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Endosomal trafficking in metabolic homeostasis and diseases

Nature Reviews Endocrinology volume 19, pages 28–45 (2023)Cite this article

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An Author Correction to this article was published on 31 October 2022

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Abstract

The global prevalences of obesity and type 2 diabetes mellitus have reached epidemic status, presenting a heavy burden on society. It is therefore essential to find novel mechanisms and targets that could be utilized in potential treatment strategies and, as such, intracellular membrane trafficking has re-emerged as a regulatory tool for controlling metabolic homeostasis. Membrane trafficking is an essential physiological process that is responsible for the sorting and distribution of signalling receptors, membrane transporters and hormones or other ligands between different intracellular compartments and the plasma membrane. Dysregulation of intracellular transport is associated with many human diseases, including cancer, neurodegeneration, immune deficiencies and metabolic diseases, such as type 2 diabetes mellitus and its associated complications. This Review focuses on the latest advances on the role of endosomal membrane trafficking in metabolic physiology and pathology in vivo, highlighting the importance of this research field in targeting metabolic diseases.

Key points

  • The endosomal system controls signalling involved in metabolic physiology by tuning the trafficking and distribution of key proteins.

  • Some of the core machineries involved in the endosomal system are altered in metabolic diseases.

  • Tuning the endosomal system could improve metabolic parameters in metabolic diseases.

  • Altering receptor trafficking through ligand-biased agonism is a potential novel therapeutic strategy for metabolic pathologies.

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Fig. 1: Overview of the endosomal system and the trafficking routes of metabolically relevant receptors and transporters.
Fig. 2: Endosomal insulin receptor signalling.
Fig. 3: GSV retention and release mechanisms.
Fig. 4: LDL receptor recycling and degradation.

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References

  1. Laaksonen, D. E. et al. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am. J. Epidemiol. 156, 1070–1077 (2002).

    Article  Google Scholar 

  2. Sattar, N. et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 108, 414–419 (2003).

    Article  CAS  Google Scholar 

  3. Noubiap, J. J. et al. Geographic distribution of metabolic syndrome and its components in the general adult population: a meta-analysis of global data from 28 million individuals. Diabetes Res. Clin. Pract. 188, 109924 (2022).

    Article  CAS  Google Scholar 

  4. Lillich, F. F., Imig, J. D. & Proschak, E. Multi-target approaches in metabolic syndrome. Front. Pharmacol. 11, 554961 (2020).

    Article  CAS  Google Scholar 

  5. Müller, T. D., Blüher, M., Tschöp, M. H. & DiMarchi, R. D. Anti-obesity drug discovery: advances and challenges. Nat. Rev. Drug Discov. 21, 201–223 (2022).

    Article  Google Scholar 

  6. Shaffner, J., Chen, B., Malhotra, D. K., Dworkin, L. D. & Gong, R. Therapeutic targeting of SGLT2: a new era in the treatment of diabetes and diabetic kidney disease. Front. Endocrinol. 12, 749010 (2021).

    Article  Google Scholar 

  7. Filipovic, B. et al. The new therapeutic approaches in the treatment of non-alcoholic fatty liver disease. Int. J. Mol. Sci. https://doi.org/10.3390/ijms222413219 (2021).

    Article  Google Scholar 

  8. Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).

    Article  CAS  Google Scholar 

  9. Tak, Y. J. & Lee, S. Y. Anti-obesity drugs: long-term efficacy and safety: an updated review. World J. Mens Health 39, 208–221 (2021).

    Article  Google Scholar 

  10. Coskun, T. et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol. Metab. 18, 3–14 (2018).

    Article  CAS  Google Scholar 

  11. Müller, T. D. et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72–130 (2019).

    Article  Google Scholar 

  12. Cullen, P. J. & Steinberg, F. To degrade or not to degrade: mechanisms and significance of endocytic recycling. Nat. Rev. Mol. Cell Biol. 19, 679–696 (2018).

    Article  CAS  Google Scholar 

  13. Villasenor, R., Kalaidzidis, Y. & Zerial, M. Signal processing by the endosomal system. Curr. Opin. Cell Biol. 39, 53–60 (2016).

    Article  CAS  Google Scholar 

  14. Villasenor, R., Nonaka, H., Del Conte-Zerial, P., Kalaidzidis, Y. & Zerial, M. Regulation of EGFR signal transduction by analogue-to-digital conversion in endosomes. Elife https://doi.org/10.7554/eLife.06156 (2015).

    Article  Google Scholar 

  15. Vazirani, R. P. et al. Disruption of adipose Rab10-dependent insulin signaling causes hepatic insulin resistance. Diabetes 65, 1577–1589 (2016).

    Article  CAS  Google Scholar 

  16. Zeigerer, A. et al. Regulation of liver metabolism by the endosomal GTPase Rab5. Cell Rep. 11, 884–892 (2015).

    Article  CAS  Google Scholar 

  17. Bartuzi, P. et al. CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nat. Commun. 7, 10961 (2016).

    Article  CAS  Google Scholar 

  18. Fedoseienko, A. et al. The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking. Circ. Res. 122, 1648–1660 (2018).

    Article  CAS  Google Scholar 

  19. Seitz, S. et al. Hepatic Rab24 controls blood glucose homeostasis via improving mitochondrial plasticity. Nat. Metab. 1, 1009–1026 (2019).

    Article  CAS  Google Scholar 

  20. Trelford, C. B. & Di Guglielmo, G. M. Molecular mechanisms of mammalian autophagy. Biochem. J. 478, 3395–3421 (2021).

    Article  CAS  Google Scholar 

  21. Papandreou, M. E. & Tavernarakis, N. Crosstalk between endo/exocytosis and autophagy in health and disease. Biotechnol. J. 15, e1900267 (2020).

    Article  Google Scholar 

  22. Buratta, S. et al. Lysosomal exocytosis, exosome release and secretory autophagy: the autophagic- and endo-lysosomal systems go extracellular. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21072576 (2020).

    Article  Google Scholar 

  23. Mayor, S., Parton, R. G. & Donaldson, J. G. Clathrin-independent pathways of endocytosis. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a016758 (2014).

    Article  Google Scholar 

  24. Merrifield, C. J. & Kaksonen, M. Endocytic accessory factors and regulation of clathrin-mediated endocytosis. Cold Spring Harb. Perspect. Biol. 6, a016733 (2014).

    Article  Google Scholar 

  25. Maxfield, F. R. Role of endosomes and lysosomes in human disease. Cold Spring Harb. Perspect. Biol. 6, a016931 (2014).

