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Annual Review of Physiology

Volume 84, 2022

β-Arrestins as Important Regulators of Glucose and Energy Homeostasis

Abstract

β-Arrestin-1 and -2 (also known as arrestin-2 and -3, respectively) are ubiquitously expressed cytoplasmic proteins that dampen signaling through G protein–coupled receptors. However, β-arrestins can also act as signaling molecules in their own right. To investigate the potential metabolic roles of the two β-arrestins in modulating glucose and energy homeostasis, recent studies analyzed mutant mice that lacked or overexpressed β-arrestin-1 and/or -2 in distinct, metabolically important cell types. Metabolic analysis of these mutant mice clearly demonstrated that both β-arrestins play key roles in regulating the function of most of these cell types, resulting in striking changes in whole-body glucose and/or energy homeostasis. These studies also revealed that β-arrestin-1 and -2, though structurally closely related, clearly differ in their metabolic roles under physiological and pathophysiological conditions. These new findings should guide the development of novel drugs for the treatment of various metabolic disorders, including type 2 diabetes and obesity.

Keyword(s): G protein–coupled receptors, genetically modified mice, insulin resistance, obesity, type 2 diabetes, β-arrestins
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/content/journals/10.1146/annurev-physiol-060721-092948
2022-02-10
2024-05-04
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Literature Cited

  1. 1. 
    Luttrell LM, Lefkowitz RJ. 2002. The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals. J. Cell Sci. 115:455–65
     [Google Scholar]
  2. 2. 
    Gurevich VV, Gurevich EV. 2014. Overview of different mechanisms of arrestin-mediated signaling. Curr. Protoc. Pharmacol. 67: https://doi.org/10.1002/0471141755.ph0210s67
    [Crossref] [Google Scholar]
  3. 3. 
    Schmid CL, Bohn LM. 2009. Physiological and pharmacological implications of β-arrestin regulation. Pharmacol. Ther. 121:285–93
     [Google Scholar]
  4. 4. 
    Luttrell LM, Gesty-Palmer D. 2010. Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol. Rev. 62:305–30
     [Google Scholar]
  5. 5. 
    Zhao J, Pei G. 2013. Arrestins in metabolic regulation. Prog. Mol. Biol. Transl. Sci. 118:413–27
     [Google Scholar]
  6. 6. 
    Ferguson SS, Zhang J, Barak LS, Caron MG. 1998. Role of β-arrestins in the intracellular trafficking of G-protein-coupled receptors. Adv. Pharmacol. 42:420–24
     [Google Scholar]
  7. 7. 
    Pierce KL, Premont RT, Lefkowitz RJ. 2002. Seven-transmembrane receptors. Nat. Rev. Mol. Cell Biol. 3:639–50
     [Google Scholar]
  8. 8. 
    Beaulieu JM, Gainetdinov RR, Caron MG. 2009. Akt/GSK3 signaling in the action of psychotropic drugs. Annu. Rev. Pharmacol. Toxicol. 49:327–47
     [Google Scholar]
  9. 9. 
    Rajagopal S, Rajagopal K, Lefkowitz RJ. 2010. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat. Rev. Drug Discov. 9:373–86
     [Google Scholar]
  10. 10. 
    Shukla AK, Xiao K, Lefkowitz RJ 2011. Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem. Sci. 36:457–69
     [Google Scholar]
  11. 11. 
    DeFea KA. 2011. Beta-arrestins as regulators of signal termination and transduction: How do they determine what to scaffold?. Cell. Signal. 23:621–29
     [Google Scholar]
  12. 12. 
    Thomsen ARB, Plouffe B, Cahill TJ 3rd, Shukla AK, Tarrasch JT et al. 2016. GPCR-G protein-β-arrestin super-complex mediates sustained G protein signaling. Cell 166:907–19
     [Google Scholar]
  13. 13. 
    Nguyen AH, Thomsen ARB, Cahill TJ 3rd, Huang R, Huang LY et al. 2019. Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex. Nat. Struct. Mol. Biol. 26:1123–31
     [Google Scholar]
  14. 14. 
