  66. 66.

    Fernandez-García, C. E. et al. Lipocalin-2, a potential therapeutic target in advanced atherosclerosis. Atherosclerosis 278, 321–322 (2018).

    PubMed  Google Scholar 

  67. 67.

    Guo, H. et al. Lipocalin-2 deficiency impairs thermogenesis and potentiates diet-induced insulin resistance in mice. Diabetes 59, 1376–1385 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Law, I. K. et al. Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity. Diabetes 59, 872–882 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Wang, G. X. et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat. Med. 20, 1436–1443 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Pfeifer, A. NRG4: an endocrine link between brown adipose tissue and liver. Cell Metab. 21, 13–14 (2015).

    CAS  PubMed  Google Scholar 

  71. 71.

    Hotamisligil, G. S. et al. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274, 1377–1379 (1996).

    CAS  PubMed  Google Scholar 

  72. 72.

    Cao, H. et al. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab. 17, 768–778 (2013).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Furuhashi, M. et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447, 959–965 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Zhang, M., Zhu, W. & Li, Y. Small molecule inhibitors of human adipocyte fatty acid binding protein (FABP4). Med. Chem. 10, 339–347 (2014).

    CAS  PubMed  Google Scholar 

  75. 75.

    Burak, M. F. et al. Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes. Sci. Transl. Med. 7, 319ra205 (2015).

    PubMed  Google Scholar 

  76. 76.

    Barchetta, I., Cimini, F. A., Ciccarelli, G., Baroni, M. G. & Cavallo, M. G. Sick fat: the good and the bad of old and new circulating markers of adipose tissue inflammation. J. Endocrinol. Invest. 42, 1257–1272 (2019).

    CAS  PubMed  Google Scholar 

  77. 77.

    Steppan, C. M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001).

    CAS  PubMed  Google Scholar 

  78. 78.

    Tarkowski, A., Bjersing, J., Shestakov, A. & Bokarewa, M. I. Resistin competes with lipopolysaccharide for binding to toll-like receptor 4. J. Cell. Mol. Med. 14, 1419–1431 (2010). (6B).

    CAS  PubMed  Google Scholar 

  79. 79.

    Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Ferry, G. et al. Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity. J. Biol. Chem. 278, 18162–18169 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Rancoule, C. et al. Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice. Diabetologia 56, 1394–1402 (2013).

    CAS  PubMed  Google Scholar 

  82. 82.

    Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Syed, I. et al. Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab. 27, 419–427.e414 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Pflimlin, E. et al. Acute and repeated treatment with 5-PAHSA or 9-PAHSA isomers does not improve glucose control in mice. Cell Metab. 28, 217–227.e213 (2018).

    CAS  PubMed  Google Scholar 

  85. 85.

    Syed, I. et al. Methodological issues in studying PAHSA biology: masking PAHSA effects. Cell Metab. 28, 543–546 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).

    PubMed  Google Scholar 

  87. 87.

    Lee, P. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 19, 302–309 (2014).

    CAS  PubMed  Google Scholar 

  88. 88.

    Svensson, K. J. et al. A secreted Slit2 fragment regulates adipose tissue thermogenesis and metabolic function. Cell Metab. 23, 454–466 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Kong, X. et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab. 28, 631–643.e633 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120.e1113 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Leiria, L. O. et al. 12-Lipoxygenase regulates cold adaptation and glucose metabolism by producing the omega-3 lipid 12-HEPE from brown fat. Cell Metab. 30, 768–783.e767 (2019).

    CAS  PubMed  Google Scholar 

  92. 92.

    Mohr, T. et al. Long-term adaptation to electrically induced cycle training in severe spinal cord injured individuals. Spinal Cord 35, 1–16 (1997).

    CAS  PubMed  Google Scholar 

  93. 93.

    Bortoluzzi, S., Scannapieco, P., Cestaro, A., Danieli, G. A. & Schiaffino, S. Computational reconstruction of the human skeletal muscle secretome. Proteins 62, 776–792 (2006).

    CAS  PubMed  Google Scholar 

  94. 94.

    Pedersen, B. K. & Febbraio, M. A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379–1406 (2008).

    CAS  PubMed  Google Scholar 

  95. 95.

    Fischer, C. P. Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc. Immunol. Rev. 12, 6–33 (2006).

    PubMed  Google Scholar 

  96. 96.

    Hiscock, N., Chan, M. H., Bisucci, T., Darby, I. A. & Febbraio, M. A. Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J. 18, 992–994 (2004).

    CAS  PubMed  Google Scholar 

  97. 97.