    Article  Google Scholar 

  26. Mellman, I. & Yarden, Y. Endocytosis and cancer. Cold Spring Harb. Perspect. Biol. 5, a016949 (2013).

    Article  Google Scholar 

  27. Gilleron, J., Gerdes, J. M. & Zeigerer, A. Metabolic regulation through the endosomal system. Traffic https://doi.org/10.1111/tra.12670 (2019).

    Article  Google Scholar 

  28. Grant, B. D. & Donaldson, J. G. Pathways and mechanisms of endocytic recycling. Nat. Rev. Mol. Cell Biol. 10, 597–608 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Hunter, T. Tyrosine phosphorylation: thirty years and counting. Curr. Opin. Cell Biol. 21, 140–146 (2009).

    Article  CAS  Google Scholar 

  31. Popovic, D., Vucic, D. & Dikic, I. Ubiquitination in disease pathogenesis and treatment. Nat. Med. 20, 1242–1253 (2014).

    Article  CAS  Google Scholar 

  32. Andreou, A. M. & Tavernarakis, N. SUMOylation and cell signalling. Biotechnol. J. 4, 1740–1752 (2009).

    Article  CAS  Google Scholar 

  33. Sanger, A., Hirst, J., Davies, A. K. & Robinson, M. S. Adaptor protein complexes and disease at a glance. J. Cell Sci. https://doi.org/10.1242/jcs.222992 (2019).

    Article  Google Scholar 

  34. Bonifacino, J. S. & Lippincott-Schwartz, J. Coat proteins: shaping membrane transport. Nat. Rev. Mol. Cell Biol. 4, 409–414 (2003).

    Article  CAS  Google Scholar 

  35. Koike, S. & Jahn, R. SNARE proteins: zip codes in vesicle targeting? Biochem. J. 479, 273–288 (2022).

    Article  CAS  Google Scholar 

  36. Wandinger-Ness, A. & Zerial, M. Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harb. Perspect. Biol. 6, a022616 (2014).

    Article  Google Scholar 

  37. Szymanska, E., Budick-Harmelin, N. & Miaczynska, M. Endosomal “sort” of signaling control: the role of ESCRT machinery in regulation of receptor-mediated signaling pathways. Semin. Cell Dev. Biol. 74, 11–20 (2018).

    Article  CAS  Google Scholar 

  38. White, M. F. & Kahn, C. R. Insulin action at a molecular level–100 years of progress. Mol. Metab. 52, 101304 (2021).

    Article  CAS  Google Scholar 

  39. Fagerholm, S., Ortegren, U., Karlsson, M., Ruishalme, I. & Stralfors, P. Rapid insulin-dependent endocytosis of the insulin receptor by caveolae in primary adipocytes. PLoS ONE 4, e5985 (2009).

    Article  Google Scholar 

  40. McClain, D. A. & Olefsky, J. M. Evidence for two independent pathways of insulin-receptor internalization in hepatocytes and hepatoma cells. Diabetes 37, 806–815 (1988).

    Article  CAS  Google Scholar 

  41. Couet, J., Li, S., Okamoto, T., Ikezu, T. & Lisanti, M. P. Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J. Biol. Chem. 272, 6525–6533 (1997).

    Article  CAS  Google Scholar 

  42. Nystrom, F. H., Chen, H., Cong, L. N., Li, Y. & Quon, M. J. Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells. Mol. Endocrinol. 13, 2013–2024 (1999).

    Article  CAS  Google Scholar 

  43. Carpentier, J. L. et al. Two steps of insulin receptor internalization depend on different domains of the beta-subunit. J. Cell Biol. 122, 1243–1252 (1993).

    Article  CAS  Google Scholar 

  44. Ceresa, B. P., Kao, A. W., Santeler, S. R. & Pessin, J. E. Inhibition of clathrin-mediated endocytosis selectively attenuates specific insulin receptor signal transduction pathways. Mol. Cell Biol. 18, 3862–3870 (1998).

    Article  CAS  Google Scholar 

  45. Iraburu, M. J., Garner, T. & Montiel-Duarte, C. Revising endosomal trafficking under insulin receptor activation. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22136978 (2021).

    Article  Google Scholar 

  46. Fan, J. Y. et al. Receptor-mediated endocytosis of insulin: role of microvilli, coated pits, and coated vesicles. Proc. Natl Acad. Sci. USA 79, 7788–7791 (1982).

    Article  CAS  Google Scholar 

  47. Cohen, A. W. et al. Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am. J. Physiol. Cell Physiol. 285, C222–C235 (2003).

    Article  CAS  Google Scholar 

  48. Razani, B. et al. Caveolin-2-deficient mice show evidence of severe pulmonary dysfunction without disruption of caveolae. Mol. Cell Biol. 22, 2329–2344 (2002).

    Article  CAS  Google Scholar 

  49. Langin, D. Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Pharmacol. Res. 53, 482–491 (2006).

    Article  CAS  Google Scholar 

  50. Kim, C. A. et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli–Seip congenital lipodystrophy. J. Clin. Endocrinol. Metab. 93, 1129–1134 (2008).

    Article  CAS  Google Scholar 

  51. Mann, J. P. & Savage, D. B. What lipodystrophies teach us about the metabolic syndrome. J. Clin. Invest. 129, 4009–4021 (2019).

    Article  Google Scholar 

  52. Boucher, J. et al. Differential roles of insulin and IGF-1 receptors in adipose tissue development and function. Diabetes 65, 2201–2213 (2016).

    Article  CAS  Google Scholar 

  53. Ansarullah et al. Inceptor counteracts insulin signalling in β-cells to control glycaemia. Nature 590, 326–331 (2021).

    Article  CAS  Google Scholar 

  54. Rosen, O. M., Herrera, R., Olowe, Y., Petruzzelli, L. M. & Cobb, M. H. Phosphorylation activates the insulin receptor tyrosine protein kinase. Proc. Natl Acad. Sci. USA 80, 3237–3240 (1983).

    Article  CAS  Google Scholar 

  55. Bevan, A. P. et al. Selective activation of the rat hepatic endosomal insulin receptor kinase. Role for the endosome in insulin signaling. J. Biol. Chem. 270, 10784–10791 (1995).

    Article  CAS  Google Scholar 

  56. Christoforidis, S., McBride, H. M., Burgoyne, R. D. & Zerial, M. The Rab5 effector EEA1 is a core component of endosome docking. Nature 397, 621–625 (1999).

    Article  CAS  Google Scholar 

  57. Schenck, A. et al. The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 133, 486–497 (2008).

    Article  CAS  Google Scholar 

  58. Kalaidzidis, I. et al. APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments. J. Cell Biol. 211, 123–144 (2015).