    Cahill TJ 3rd, Thomsen AR, Tarrasch JT, Plouffe B, Nguyen AH et al. 2017. Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis. PNAS 114:2562–67
     [Google Scholar]
  15. 15. 
    Grundmann M, Merten N, Malfacini D, Inoue A, Preis P et al. 2018. Lack of β-arrestin signaling in the absence of active G proteins. Nat. Commun. 9:341
     [Google Scholar]
  16. 16. 
    Smith JS, Pack TF, Inoue A, Lee C, Zheng K et al. 2021. Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors. Science 371:eaay1833
     [Google Scholar]
  17. 17. 
    Gurevich VV, Gurevich EV. 2019. Plethora of functions packed into 45 kDa arrestins: biological implications and possible therapeutic strategies. Cell. Mol. Life Sci. 76:4413–21
     [Google Scholar]
  18. 18. 
    Gurevich VV, Gurevich EV. 2020. Biased GPCR signaling: possible mechanisms and inherent limitations. Pharmacol. Ther. 211:107540
     [Google Scholar]
  19. 19. 
    Kang J, Shi Y, Xiang B, Qu B, Su W et al. 2005. A nuclear function of β-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell 123:833–47
     [Google Scholar]
  20. 20. 
    Tao Y, Ma L, Liao Z, Le Q, Yu J et al. 2015. Astroglial β-arrestin1-mediated nuclear signaling regulates the expansion of neural precursor cells in adult hippocampus. Sci. Rep. 5:15506
     [Google Scholar]
  21. 21. 
    Mo W, Zhang L, Yang G, Zhai J, Hu Z et al. 2008. Nuclear β-arrestin1 functions as a scaffold for the dephosphorylation of STAT1 and moderates the antiviral activity of IFN-γ. Mol. Cell 31:695–707
     [Google Scholar]
  22. 22. 
    Hoeppner CZ, Cheng N, Ye RD. 2012. Identification of a nuclear localization sequence in β-arrestin-1 and its functional implications. J. Biol. Chem. 287:8932–43
     [Google Scholar]
  23. 23. 
    Luttrell LM, Maudsley S, Bohn LM 2015. Fulfilling the promise of “biased” G protein-coupled receptor agonism. Mol. Pharmacol. 88:579–88
     [Google Scholar]
  24. 24. 
    Kenakin T, Christopoulos A. 2013. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat. Rev. Drug Discov. 12:205–16
     [Google Scholar]
  25. 25. 
    Wootten D, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM. 2018. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 19:638–53
     [Google Scholar]
  26. 26. 
    Smith JS, Lefkowitz RJ, Rajagopal S. 2018. Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 17:243–60
     [Google Scholar]
  27. 27. 
    Smith JS, Rajagopal S. 2016. The β-arrestins: multifunctional regulators of G protein-coupled receptors. J. Biol. Chem. 291:8969–77
     [Google Scholar]
  28. 28. 
    Srivastava A, Gupta B, Gupta C, Shukla AK. 2015. Emerging functional divergence of β-arrestin isoforms in GPCR function. Trends Endocrinol. Metab. 26:628–42
     [Google Scholar]
  29. 29. 
    Luan B, Zhao J, Wu H, Duan B, Shu G et al. 2009. Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance. Nature 457:1146–49
     [Google Scholar]
  30. 30. 
    Zhuang LN, Hu WX, Zhang ML, Xin SM, Jia WP et al. 2011. β-Arrestin-1 protein represses diet-induced obesity. J. Biol. Chem. 286:28396–402
     [Google Scholar]
  31. 31. 
    Sonoda N, Imamura T, Yoshizaki T, Babendure JL, Lu JC, Olefsky JM. 2008. β-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic β cells. PNAS 105:6614–19
     [Google Scholar]
  32. 32. 
    Oh DY, Olefsky JM. 2016. G protein-coupled receptors as targets for anti-diabetic therapeutics. Nat. Rev. Drug Discov. 15:161–72
     [Google Scholar]
  33. 33. 
    Wilbanks AM, Fralish GB, Kirby ML, Barak LS, Li YX, Caron MG 2004. β-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway. Science 306:2264–67
     [Google Scholar]
  34. 34. 