    Febbraio, M. A. et al. Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J. Physiol. (Lond.) 549, 607–612 (2003).

    CAS  Google Scholar 

  98. 98.

    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 

  99. 99.

    Febbraio, M. A., Hiscock, N., Sacchetti, M., Fischer, C. P. & Pedersen, B. K. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53, 1643–1648 (2004).

    CAS  PubMed  Google Scholar 

  100. 100.

    Steensberg, A. et al. Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans. J. Physiol. (Lond.) 548, 631–638 (2003).

    CAS  Google Scholar 

  101. 101.

    Pedersen, B. K. & Febbraio, M. A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).

    CAS  PubMed  Google Scholar 

  102. 102.

    McPherron, A. C., Lawler, A. M. & Lee, S. J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387, 83–90 (1997).

    CAS  PubMed  Google Scholar 

  103. 103.

    McPherron, A. C. & Lee, S. J. Suppression of body fat accumulation in myostatin-deficient mice. J. Clin. Invest. 109, 595–601 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Feldman, B. J., Streeper, R. S., Farese, R. V. Jr. & Yamamoto, K. R. Myostatin modulates adipogenesis to generate adipocytes with favorable metabolic effects. Proc. Natl Acad. Sci. USA 103, 15675–15680 (2006).

    CAS  PubMed  Google Scholar 

  105. 105.

    Hittel, D. S., Berggren, J. R., Shearer, J., Boyle, K. & Houmard, J. A. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 58, 30–38 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Hansen, J. et al. Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine. Endocrinology 152, 164–171 (2011).

    CAS  PubMed  Google Scholar 

  107. 107.

    Hansen, J. S. & Plomgaard, P. Circulating follistatin in relation to energy metabolism. Mol. Cell. Endocrinol. 433, 87–93 (2016).

    CAS  PubMed  Google Scholar 

  108. 108.

    Otero-Díaz, B. et al. Exercise induces white adipose tissue browning across the weight spectrum in humans. Front. Physiol. 9, 1781 (2018).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Boström, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Wrann, C. D. et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 18, 649–659 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Roberts, L. D. et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Lee, C. et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 21, 443–454 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Du, C. et al. Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance. Pediatr. Diabetes 19, 1058–1064 (2018).

    CAS  Google Scholar 

  114. 114.

    Nielsen, A. R. & Pedersen, B. K. The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15. Appl. Physiol. Nutr. Metab. 32, 833–839 (2007).

    CAS  PubMed  Google Scholar 

  115. 115.

    Carbó, N. et al. Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control. Biochim. Biophys. Acta 1526, 17–24 (2001).

    PubMed  Google Scholar 

  116. 116.

    Quinn, L. S., Strait-Bodey, L., Anderson, B. G., Argilés, J. M. & Havel, P. J. Interleukin-15 stimulates adiponectin secretion by 3T3-L1 adipocytes: evidence for a skeletal muscle-to-fat signalling pathway. Cell Biol. Int. 29, 449–457 (2005).

    CAS  PubMed  Google Scholar 

  117. 117.

    Hamrick, M. W., McNeil, P. L. & Patterson, S. L. Role of muscle-derived growth factors in bone formation. J. Musculoskelet. Neuronal Interact. 10, 64–70 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Ouchi, N. et al. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J. Biol. Chem. 283, 32802–32811 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Oshima, Y. et al. Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart. Circulation 117, 3099–3108 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Macleod, J. J. Pancreatic extract and diabetes. Can. Med. Assoc. J. 12, 423–425 (1922).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Klip, A., McGraw, T. E. & James, D. E. 30 sweet years of GLUT4. J. Biol. Chem. 294, 11369–11381 (2019).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Titchenell, P. M., Lazar, M. A. & Birnbaum, M. J. Unraveling the regulation of hepatic metabolism by insulin. Trends Endocrinol. Metab. 28, 497–505 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Liu, S. & Borgland, S. L. Insulin actions in the mesolimbic dopamine system. Exp. Neurol. 320, 113006 (2019).

    CAS  PubMed  Google Scholar 

  124. 124.

    Guo, S. Insulin signalling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J. Endocrinol. 220, T1–T23 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Mathieu, C., Gillard, P. & Benhalima, K. Insulin analogues in type 1 diabetes mellitus: getting better all the time. Nat. Rev. Endocrinol. 13, 385–399 (2017).

    CAS  PubMed  Google Scholar 

  126. 126.

    UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837–853 (1998).

    Google Scholar 

  127. 127.