    Article  CAS  Google Scholar 

  59. Mitsuuchi, Y. et al. Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Oncogene 18, 4891–4898 (1999).

    Article  CAS  Google Scholar 

  60. Ryu, J. et al. APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep. 7, 1227–1238 (2014).

    Article  CAS  Google Scholar 

  61. Tan, Y., You, H., Coffey, F. J., Wiest, D. L. & Testa, J. R. Appl1 is dispensable for Akt signaling in vivo and mouse T-cell development. Genesis 48, 531–539 (2010).

    Article  CAS  Google Scholar 

  62. Cheng, K. K. et al. APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cell Metab. 9, 417–427 (2009).

    Article  CAS  Google Scholar 

  63. Alliouachene, S. et al. Inactivation of the class II PI3K-C2β potentiates insulin signaling and sensitivity. Cell Rep. 13, 1881–1894 (2015).

    Article  CAS  Google Scholar 

  64. Hunker, C. M. et al. Role of Rab5 in insulin receptor-mediated endocytosis and signaling. Arch. Biochem. Biophys. 449, 130–142 (2006).

    Article  CAS  Google Scholar 

  65. Haeusler, R. A., McGraw, T. E. & Accili, D. Biochemical and cellular properties of insulin receptor signalling. Nat. Rev. Mol. Cell Biol. 19, 31–44 (2018).

    Article  CAS  Google Scholar 

  66. Zeigerer, A. et al. Rab5 is necessary for the biogenesis of the endolysosomal system in vivo. Nature 485, 465–470 (2012).

    Article  CAS  Google Scholar 

  67. Tokarz, V. L., MacDonald, P. E. & Klip, A. The cell biology of systemic insulin function. J. Cell Biol. 217, 2273–2289 (2018).

    Article  CAS  Google Scholar 

  68. Seely, B. L. et al. Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes 45, 1379–1385 (1996).

    Article  CAS  Google Scholar 

  69. Byon, J. C., Kusari, A. B. & Kusari, J. Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction. Mol. Cell Biochem. 182, 101–108 (1998).

    Article  CAS  Google Scholar 

  70. Carpentier, J. L., Fehlmann, M., Van Obberghen, E., Gorden, P. & Orci, L. Insulin receptor internalization and recycling: mechanism and significance. Biochimie 67, 1143–1145 (1985).

    Article  CAS  Google Scholar 

  71. Gillingham, A. K. & Munro, S. The small G proteins of the Arf family and their regulators. Annu. Rev. Cell Dev. Biol. 23, 579–611 (2007).

    Article  CAS  Google Scholar 

  72. Rodiger, M. et al. Adiponectin release and insulin receptor targeting share trans-Golgi-dependent endosomal trafficking routes. Mol. Metab. 8, 167–179 (2018).

    Article  Google Scholar 

  73. Authier, F. & Desbuquois, B. Glucagon receptors. Cell Mol. Life Sci. 65, 1880–1899 (2008).

    Article  CAS  Google Scholar 

  74. Zeigerer, A. et al. Glucagon’s metabolic action in health and disease. Compr. Physiol. 11, 1759–1783 (2021).

    Article  Google Scholar 

  75. Merlen, C., Fabrega, S., Desbuquois, B., Unson, C. G. & Authier, F. Glucagon-mediated internalization of serine-phosphorylated glucagon receptor and Gsα in rat liver. FEBS Lett. 580, 5697–5704 (2006).

    Article  CAS  Google Scholar 

  76. Watanabe, J., Kanai, K. & Kanamura, S. Glucagon receptors in endothelial and Kupffer cells of mouse liver. J. Histochem. Cytochem. 36, 1081–1089 (1988).

    Article  CAS  Google Scholar 

  77. Krilov, L. et al. Dual mode of glucagon receptor internalization: role of PKCα, GRKs and β-arrestins. Exp. Cell Res. 317, 2981–2994 (2011).

    Article  CAS  Google Scholar 

  78. Authier, F., Janicot, M., Lederer, F. & Desbuquois, B. Fate of injected glucagon taken up by rat liver in vivo. Degradation of internalized ligand in the endosomal compartment. Biochem. J. 272, 703–712 (1990).

    Article  CAS  Google Scholar 

  79. Krilov, L., Nguyen, A., Miyazaki, T., Unson, C. G. & Bouscarel, B. Glucagon receptor recycling: role of carboxyl terminus, β-arrestins, and cytoskeleton. Am. J. Physiol. Cell Physiol. 295, C1230–C1237 (2008).

    Article  CAS  Google Scholar 

  80. Bomholt, A. B. et al. Evaluation of commercially available glucagon receptor antibodies and glucagon receptor expression. bioRxiv https://doi.org/10.1101/2021.12.21.473442 (2021).

    Article  Google Scholar 

  81. Van Der Sluijs, P. et al. The small GTP-binding protein rab4 is associated with early endosomes. Proc. Natl Acad. Sci. USA 88, 6313–6317 (1991).

    Article  Google Scholar 

  82. Perrin, L. et al. Rab4b controls an early endosome sorting event by interacting with the γ-subunit of the clathrin adaptor complex 1. J. Cell Sci. 126, 4950–4962 (2013).

    CAS  Google Scholar 

  83. Kaur, S., Chen, Y. & Shenoy, S. K. Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling. J. Biol. Chem. 295, 16630–16642 (2020).

    Article  CAS  Google Scholar 

  84. Cegla, J. et al. RAMP2 influences glucagon receptor pharmacology via trafficking and signaling. Endocrinology 158, 2680–2693 (2017).

    Article  CAS  Google Scholar 

  85. McGlone, E. R. et al. Receptor activity-modifying protein 2 (RAMP2) alters glucagon receptor trafficking in hepatocytes with functional effects on receptor signalling. Mol. Metab. 53, 101296 (2021).

    Article  CAS  Google Scholar 

  86. Zhu, L. et al. Hepatic β-arrestin 2 is essential for maintaining euglycemia. J. Clin. Invest. 127, 2941–2945 (2017).

    Article  Google Scholar 

  87. Wang, Y. et al. Glucagon is associated with NAFLD inflammatory progression in type 2 diabetes, not with NAFLD fibrotic progression. Eur. J. Gastroenterol. Hepatol. 33, e818–e823 (2021).

    Article  CAS  Google Scholar 

  88. Sorensen, H. et al. Glucagon receptor knockout mice display increased insulin sensitivity and impaired β-cell function. Diabetes 55, 3463–3469 (2006).

    Article  Google Scholar 

  89. Conarello, S. L. et al. Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia 50, 142–150 (2007).

    Article  CAS  Google Scholar 

  90. Drucker, D. J. & Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696–1705 (2006).

    Article  CAS  Google Scholar 

  91. Campbell, J. E. Targeting the GIPR for obesity: to agonize or antagonize? Potential mechanisms. Mol. Metab. 46, 101139 (2021).