    Kovacs JJ, Hara MR, Davenport CL, Kim J, Lefkowitz RJ 2009. Arrestin development: emerging roles for β-arrestins in developmental signaling pathways. Dev. Cell 17:443–58
     [Google Scholar]
  35. 35. 
    Philipp M, Evron T, Caron MG 2013. The role of arrestins in development. Prog. Mol. Biol. Transl. Sci. 118:225–42
     [Google Scholar]
  36. 36. 
    Urs NM, Gee SM, Pack TF, McCorvy JD, Evron T et al. 2016. Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. PNAS 113:E8178–86
     [Google Scholar]
  37. 37. 
    Kim J, Grotegut CA, Wisler JW, Li T, Mao L et al. 2018. β-arrestin 1 regulates β2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility. Skelet. Muscle 8:39
     [Google Scholar]
  38. 38. 
    Zhu L, Almaca J, Dadi PK, Hong H, Sakamoto W et al. 2017. β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions. Nat. Commun. 8:14295
     [Google Scholar]
  39. 39. 
    Lin HV, Accili D. 2011. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab 14:9–19
     [Google Scholar]
  40. 40. 
    Postic C, Dentin R, Girard J. 2004. Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab. 30:398–408
     [Google Scholar]
  41. 41. 
    Unger RH, Cherrington AD. 2012. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Investig. 122:4–12
     [Google Scholar]
  42. 42. 
    Regard JB, Sato IT, Coughlin SR. 2008. Anatomical profiling of G protein-coupled receptor expression. Cell 135:561–71
     [Google Scholar]
  43. 43. 
    Akhmedov D, Mendoza-Rodriguez MG, Rajendran K, Rossi M, Wess J, Berdeaux R 2017. Gs-DREADD knock-in mice for tissue-specific, temporal stimulation of cAMP signaling. Mol. Cell. Biol. 37:e00584-16
     [Google Scholar]
  44. 44. 
    Li JH, Jain S, McMillin SM, Cui Y, Gautam D et al. 2013. A novel experimental strategy to assess the metabolic effects of selective activation of a Gq-coupled receptor in hepatocytes in vivo. Endocrinology 154:3539–51
     [Google Scholar]
  45. 45. 
    Rossi M, Zhu L, McMillin SM, Pydi SP, Jain S et al. 2018. Hepatic Gi signaling regulates whole-body glucose homeostasis. J. Clin. Investig. 128:746–59
     [Google Scholar]
  46. 46. 
    Cho YM, Merchant CE, Kieffer TJ. 2012. Targeting the glucagon receptor family for diabetes and obesity therapy. Pharmacol. Ther. 135:247–78
     [Google Scholar]
  47. 47. 
    Estall JL, Drucker DJ. 2006. Glucagon and glucagon-like peptide receptors as drug targets. Curr. Pharm. Des. 12:1731–50
     [Google Scholar]
  48. 48. 
    D'Alessio D. 2011. The role of dysregulated glucagon secretion in type 2 diabetes. Diabetes Obes. Metab. 13:Suppl. 1126–32
     [Google Scholar]
  49. 49. 
    Zhu L, Rossi M, Cui Y, Lee RJ, Sakamoto W et al. 2017. Hepatic β-arrestin 2 is essential for maintaining euglycemia. J. Clin. Investig. 127:2941–45
     [Google Scholar]
  50. 50. 
    Hruby A, Hu FB. 2015. The epidemiology of obesity: a big picture. Pharmacoeconomics 33:673–89
     [Google Scholar]
  51. 51. 
    Gonzalez-Muniesa P, Martinez-Gonzalez MA, Hu FB, Despres JP, Matsuzawa Y et al. 2017. Obesity.. Nat. Rev. Dis. Primers 3:17034
     [Google Scholar]
  52. 52. 
    Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. 2009. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 9:88
     [Google Scholar]
  53. 53. 
    Ghaben AL, Scherer PE. 2019. Adipogenesis and metabolic health. Nat. Rev. Mol. Cell Biol. 20:242–58
     [Google Scholar]
  54. 54. 
    Kusminski CM, Bickel PE, Scherer PE. 2016. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat. Rev. Drug Discov. 15:639–60
     [Google Scholar]
  55. 55. 