    Riddle, M., Umpierrez, G., DiGenio, A., Zhou, R. & Rosenstock, J. Contributions of basal and postprandial hyperglycaemia over a wide range of A1C levels before and after treatment intensification in type 2 diabetes. Diabetes Care 34, 2508–2514 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Wallia, A. & Molitch, M. E. Insulin therapy for type 2 diabetes mellitus. J. Am. Med. Assoc. 311, 2315–2325 (2014).

    Google Scholar 

  129. 129.

    Lin, H. V. & Accili, D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab. 14, 9–19 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Habegger, K. M. et al. The metabolic actions of glucagon revisited. Nat. Rev. Endocrinol. 6, 689–697 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Day, J. W. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009).

    CAS  PubMed  Google Scholar 

  132. 132.

    Kim, T. et al. Glucagon receptor signalling regulates energy metabolism via hepatic farnesoid X receptor and fibroblast growth factor 21. Diabetes 67, 1773–1782 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Nauck, M. A. & Meier, J. J. Incretin hormones: their role in health and disease. Diabetes Obes. Metab. 20, 5–21 (2018). (Suppl. 1).

    CAS  PubMed  Google Scholar 

  134. 134.

    Muscelli, E. et al. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 57, 1340–1348 (2008).

    CAS  PubMed  Google Scholar 

  135. 135.

    Nauck, M. A., Bartels, E., Orskov, C., Ebert, R. & Creutzfeldt, W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J. Clin. Endocrinol. Metab. 76, 912–917 (1993).

    CAS  PubMed  Google Scholar 

  136. 136.

    Nauck, M. A. et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Invest. 91, 301–307 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Flint, A., Raben, A., Astrup, A. & Holst, J. J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Invest. 101, 515–520 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Verdich, C. et al. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J. Clin. Endocrinol. Metab. 86, 4382–4389 (2001).

    CAS  PubMed  Google Scholar 

  139. 139.

    Ranganath, L. R. et al. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 38, 916–919 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Laferrère, B. Effect of gastric bypass surgery on the incretins. Diabetes Metab. 35, 513–517 (2009).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Drucker, D. J. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 24, 15–30 (2016).

    CAS  PubMed  Google Scholar 

  142. 142.

    Zhong, J., Maiseyeu, A., Davis, S. N. & Rajagopalan, S. DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ. Res. 116, 1491–1504 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Svane, M. S. et al. Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery. Int. J. Obes. (Lond.) 40, 1699–1706 (2016).

    CAS  Google Scholar 

  144. 144.

    Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Tschöp, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).

    PubMed  Google Scholar 

  146. 146.

    Colldén, G., Tschöp, M. H. & Müller, T. D. Therapeutic potential of targeting the ghrelin pathway. Int. J. Mol. Sci. 18, E798 (2017).

    PubMed  Google Scholar 

  147. 147.

    Yasuda, T., Masaki, T., Kakuma, T. & Yoshimatsu, H. Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats. Neurosci. Lett. 349, 75–78 (2003).

    CAS  PubMed  Google Scholar 

  148. 148.

    Theander-Carrillo, C. et al. Ghrelin action in the brain controls adipocyte metabolism. J. Clin. Invest. 116, 1983–1993 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Gnanapavan, S. et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J. Clin. Endocrinol. Metab. 87, 2988 (2002).

    CAS  PubMed  Google Scholar 

  150. 150.

    Gauna, C. et al. Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. J. Clin. Endocrinol. Metab. 90, 1055–1060 (2005).

    CAS  PubMed  Google Scholar 

  151. 151.

    Gauna, C. et al. Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. J. Clin. Endocrinol. Metab. 89, 5035–5042 (2004).

    CAS  PubMed  Google Scholar 

  152. 152.

    Sun, Y., Asnicar, M., Saha, P. K., Chan, L. & Smith, R. G. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 3, 379–386 (2006).

    CAS  PubMed  Google Scholar 

  153. 153.

    Li, Y. et al. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. Endocrine 43, 376–386 (2013).

    CAS  PubMed  Google Scholar 

  154. 154.

    Gortan Cappellari, G. et al. Unacylated ghrelin reduces skeletal muscle reactive oxygen species generation and inflammation and prevents high-fat diet-induced hyperglycemia and whole-body insulin resistance in rodents. Diabetes 65, 874–886 (2016).

    PubMed  Google Scholar 

  155. 155.