    Article  CAS  Google Scholar 

  92. Morgan, L. M., Flatt, P. R. & Marks, V. Nutrient regulation of the enteroinsular axis and insulin secretion. Nutr. Res. Rev. 1, 79–97 (1988).

    Article  CAS  Google Scholar 

  93. Yamada, Y. & Seino, Y. Physiology of GIP–a lesson from GIP receptor knockout mice. Horm. Metab. Res. 36, 771–774 (2004).

    Article  CAS  Google Scholar 

  94. El, K. & Campbell, J. E. The role of GIP in α-cells and glucagon secretion. Peptides 125, 170213 (2020).

    Article  CAS  Google Scholar 

  95. Zhang, Q. et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab. 33, 833–844.e5 (2021).

    Article  CAS  Google Scholar 

  96. Mohammad, S. et al. Gastric inhibitory peptide controls adipose insulin sensitivity via activation of cAMP-response element-binding protein and p110β isoform of phosphatidylinositol 3-kinase. J. Biol. Chem. 286, 43062–43070 (2011).

    Article  CAS  Google Scholar 

  97. Mohammad, S. et al. A naturally occurring GIP receptor variant undergoes enhanced agonist-induced desensitization, which impairs GIP control of adipose insulin sensitivity. Mol. Cell Biol. 34, 3618–3629 (2014).

    Article  Google Scholar 

  98. Gabe, M. B. N. et al. Human GIP(3-30)NH2 inhibits G protein-dependent as well as G protein-independent signaling and is selective for the GIP receptor with high-affinity binding to primate but not rodent GIP receptors. Biochem. Pharmacol. 150, 97–107 (2018).

    Article  CAS  Google Scholar 

  99. Abdullah, N., Beg, M., Soares, D., Dittman, J. S. & McGraw, T. E. Downregulation of a GPCR by β-arrestin2-mediated switch from an endosomal to a TGN recycling pathway. Cell Rep. 17, 2966–2978 (2016).

    Article  CAS  Google Scholar 

  100. Ismail, S. et al. Internalized receptor for glucose-dependent insulinotropic peptide stimulates adenylyl cyclase on early endosomes. Biochem. Pharmacol. 120, 33–45 (2016).

    Article  CAS  Google Scholar 

  101. Roussel, M., Mathieu, J. & Dalle, S. Molecular mechanisms redirecting the GLP-1 receptor signalling profile in pancreatic β-cells during type 2 diabetes. Horm. Mol. Biol. Clin. Investig. 26, 87–95 (2016).

    CAS  Google Scholar 

  102. Pierce, K. L., Premont, R. T. & Lefkowitz, R. J. Seven-transmembrane receptors. Nat. Rev. Mol. Cell Biol. 3, 639–650 (2002).

    Article  CAS  Google Scholar 

  103. Girada, S. B. et al. Gαs regulates glucagon-like peptide 1 receptor-mediated cyclic AMP generation at Rab5 endosomal compartment. Mol. Metab. 6, 1173–1185 (2017).

    Article  CAS  Google Scholar 

  104. Syme, C. A., Zhang, L. & Bisello, A. Caveolin-1 regulates cellular trafficking and function of the glucagon-like peptide 1 receptor. Mol. Endocrinol. 20, 3400–3411 (2006).

    Article  CAS  Google Scholar 

  105. Buenaventura, T. et al. A targeted RNAi screen identifies endocytic trafficking factors that control GLP-1 receptor signaling in pancreatic β-cells. Diabetes 67, 385–399 (2018).

    Article  CAS  Google Scholar 

  106. Li, D. T. et al. GLUT4 storage vesicles: specialized organelles for regulated trafficking. Yale J. Biol. Med. 92, 453–470 (2019).

    CAS  Google Scholar 

  107. Gould, G. W., Brodsky, F. M. & Bryant, N. J. Building GLUT4 vesicles: CHC22 clathrin’s human touch. Trends Cell Biol. 30, 705–719 (2020).

    Article  CAS  Google Scholar 

  108. Batty, S. R. & Langlais, P. R. Microtubules in insulin action: what’s on the tube? Trends Endocrinol. Metab. 32, 776–789 (2021).

    Article  CAS  Google Scholar 

  109. Jaldin-Fincati, J. R., Pavarotti, M., Frendo-Cumbo, S., Bilan, P. J. & Klip, A. Update on GLUT4 vesicle traffic: a cornerstone of insulin action. Trends Endocrinol. Metab. 28, 597–611 (2017).

    Article  CAS  Google Scholar 

  110. Stockli, J., Fazakerley, D. J. & James, D. E. GLUT4 exocytosis. J. Cell Sci. 124, 4147–4159 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  112. Foley, K., Boguslavsky, S. & Klip, A. Endocytosis, recycling, and regulated exocytosis of glucose transporter 4. Biochemistry 50, 3048–3061 (2011).

    Article  CAS  Google Scholar 

  113. Bogan, J. S. Regulation of glucose transporter translocation in health and diabetes. Annu. Rev. Biochem. 81, 507–532 (2012).

    Article  CAS  Google Scholar 

  114. Zeigerer, A. et al. GLUT4 retention in adipocytes requires two intracellular insulin-regulated transport steps. Mol. Biol. Cell 13, 2421–2435 (2002).

    Article  CAS  Google Scholar 

  115. Volchuk, A. et al. Perturbation of dynamin II with an amphiphysin SH3 domain increases GLUT4 glucose transporters at the plasma membrane in 3T3-L1 adipocytes. Dynamin II participates in GLUT4 endocytosis. J. Biol. Chem. 273, 8169–8176 (1998).

    Article  CAS  Google Scholar 

  116. Nishimura, H., Zarnowski, M. J. & Simpson, I. A. Glucose transporter recycling in rat adipose cells. Effects of potassium depletion. J. Biol. Chem. 268, 19246–19253 (1993).

    Article  CAS  Google Scholar 

  117. Robinson, L. J., Pang, S., Harris, D. S., Heuser, J. & James, D. E. Translocation of the glucose transporter (GLUT4) to the cell surface in permeabilized 3T3-L1 adipocytes: effects of ATP insulin, and GTP gamma S and localization of GLUT4 to clathrin lattices. J. Cell Biol. 117, 1181–1196 (1992).

    Article  CAS  Google Scholar 

  118. Marsh, B. J., Alm, R. A., McIntosh, S. R. & James, D. E. Molecular regulation of GLUT-4 targeting in 3T3-L1 adipocytes. J. Cell Biol. 130, 1081–1091 (1995).