    Saltiel AR, Olefsky JM. 2017. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Investig. 127:1–4
     [Google Scholar]
  56. 56. 
    Harms M, Seale P. 2013. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19:1252–63
     [Google Scholar]
  57. 57. 
    Cohen P, Spiegelman BM. 2015. Brown and beige fat: molecular parts of a thermogenic machine. Diabetes 64:2346–51
     [Google Scholar]
  58. 58. 
    Scherer PE. 2019. The many secret lives of adipocytes: implications for diabetes. Diabetologia 62:223–32
     [Google Scholar]
  59. 59. 
    Cypess AM, Lehman S, Williams G, Tal I, Rodman D et al. 2009. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360:1509–17
     [Google Scholar]
  60. 60. 
    Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L et al. 2013. Evidence for two types of brown adipose tissue in humans. Nat. Med. 19:631–34
     [Google Scholar]
  61. 61. 
    Rosen ED, Spiegelman BM. 2014. What we talk about when we talk about fat. Cell 156:20–44
     [Google Scholar]
  62. 62. 
    van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ et al. 2009. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360:1500–8
     [Google Scholar]
  63. 63. 
    Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R et al. 2009. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360:1518–25
     [Google Scholar]
  64. 64. 
    Wang W, Seale P 2016. Control of brown and beige fat development. Nat. Rev. Mol. Cell Biol. 17:691–702
     [Google Scholar]
  65. 65. 
    Wu J, Bostrom P, Sparks LM, Ye L, Choi JH et al. 2012. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:366–76
     [Google Scholar]
  66. 66. 
    Amisten S, Neville M, Hawkes R, Persaud SJ, Karpe F, Salehi A 2015. An atlas of G-protein coupled receptor expression and function in human subcutaneous adipose tissue. Pharmacol. Ther. 146:61–93
     [Google Scholar]
  67. 67. 
    Bartelt A, Heeren J. 2014. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10:24–36
     [Google Scholar]
  68. 68. 
    Gnad T, Scheibler S, von Kügelgen I, Scheele C, Kilic A et al. 2014. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516:395–99
     [Google Scholar]
  69. 69. 
    Pydi SP, Jain S, Tung W, Cui Y, Zhu L et al. 2019. Adipocyte β-arrestin-2 is essential for maintaining whole body glucose and energy homeostasis. Nat. Commun. 10:2936
     [Google Scholar]
  70. 70. 
    Collins S, Surwit RS 2001. The β-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog. Hormone Res. 56:309–28
     [Google Scholar]
  71. 71. 
    Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F. 2009. The β3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol. Res. 59:221–34
     [Google Scholar]
  72. 72. 
    Ceddia RP, Collins S. 2020. A compendium of G-protein-coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure. Clin. Sci. 134:473–512
     [Google Scholar]
  73. 73. 
    Nantel F, Bonin H, Emorine LJ, Zilberfarb V, Strosberg AD et al. 1993. The human β3-adrenergic receptor is resistant to short term agonist-promoted desensitization. Mol. Pharmacol. 43:548–55
     [Google Scholar]
  74. 74. 
    Breit A, Lagace M, Bouvier M. 2004. Hetero-oligomerization between β2- and β3-adrenergic receptors generates a β-adrenergic signaling unit with distinct functional properties. J. Biol. Chem. 279:28756–65
     [Google Scholar]
  75. 75. 
    Liggett SB, Freedman NJ, Schwinn DA, Lefkowitz RJ. 1993. Structural basis for receptor subtype-specific regulation revealed by a chimeric β3/β2-adrenergic receptor. PNAS 90:3665–69
     [Google Scholar]
  76. 76. 
    Cannon B, Nedergaard J. 2004. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84:277–359
     [Google Scholar]
  77. 77. 
    Lafontan M, Berlan M. 1993. Fat cell adrenergic receptors and the control of white and brown fat cell function. J. Lipid Res. 34:1057–91
     [Google Scholar]
  78. 78. 
    Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH et al. 2020. Human brown adipocyte thermogenesis is driven by β2-AR stimulation. Cell Metab 32:287–300.e7
     [Google Scholar]
  79. 79. 