    Kraft, E. N., Cervone, D. T. & Dyck, D. J. Ghrelin stimulates fatty acid oxidation and inhibits lipolysis in isolated muscle from male rats. Physiol. Rep. 7, e14028 (2019).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Khatib, M. N. et al. Effect of ghrelin on mortality and cardiovascular outcomes in experimental rat and mice models of heart failure: a systematic review and meta-analysis. PLoS One 10, e0126697 (2015).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Erspamer, V. & Asero, B. Identification of enteramine, the specific hormone of the enterochromaffin cell system, as 5-hydroxytryptamine. Nature 169, 800–801 (1952).

    CAS  Google Scholar 

  158. 158.

    Kim, H. et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat. Med. 16, 804–808 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Paulmann, N. et al. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol. 7, e1000229 (2009).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Sumara, G., Sumara, O., Kim, J. K. & Karsenty, G. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab. 16, 588–600 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Oh, C. M. et al. Regulation of systemic energy homeostasis by serotonin in adipose tissues. Nat. Commun. 6, 6794 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Tanaka, M. & Itoh, H. Hypertension as a metabolic disorder and the novel role of the gut. Curr. Hypertens. Rep. 21, 63 (2019).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Ma, Y., He, F. J. & MacGregor, G. A. High salt intake: independent risk factor for obesity? Hypertension 66, 843–849 (2015).

    CAS  PubMed  Google Scholar 

  164. 164.

    Lee, M., Sorn, S. R., Lee, Y. & Kang, I. Salt induces adipogenesis/lipogenesis and inflammatory adipocytokines secretion in adipocytes. Int. J. Mol. Sci. 20, E160 (2019).

    PubMed  Google Scholar 

  165. 165.

    Zhu, Z., Xiong, S. & Liu, D. The gastrointestinal tract: an initial organ of metabolic hypertension? Cell. Physiol. Biochem. 38, 1681–1694 (2016).

    CAS  PubMed  Google Scholar 

  166. 166.

    Frigolet, M. E., Torres, N. & Tovar, A. R. The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity. J. Nutr. Biochem. 24, 2003–2015 (2013).

    CAS  PubMed  Google Scholar 

  167. 167.

    Ohashi, K. et al. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 47, 1108–1116 (2006).

    CAS  PubMed  Google Scholar 

  168. 168.

    Zhao, Y. et al. Sodium intake regulates glucose homeostasis through the PPARδ/adiponectin-mediated SGLT2 pathway. Cell Metab. 23, 699–711 (2016).

    CAS  PubMed  Google Scholar 

  169. 169.

    Okamoto, Y. et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106, 2767–2770 (2002).

    CAS  PubMed  Google Scholar 

  170. 170.

    Shibata, R. et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat. Med. 10, 1384–1389 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Shibata, R. et al. Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat. Med. 11, 1096–1103 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Juárez-Rojas, J. G. et al. Association of adiponectin with subclinical atherosclerosis in a Mexican-mestizo population. Arch. Med. Res. 48, 73–78 (2017).

    PubMed  Google Scholar 

  173. 173.

    Makowski, L. et al. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat. Med. 7, 699–705 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Makowski, L., Brittingham, K. C., Reynolds, J. M., Suttles, J. & Hotamisligil, G. S. The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IκB kinase activities. J. Biol. Chem. 280, 12888–12895 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Shimba, Y. et al. Skeletal muscle-specific PGC-1α overexpression suppresses atherosclerosis in apolipoprotein E-knockout mice. Sci. Rep. 9, 4077 (2019).

    PubMed  PubMed Central  Google Scholar 

  176. 176.

    Lee, M. J. et al. Irisin, a novel myokine is an independent predictor for sarcopenia and carotid atherosclerosis in dialysis patients. Atherosclerosis 242, 476–482 (2015).

    CAS  PubMed  Google Scholar 

  177. 177.

    Sawada, M., Yamamoto, H., Ogasahara, A., Tanaka, Y. & Kihara, S. β-aminoisobutyric acid protects against vascular inflammation through PGC-1β-induced antioxidative properties. Biochem. Biophys. Res. Commun. 516, 963–968 (2019).

    CAS  PubMed  Google Scholar 

  178. 178.

    Seldin, M. M. et al. Trimethylamine N-oxide promotes vascular inflammation through signalling of mitogen-activated protein kinase and nuclear factor-κB. J. Am. Heart Assoc. 5, e002767 (2016).

    PubMed  PubMed Central  Google Scholar 

  179. 179.

    Miao, J. et al. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat. Commun. 6, 6498 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Schugar, R. C. et al. The TMAO-producing enzyme flavin-containing monooxygenase 3 regulates obesity and the beiging of white adipose tissue. Cell Rep. 19, 2451–2461 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Dallabrida, S. M. et al. Adipose tissue growth and regression are regulated by angiopoietin-1. Biochem. Biophys. Res. Commun. 311, 563–571 (2003).