    Article  CAS  Google Scholar 

  119. Pan, X., Zaarur, N., Singh, M., Morin, P. & Kandror, K. V. Sortilin and retromer mediate retrograde transport of Glut4 in 3T3-L1 adipocytes. Mol. Biol. Cell 28, 1667–1675 (2017).

    Article  CAS  Google Scholar 

  120. Yang, Z. et al. Functional characterization of retromer in GLUT4 storage vesicle formation and adipocyte differentiation. FASEB J. 30, 1037–1050 (2016).

    Article  CAS  Google Scholar 

  121. Blot, V. & McGraw, T. E. Molecular mechanisms controlling GLUT4 intracellular retention. Mol. Biol. Cell 19, 3477–3487 (2008).

    Article  CAS  Google Scholar 

  122. Foley, K. P. & Klip, A. Dynamic GLUT4 sorting through a syntaxin-6 compartment in muscle cells is derailed by insulin resistance-causing ceramide. Biol. Open 3, 314–325 (2014).

    Article  CAS  Google Scholar 

  123. Shewan, A. M. et al. GLUT4 recycles via a trans-Golgi network (TGN) subdomain enriched in syntaxins 6 and 16 but not TGN38: involvement of an acidic targeting motif. Mol. Biol. Cell 14, 973–986 (2003).

    Article  CAS  Google Scholar 

  124. Proctor, K. M., Miller, S. C., Bryant, N. J. & Gould, G. W. Syntaxin 16 controls the intracellular sequestration of GLUT4 in 3T3-L1 adipocytes. Biochem. Biophys. Res. Commun. 347, 433–438 (2006).

    Article  CAS  Google Scholar 

  125. Li, L. V. & Kandror, K. V. Golgi-localized, γ-ear-containing, Arf-binding protein adaptors mediate insulin-responsive trafficking of glucose transporter 4 in 3T3-L1 adipocytes. Mol. Endocrinol. 19, 2145–2153 (2005).

    Article  CAS  Google Scholar 

  126. Vollenweider, P. et al. The small guanosine triphosphate-binding protein Rab4 is involved in insulin-induced GLUT4 translocation and actin filament rearrangement in 3T3-L1 cells. Endocrinology 138, 4941–4949 (1997).

    Article  CAS  Google Scholar 

  127. Cormont, M. et al. Potential role of Rab4 in the regulation of subcellular localization of Glut4 in adipocytes. Mol. Cell Biol. 16, 6879–6886 (1996).

    Article  CAS  Google Scholar 

  128. Mari, M. et al. The Rab4 effector Rabip4 plays a role in the endocytotic trafficking of Glut 4 in 3T3-L1 adipocytes. J. Cell Sci. 119, 1297–1306 (2006).

    Article  CAS  Google Scholar 

  129. Lampson, M. A., Schmoranzer, J., Zeigerer, A., Simon, S. M. & McGraw, T. E. Insulin-regulated release from the endosomal recycling compartment is regulated by budding of specialized vesicles. Mol. Biol. Cell 12, 3489–3501 (2001).

    Article  CAS  Google Scholar 

  130. Hirshman, M. F., Goodyear, L. J., Wardzala, L. J., Horton, E. D. & Horton, E. S. Identification of an intracellular pool of glucose transporters from basal and insulin-stimulated rat skeletal muscle. J. Biol. Chem. 265, 987–991 (1990).

    Article  CAS  Google Scholar 

  131. Tanti, J. F., Gremeaux, T., Van Obberghen, E. & Le Marchand-Brustel, Y. Insulin receptor substrate 1 is phosphorylated by the serine kinase activity of phosphatidylinositol 3-kinase. Biochem. J. 304, 17–21 (1994).

    Article  CAS  Google Scholar 

  132. Hopkins, B. D., Goncalves, M. D. & Cantley, L. C. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat. Rev. Endocrinol. 16, 276–283 (2020).

    Article  CAS  Google Scholar 

  133. Bjornholm, M., Kawano, Y., Lehtihet, M. & Zierath, J. R. Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46, 524–527 (1997).

    Article  CAS  Google Scholar 

  134. Dannhauser, P. N. et al. CHC22 and CHC17 clathrins have distinct biochemical properties and display differential regulation and function. J. Biol. Chem. 292, 20834–20844 (2017).

    Article  CAS  Google Scholar 

  135. Camus, S. M. et al. CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis. J. Cell Biol. https://doi.org/10.1083/jcb.201812135 (2020).

    Article  Google Scholar 

  136. Garvey, W. T. et al. Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. J. Clin. Invest. 101, 2377–2386 (1998).

    Article  CAS  Google Scholar 

  137. Maianu, L., Keller, S. R. & Garvey, W. T. Adipocytes exhibit abnormal subcellular distribution and translocation of vesicles containing glucose transporter 4 and insulin-regulated aminopeptidase in type 2 diabetes mellitus: implications regarding defects in vesicle trafficking. J. Clin. Endocrinol. Metab. 86, 5450–5456 (2001).

    Article  CAS  Google Scholar 

  138. Zierath, J. R. et al. Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia 39, 1180–1189 (1996).

    Article  CAS  Google Scholar 

  139. Benninghoff, T. et al. The RabGAPs TBC1D1 and TBC1D4 control uptake of long-chain fatty acids into skeletal muscle via fatty acid transporter SLC27A4/FATP4. Diabetes 69, 2281–2293 (2020).

    Article  CAS  Google Scholar 

  140. Sano, H. et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem. 278, 14599–14602 (2003).

    Article  CAS  Google Scholar 

  141. Mafakheri, S. et al. AKT and AMP-activated protein kinase regulate TBC1D1 through phosphorylation and its interaction with the cytosolic tail of insulin-regulated aminopeptidase IRAP. J. Biol. Chem. 293, 17853–17862 (2018).

    Article  CAS  Google Scholar 

  142. Sakamoto, K. & Holman, G. D. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am. J. Physiol. Endocrinol. Metab. 295, E29–E37 (2008).

    Article  CAS  Google Scholar 

  143. Hatakeyama, H., Morino, T., Ishii, T. & Kanzaki, M. Cooperative actions of Tbc1d1 and AS160/Tbc1d4 in GLUT4-trafficking activities. J. Biol. Chem. 294, 1161–1172 (2019).

    Article  CAS  Google Scholar 

  144. Dash, S. et al. A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proc. Natl Acad. Sci. USA 106, 9350–9355 (2009).

    Article  CAS  Google Scholar 

  145. Miinea, C. P. et al. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem. J. 391, 87–93 (2005).

    Article  CAS  Google Scholar 

  146. Roach, W. G., Chavez, J. A., Miinea, C. P. & Lienhard, G. E. Substrate specificity and effect on GLUT4 translocation of the Rab GTPase-activating protein Tbc1d1. Biochem. J. 403, 353–358 (2007).