    Revelli JP, Muzzin P, Paoloni A, Moinat M, Giacobino JP. 1993. Expression of the β3-adrenergic receptor in human white adipose tissue. J. Mol. Endocrinol. 10:193–97
     [Google Scholar]
  80. 80. 
    Krief S, Lonnqvist F, Raimbault S, Baude B, Van Spronsen A et al. 1993. Tissue distribution of β3-adrenergic receptor mRNA in man. J. Clin. Investig. 91:344–49
     [Google Scholar]
  81. 81. 
    O'Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S et al. 2020. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J. Clin. Investig. 130:2209–19
     [Google Scholar]
  82. 82. 
    Finlin BS, Memetimin H, Zhu B, Confides AL, Vekaria HJ et al. 2020. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. J. Clin. Investig. 130:2319–31
     [Google Scholar]
  83. 83. 
    Cypess AM, Weiner LS, Roberts-Toler C, Elia EF, Kessler SH et al. 2015. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 21:33–38
     [Google Scholar]
  84. 84. 
    Pydi SP, Jain S, Barella LF, Zhu L, Sakamoto W et al. 2020. β-arrestin-1 suppresses myogenic reprogramming of brown fat to maintain euglycemia. Sci. Adv. 6:eaba1733
     [Google Scholar]
  85. 85. 
    Seale P, Bjork B, Yang W, Kajimura S, Chin S et al. 2008. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454:961–67
     [Google Scholar]
  86. 86. 
    Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV et al. 2009. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 460:1154–58
     [Google Scholar]
  87. 87. 
    Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T et al. 2007. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. PNAS 104:4401–6
     [Google Scholar]
  88. 88. 
    Lee SJ, McPherron AC. 1999. Myostatin and the control of skeletal muscle mass. Curr. Opin. Genet. Dev. 9:604–7
     [Google Scholar]
  89. 89. 
    McPherron AC, Lawler AM, Lee SJ. 1997. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 387:83–90
     [Google Scholar]
  90. 90. 
    Fournier B, Murray B, Gutzwiller S, Marcaletti S, Marcellin D et al. 2012. Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism. Mol. Cell. Biol. 32:2871–79
     [Google Scholar]
  91. 91. 
    Braga M, Pervin S, Norris K, Bhasin S, Singh R. 2013. Inhibition of in vitro and in vivo brown fat differentiation program by myostatin. Obesity 21:1180–88
     [Google Scholar]
  92. 92. 
    Steculorum SM, Ruud J, Karakasilioti I, Backes H, Engstrom Ruud L et al. 2016. AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell 165:125–38
     [Google Scholar]
  93. 93. 
    Kong X, Yao T, Zhou P, Kazak L, Tenen D et al. 2018. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab 28:631–43.e3
     [Google Scholar]
  94. 94. 
    Ji M, Zhang Q, Ye J, Wang X, Yang W, Zhu D 2008. Myostatin induces p300 degradation to silence cyclin D1 expression through the PI3K/PTEN/Akt pathway. Cell Signal 20:1452–58
     [Google Scholar]
  95. 95. 
    Wang C, Zeng X, Zhou Z, Zhao J, Pei G. 2016. β-arrestin-1 contributes to brown fat function and directly interacts with PPARα and PPARγ. Sci. Rep. 6:26999
     [Google Scholar]
  96. 96. 
    Petersen MC, Shulman GI. 2018. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98:2133–223
     [Google Scholar]
  97. 97. 
    Scharfmann R, Pechberty S, Hazhouz Y, von Bulow M, Bricout-Neveu E et al. 2014. Development of a conditionally immortalized human pancreatic β cell line. J. Clin. Investig. 124:2087–98
     [Google Scholar]
  98. 98. 
    Dadi PK, Vierra NC, Ustione A, Piston DW, Colbran RJ, Jacobson DA. 2014. Inhibition of pancreatic β-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance. J. Biol. Chem. 289:12435–45
     [Google Scholar]
  99. 99. 
    Matsumoto K, Fukunaga K, Miyazaki J, Shichiri M, Miyamoto E. 1995. Ca2+/calmodulin-dependent protein kinase II and synapsin I-like protein in mouse insulinoma MIN6 cells. Endocrinology 136:3784–93
     [Google Scholar]
  100. 100. 