    CAS  PubMed  Google Scholar 

  182. 182.

    An, Y. A. et al. Angiopoietin-2 in white adipose tissue improves metabolic homeostasis through enhanced angiogenesis. eLife 6, e24071 (2017).

    PubMed  PubMed Central  Google Scholar 

  183. 183.

    Voros, G. et al. Modulation of angiogenesis during adipose tissue development in murine models of obesity. Endocrinology 146, 4545–4554 (2005).

    CAS  PubMed  Google Scholar 

  184. 184.

    Jung, Y. J. et al. The effects of designed angiopoietin-1 variant on lipid droplet diameter, vascular endothelial cell density and metabolic parameters in diabetic db/db mice. Biochem. Biophys. Res. Commun. 420, 498–504 (2012).

    CAS  PubMed  Google Scholar 

  185. 185.

    Lee, S. et al. Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes. Nephrol. Dial. Transplant. 22, 396–408 (2007).

    CAS  PubMed  Google Scholar 

  186. 186.

    Tabata, M. et al. Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metab. 10, 178–188 (2009).

    CAS  PubMed  Google Scholar 

  187. 187.

    Horio, E. et al. Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. Arterioscler. Thromb. Vasc. Biol. 34, 790–800 (2014).

    CAS  PubMed  Google Scholar 

  188. 188.

    Kersten, S. New insights into angiopoietin-like proteins in lipid metabolism and cardiovascular disease risk. Curr. Opin. Lipidol. 30, 205–211 (2019).

    CAS  PubMed  Google Scholar 

  189. 189.

    Romeo, S. et al. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J. Clin. Invest. 119, 70–79 (2009).

    CAS  PubMed  Google Scholar 

  190. 190.

    Aryal, B. et al. Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis. JCI Insight 3, 97918 (2018).

    PubMed  Google Scholar 

  191. 191.

    Lusis, A. J. et al. The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits. J. Lipid Res. 57, 925–942 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Seldin, M. M. et al. A strategy for discovery of endocrine interactions with application to whole-body metabolism. Cell Metab. 27, 1138–1155.e1136 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Heron, M. Deaths: leading causes for 2010. Natl Vital Stat. Rep. 62, 1–96 (2013).

    PubMed  Google Scholar 

  194. 194.

    Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    Libby, P. & Hansson, G. K. Inflammation and immunity in diseases of the arterial tree: players and layers. Circ. Res. 116, 307–311 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Gisterå, A. & Hansson, G. K. The immunology of atherosclerosis. Nat. Rev. Nephrol. 13, 368–380 (2017).

    PubMed  Google Scholar 

  197. 197.

    Lee, S. D. & Tontonoz, P. Liver X receptors at the intersection of lipid metabolism and atherogenesis. Atherosclerosis 242, 29–36 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Rahman, K. & Fisher, E. A. Insights from pre-clinical and clinical studies on the role of innate inflammation in atherosclerosis regression. Front. Cardiovasc. Med. 5, 32 (2018).

    PubMed  PubMed Central  Google Scholar 

  199. 199.

    Farr, O. M., Li, C. R. & Mantzoros, C. S. Central nervous system regulation of eating: insights from human brain imaging. Metabolism 65, 699–713 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200.

    Soto, M., Cai, W., Konishi, M. & Kahn, C. R. Insulin signalling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc. Natl Acad. Sci. USA 116, 6379–6384 (2019).

    CAS  PubMed  Google Scholar 

  201. 201.

    He, Z. et al. Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol. Metab. 18, 107–119 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Tkach, M. & Théry, C. Communication by extracellular vesicles: where we are and where we need to go. Cell 164, 1226–1232 (2016).

    CAS  PubMed  Google Scholar 

  203. 203.

    Crewe, C. et al. An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state. Cell 175, 695–708.e613 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Chen, Y. et al. Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat. Commun. 7, 11420 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Deng, Z. B. et al. Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance. Diabetes 58, 2498–2505 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Xie, Z. et al. Adipose-derived exosomes exert proatherogenic effects by regulating macrophage foam cell formation and polarization. J. Am. Heart Assoc. 7, e007442 (2018).

    PubMed  PubMed Central  Google Scholar 

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C.P. and P.T. prepared the original draft and revised the manuscript. C.P. prepared the figures.

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Priest, C., Tontonoz, P. Inter-organ cross-talk in metabolic syndrome. Nat Metab 1, 1177–1188 (2019). https://doi.org/10.1038/s42255-019-0145-5

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