    Article  CAS  Google Scholar 

  147. Stockli, J., Fazakerley, D. J., Coster, A. C., Holman, G. D. & James, D. E. Muscling in on GLUT4 kinetics. Commun. Integr. Biol. 3, 260–262 (2010).

    Article  Google Scholar 

  148. Fazakerley, D. J., Koumanov, F. & Holman, G. D. GLUT4 on the move. Biochem. J. 479, 445–462 (2022).

    Article  CAS  Google Scholar 

  149. Belman, J. P. et al. Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin-responsive intracellular compartment. J. Biol. Chem. 290, 4447–4463 (2015).

    Article  CAS  Google Scholar 

  150. Bogan, J. S. et al. Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation. J. Biol. Chem. 287, 23932–23947 (2012).

    Article  CAS  Google Scholar 

  151. Habtemichael, E. N. et al. Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes. J. Biol. Chem. 293, 10466–10486 (2018).

    Article  CAS  Google Scholar 

  152. Habtemichael, E. N. et al. Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake. Nat. Metab. 3, 378–393 (2021).

    Article  CAS  Google Scholar 

  153. Fischer, A. W. et al. The adaptor protein PID1 regulates receptor-dependent endocytosis of postprandial triglyceride-rich lipoproteins. Mol. Metab. 16, 88–99 (2018).

    Article  CAS  Google Scholar 

  154. Jedrychowski, M. P. et al. Proteomic analysis of GLUT4 storage vesicles reveals LRP1 to be an important vesicle component and target of insulin signaling. J. Biol. Chem. 285, 104–114 (2010).

    Article  CAS  Google Scholar 

  155. Fischer, A. W. et al. PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles. Biochim. Biophys. Acta Mol. Basis Dis. 1865, 1592–1603 (2019).

    Article  CAS  Google Scholar 

  156. Goldstein, J. L. & Brown, M. S. The LDL receptor. Arterioscler. Thromb. Vasc. Biol. 29, 431–438 (2009).

    Article  CAS  Google Scholar 

  157. Go, G. W. & Mani, A. Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis. Yale J. Biol. Med. 85, 19–28 (2012).

    CAS  Google Scholar 

  158. Mishra, S. K., Watkins, S. C. & Traub, L. M. The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery. Proc. Natl Acad. Sci. USA 99, 16099–16104 (2002).

    Article  CAS  Google Scholar 

  159. He, G. et al. ARH is a modular adaptor protein that interacts with the LDL receptor, clathrin, and AP-2. J. Biol. Chem. 277, 44044–44049 (2002).

    Article  CAS  Google Scholar 

  160. Garuti, R. et al. The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits. J. Biol. Chem. 280, 40996–41004 (2005).

    Article  CAS  Google Scholar 

  161. Wu, J. H. et al. The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor. J. Biol. Chem. 278, 44238–44245 (2003).

    Article  CAS  Google Scholar 

  162. Kim, J. et al. Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration. Circ. Res. 103, 70–79 (2008).

    Article  CAS  Google Scholar 

  163. Zhang, C., Hao, C., Shui, G. & Li, W. BLOS1 mediates kinesin switch during endosomal recycling of LDL receptor. Elife https://doi.org/10.7554/eLife.58069 (2020).

    Article  Google Scholar 

  164. Scott, I., Wang, L., Wu, K., Thapa, D. & Sack, M. N. GCN5L1/BLOS1 links acetylation, organelle remodeling, and metabolism. Trends Cell Biol. 28, 346–355 (2018).

    Article  CAS  Google Scholar 

  165. Vos, D. Y. & van de Sluis, B. Function of the endolysosomal network in cholesterol homeostasis and metabolic-associated fatty liver disease (MAFLD). Mol. Metab. 50, 101146 (2021).

    Article  CAS  Google Scholar 

  166. Wijers, M. et al. The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance. JCI Insight https://doi.org/10.1172/jci.insight.126462 (2019).

    Article  Google Scholar 

  167. Zelcer, N., Hong, C., Boyadjian, R. & Tontonoz, P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325, 100–104 (2009).

    Article  CAS  Google Scholar 

  168. Poirier, S. & Mayer, G. The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol. Drug Des. Devel Ther. 7, 1135–1148 (2013).

    Google Scholar 

  169. Goldstein, J. L., Anderson, R. G. W. & Brown, M. S. In Ciba Foundation Symposium 92–Membrane Recycling Ch. 5 (eds Evered, D. & Collins, G.M.) 77–95 (Pitman, 1982).

  170. Jang, H. D. et al. Cyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9. Eur. Heart J. 41, 239–252 (2020).

    Article  CAS  Google Scholar 

  171. Ruscica, M. et al. Liver fat accumulation is associated with circulating PCSK9. Ann. Med. 48, 384–391 (2016).

    Article  CAS  Google Scholar 

  172. Krahmer, N. et al. Organellar proteomics and phospho-proteomics reveal subcellular reorganization in diet-induced hepatic steatosis. Dev. Cell 47, 205–221.e7 (2018).

    Article  CAS  Google Scholar 

  173. Luiken, J., Nabben, M., Neumann, D. & Glatz, J. F. C. Understanding the distinct subcellular trafficking of CD36 and GLUT4 during the development of myocardial insulin resistance. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165775 (2020).

    Article  CAS  Google Scholar 

  174. Xue, B. et al. Effects of high fat feeding on adipose tissue gene expression in diabetic Goto-Kakizaki rats. Gene Regul. Syst. Bio 9, 15–26 (2015).

    CAS  Google Scholar 

  175. Kita, Y. et al. Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. PLoS ONE 7, e43056 (2012).

    Article  CAS  Google Scholar 

  176. Gilleron, J. et al. Rab4b deficiency in T cells promotes adipose Treg/Th17 imbalance, adipose tissue dysfunction, and insulin resistance. Cell Rep. 25, 3329–3341.e25 (2018).

    Article  CAS  Google Scholar 

  177. Gandasi, N. R. et al. Glucose-dependent granule docking limits insulin secretion and is decreased in human type 2 diabetes. Cell Metab. 27, 470–478.e4 (2018).

    Article  CAS  Google Scholar 

  178. Kaddai, V. et al. Involvement of TNF-α in abnormal adipocyte and muscle sortilin expression in obese mice and humans. Diabetologia 52, 932–940 (2009).

    Article  CAS  Google Scholar 

  179. Salani, B. et al. Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells. FASEB J. 26, 788–798 (2012).

    Article  CAS  Google Scholar 

  180. Salis, O., Bedir, A., Ozdemir, T., Okuyucu, A. & Alacam, H. The relationship between anticancer effect of metformin and the transcriptional regulation of certain genes (CHOP, CAV-1, HO-1, SGK-1 and Par-4) on MCF-7 cell line. Eur. Rev. Med. Pharmacol. Sci. 18, 1602–1609 (2014).

    CAS  Google Scholar 

  181. Strong, A., Patel, K. & Rader, D. J. Sortilin and lipoprotein metabolism: making sense out of complexity. Curr. Opin. Lipidol. 25, 350–357 (2014).

    Article  CAS  Google Scholar 

  182. Musunuru, K. et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–719 (2010).

    Article  CAS  Google Scholar 

  183. Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).

    Article  CAS  Google Scholar 

  184. Conlon, D. M. et al. Sortilin restricts secretion of apolipoprotein B-100 by hepatocytes under stressed but not basal conditions. J. Clin. Invest. https://doi.org/10.1172/JCI144334 (2022).

    Article  Google Scholar 

  185. Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189–197 (2008).

    Article  CAS  Google Scholar 

  186. Myocardial Infarction Genetics Consortiumet al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009).

    Article  Google Scholar 

  187. Strong, A. et al. Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J. Clin. Invest. 122, 2807–2816 (2012).

    Article  CAS  Google Scholar 

  188. Conlon, D. M. Role of sortilin in lipid metabolism. Curr. Opin. Lipidol. 30, 198–204 (2019).

    Article  CAS  Google Scholar 

  189. Rabinowich, L. et al. Sortilin deficiency improves the metabolic phenotype and reduces hepatic steatosis of mice subjected to diet-induced obesity. J. Hepatol. 62, 175–181 (2015).

    Article  CAS  Google Scholar 

  190. Chen, C., Li, J., Matye, D. J., Wang, Y. & Li, T. Hepatocyte sortilin 1 knockout and treatment with a sortilin 1 inhibitor reduced plasma cholesterol in Western diet-fed mice. J. Lipid Res. 60, 539–549 (2019).

    Article  CAS  Google Scholar 

  191. Wu, L. et al. Rab8a-AS160-MSS4 regulatory circuit controls lipid droplet fusion and growth. Dev. Cell 30, 378–393 (2014).

    Article  CAS  Google Scholar 

  192. Deus, C. M., Yambire, K. F., Oliveira, P. J. & Raimundo, N. Mitochondria-lysosome crosstalk: from physiology to neurodegeneration. Trends Mol. Med. 26, 71–88 (2020).

    Article  CAS  Google Scholar 

  193. Hsu, F. et al. Rab5 and Alsin regulate stress-activated cytoprotective signaling on mitochondria. Elife https://doi.org/10.7554/eLife.32282 (2018).

    Article  Google Scholar 

  194. Sugiura, A., McLelland, G. L., Fon, E. A. & McBride, H. M. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J. 33, 2142–2156 (2014).

    Article  CAS  Google Scholar 

  195. Shin, H. W. et al. An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J. Cell Biol. 170, 607–618 (2005).

    Article  CAS  Google Scholar 

  196. Bilanges, B. et al. Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism. Nat. Commun. 8, 1804 (2017).

    Article  Google Scholar 

  197. Hamdi, A. et al. Erythroid cell mitochondria receive endosomal iron by a “kiss-and-run” mechanism. Biochim. Biophys. Acta 1863, 2859–2867 (2016).

    Article  CAS  Google Scholar 

  198. Wei, Z., Su, W., Lou, H., Duan, S. & Chen, G. Trafficking pathway between plasma membrane and mitochondria via clathrin-mediated endocytosis. J. Mol. Cell Biol. 10, 539–548 (2018).

    Article  CAS  Google Scholar 

  199. Hothersall, J. D., Brown, A. J., Dale, I. & Rawlins, P. Can residence time offer a useful strategy to target agonist drugs for sustained GPCR responses? Drug Discov. Today 21, 90–96 (2016).

    Article  CAS  Google Scholar 

  200. Jones, B. et al. Targeting GLP-1 receptor trafficking to improve agonist efficacy. Nat. Commun. 9, 1602 (2018).

    Article  Google Scholar 

  201. Pickford, P. et al. Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide. Br. J. Pharmacol. 177, 3905–3923 (2020).

    Article  CAS  Google Scholar 

  202. Novikoff, A. et al. Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Mol. Metab. 49, 101181 (2021).

    Article  CAS  Google Scholar 

  203. Wu, Q. et al. Biased agonists with less glucagon-like peptide-1 receptor-mediated endocytosis prolong hypoglycaemic effects. Eur. J. Pharmacol. 907, 174203 (2021).

    Article  CAS  Google Scholar 

  204. Marzook, A., Tomas, A. & Jones, B. The interplay of glucagon-like peptide-1 receptor trafficking and signalling in pancreatic beta cells. Front. Endocrinol. 12, 678055 (2021).

    Article  Google Scholar 

  205. Miaczynska, M. Effects of membrane trafficking on signaling by receptor tyrosine kinases. Cold Spring Harb. Perspect. Biol. 5, a009035 (2013).

    Article  Google Scholar 

  206. Eichel, K. & von Zastrow, M. Subcellular organization of GPCR signaling. Trends Pharmacol. Sci. 39, 200–208 (2018).

    Article  CAS  Google Scholar 

  207. Calebiro, D. et al. Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biol. 7, e1000172 (2009).

    Article  Google Scholar 

  208. Ahlqvist, E. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 6, 361–369 (2018).

    Article  Google Scholar 

  209. Zaharia, O. P. et al. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinol. 7, 684–694 (2019).

    Article  Google Scholar 

  210. Picatoste, B. et al. Defective insulin-stimulated GLUT4 translocation in brown adipocytes induces systemic glucose homeostasis dysregulation independent of thermogenesis in female mice. Mol. Metab. 53, 101305 (2021).

    Article  CAS  Google Scholar 

  211. Meier, J. J., Veldhuis, J. D. & Butler, P. C. Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes 54, 1649–1656 (2005).

    Article  CAS  Google Scholar 

  212. Farris, W. et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc. Natl Acad. Sci. USA 100, 4162–4167 (2003).

    Article  CAS  Google Scholar 

  213. Abdul-Hay, S. O. et al. Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS ONE 6, e20818 (2011).

    Article  CAS  Google Scholar 

  214. Steneberg, P. et al. The type 2 diabetes-associated gene Ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes 62, 2004–2014 (2013).

    Article  CAS  Google Scholar 

  215. Villasenor, R., Lampe, J., Schwaninger, M. & Collin, L. Intracellular transport and regulation of transcytosis across the blood-brain barrier. Cell Mol. Life Sci. 76, 1081–1092 (2019).

    Article  CAS  Google Scholar 

  216. Storck, S. E. et al. Endothelial LRP1 transports amyloid-β(1-42) across the blood-brain barrier. J. Clin. Invest. 126, 123–136 (2016).

    Article  Google Scholar 

  217. Nikolakopoulou, A. M. et al. Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A. J. Exp. Med. https://doi.org/10.1084/jem.20202207 (2021).

    Article  Google Scholar 

  218. Zhou, A. L. et al. Apolipoprotein A-I crosses the blood-brain barrier through clathrin-independent and cholesterol-mediated endocytosis. J. Pharmacol. Exp. Ther. 369, 481–488 (2019).

    Article  CAS  Google Scholar 

  219. Duquenne, M. et al. Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function. Nat. Metab. 3, 1071–1090 (2021).

    Article  CAS  Google Scholar 

  220. Kaksonen, M. & Roux, A. Mechanisms of clathrin-mediated endocytosis. Nat. Rev. Mol. Cell Biol. 19, 313–326 (2018).

    Article  CAS  Google Scholar 

  221. Chen, Z. & Schmid, S. L. Evolving models for assembling and shaping clathrin-coated pits. J. Cell Biol. https://doi.org/10.1083/jcb.202005126 (2020).

    Article  Google Scholar 

  222. Sorkin, A. Cargo recognition during clathrin-mediated endocytosis: a team effort. Curr. Opin. Cell Biol. 16, 392–399 (2004).

    Article  CAS  Google Scholar 

  223. Kelly, B. T. et al. A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex. Nature 456, 976–979 (2008).

    Article  CAS  Google Scholar 

  224. Lamaze, C., Tardif, N., Dewulf, M., Vassilopoulos, S. & Blouin, C. M. The caveolae dress code: structure and signaling. Curr. Opin. Cell Biol. 47, 117–125 (2017).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Sekar, S. Herzig and T.D. Müller (all at The Institute for Diabetes and Cancer, Helmholtz Munich, Germany), J. Heeren (University Clinic Hamburg Eppendorf, Hamburg, Germany), J.-F. Tanti and M. Cormont (both at the Université Côte d’Azur, INSERM UMR1065 C3M, Nice, France) and A. Schürmann (German Institute for Human Nutrition Potsdam-Rehbruecke, Potsdam, Germany) for helpful discussions and critical comments to the review. We thank L. Harrison (The Institute for Diabetes and Cancer, Helmholtz Munich, Germany) for creating the first drafts of the figures. The authors acknowledge the support of the DFG grants ZE1037/1-3 and ZE1037/3-2, H2020-MSCA-ITN 2020 Network grant ‘EndoConnect’ and the BMBF grant 16LW0116K to A.Z., and of INSERM, the Université Côte d’Azur and the Young Investigator Program of the ANR to J.G. (ANR18-CE14-0035-01-GILLERON).

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Author notes

  1. These authors contributed equally: Jerome Gilleron, Anja Zeigerer.

Authors and Affiliations

  1. Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1065 C3M, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France

    Jerome Gilleron

  2. Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany

    Anja Zeigerer

  3. German Center for Diabetes Research (DZD), Neuherberg, Germany

    Anja Zeigerer

Authors
  1. Jerome Gilleron
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J.G. and A.Z. contributed equally to all aspects of the article.

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Correspondence to Jerome Gilleron or Anja Zeigerer.

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Nature Reviews Endocrinology thanks Jacqueline Stöckli, Amira Klip and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Metabolic syndrome

A cluster of conditions that occur together, increasing the risk of heart disease, stroke and type 2 diabetes mellitus.

Non-alcoholic fatty liver disease

A generic term for liver steatosis unrelated to excessive alcoholic consumption.

Endocytosis

A process requiring complex molecular machineries to internalize plasma membrane-containing cargo.

Exocytosis

A cellular mechanism by which various molecules or proteins are transported from intracellular compartments towards the plasma membrane.

Endosomal system

A complex network of interacting organelles that comprise early, late and recycling endosomes.

Early endosomes

Also called sorting endosomes, these are endosomal compartments dedicated to cargo sorting to recycling or degradation pathways.

Late endosomes

Also called multivesicular bodies, these are intermediate endosomal compartments between early endosomes and lysosomes dedicated to concentrating cargo for degradation within intraluminal vesicles (vesicles generated within the lumen of endolysosomal organelles).

Recycling endosomes

Endosomal compartments dedicated to the recycling of cargo to the plasma membrane.

Lysosomes

Specialized organelles dedicated to the degradation of cargo.

Receptor desensitization

A process leading to a decrease in the responsiveness of downstream signalling of receptors.

Endolysosomal system

A complex network of interacting organelles that comprise the endosomal system plus lysosomes.

Endocytic system

A complex network of all organelles involved in endocytosis and endocytic trafficking.

Endosomal tubules

Tubules that arise from endosomes.

Ubiquitination

Post-translational modification that covalently links ubiquitin molecules to a protein.

Trans-Golgi network

A tubulovesicular network of membrane compartments located at the trans-side of the Golgi apparatus.

Intracellular storage pool

A pool of receptors and transmembrane proteins intracellularly stored within compartments that can be recruited at the plasma membrane in response to a specific signal.

Adaptor proteins

Proteins that act as connecting molecules. During endocytosis, adaptor proteins connect cargo to be internalized with the molecular machinery performing endocytosis.

Cargo

A generic term referring to transmembrane proteins (receptors, transporters, etc.), signalling ligands (hormones, growth factors, etc.) and internalized extracellular proteins or macromolecules (transferrin, lipoproteins, etc.).

Coat proteins

Proteins that act to shape and/or form vesicles.

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors

A large protein family whose members mediate vesicle fusion.

Endosomal sorting complexes required for transport

A large protein family whose members mediate intraluminal vesicle formation.

GTPase-activating proteins

Proteins able to activate the GTPase activity of proteins.

Dominant-negative RAB

A mutant form of RAB that preferentially binds GDP and out-competes the endogenous RAB pool for the binding of regulatory elements.

Endoplasmic reticulum-to-Golgi intermediate compartment

A tubule-vesicular network of membrane compartments located at the interface between the endoplasmic reticulum and the Golgi apparatus.

Non-alcoholic steatohepatitis

A form of NAFLD in which, in addition to liver steatosis, liver inflammation and damage appears.

Transcytosis

Cellular mechanism by which various molecules or proteins are transported across the cell.

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Gilleron, J., Zeigerer, A. Endosomal trafficking in metabolic homeostasis and diseases. Nat Rev Endocrinol 19, 28–45 (2023). https://doi.org/10.1038/s41574-022-00737-9

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