    Yamamoto H, Matsumoto K, Araki E, Miyamoto E 2003. New aspects of neurotransmitter release and exocytosis: involvement of Ca2+/calmodulin-dependent phosphorylation of synapsin I in insulin exocytosis. J. Pharmacol. Sci. 93:30–34
     [Google Scholar]
  101. 101. 
    Hudmon A, Schulman H, Kim J, Maltez JM, Tsien RW, Pitt GS. 2005. CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation. J. Cell Biol. 171:537–47
     [Google Scholar]
  102. 102. 
    Xiao K, McClatchy DB, Shukla AK, Zhao Y, Chen M et al. 2007. Functional specialization of β-arrestin interactions revealed by proteomic analysis. PNAS 104:12011–16
     [Google Scholar]
  103. 103. 
    Mangmool S, Shukla AK, Rockman HA. 2010. β-Arrestin-dependent activation of Ca2+/calmodulin kinase II after β1-adrenergic receptor stimulation. J. Cell Biol. 189:573–87
     [Google Scholar]
  104. 104. 
    Zhang M, Zhu Y, Mu K, Li L, Lu J et al. 2013. Loss of β-arrestin2 mediates pancreatic-islet dysfunction in mice. Biochem. Biophys. Res. Commun. 435:345–49
     [Google Scholar]
  105. 105. 
    Ravier MA, Leduc M, Richard J, Linck N, Varrault A et al. 2014. β-Arrestin2 plays a key role in the modulation of the pancreatic β cell mass in mice. Diabetologia 57:532–41
     [Google Scholar]
  106. 106. 
    Barella LF, Rossi M, Zhu L, Cui Y, Mei FC et al. 2019. β-Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion. J. Clin. Investig. 130:3732–37
     [Google Scholar]
  107. 107. 
    Proks P, Reimann F, Green N, Gribble F, Ashcroft F 2002. Sulfonylurea stimulation of insulin secretion. Diabetes 51:Suppl. 3S368–76
     [Google Scholar]
  108. 108. 
    Zhang CL, Katoh M, Shibasaki T, Minami K, Sunaga Y et al. 2009. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science 325:607–10
     [Google Scholar]
  109. 109. 
    Hinke SA. 2009. Epac2: a molecular target for sulfonylurea-induced insulin release. Sci. Signal. 2:pe54
     [Google Scholar]
  110. 110. 
    Takahashi T, Shibasaki T, Takahashi H, Sugawara K, Ono A et al. 2013. Antidiabetic sulfonylureas and cAMP cooperatively activate Epac2A. Sci Signal 6:ra94
     [Google Scholar]
  111. 111. 
    Herbst KJ, Coltharp C, Amzel LM, Zhang J. 2011. Direct activation of Epac by sulfonylurea is isoform selective. Chem. Biol. 18:243–51
     [Google Scholar]
  112. 112. 
    Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K et al. 2007. Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP. PNAS 104:19333–38
     [Google Scholar]
  113. 113. 
    Barella LF, Rossi M, Pydi SP, Meister J, Jain S et al. 2021. β-Arrestin-1 is required for adaptive β-cell mass expansion during obesity. Nat. Commun. 12:3385
     [Google Scholar]
  114. 114. 
    Sachdeva MM, Stoffers DA. 2009. Minireview: meeting the demand for insulin: molecular mechanisms of adaptive postnatal β-cell mass expansion. Mol. Endocrinol. 23:747–58
     [Google Scholar]
  115. 115. 
    Golson ML, Misfeldt AA, Kopsombut UG, Petersen CP, Gannon M. 2010. High fat diet regulation of β-cell proliferation and β-cell mass. Open. Endocrinol. J. 2010:4
     [Google Scholar]
  116. 116. 
    Aguayo-Mazzucato C, Bonner-Weir S. 2018. Pancreatic β cell regeneration as a possible therapy for diabetes. Cell Metab 27:57–67
     [Google Scholar]
  117. 117. 
    Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, Garcia-Ocana A, Stewart AF. 2015. Diabetes mellitus—advances and challenges in human β-cell proliferation. Nat. Rev. Endocrinol. 11:201–12
     [Google Scholar]
  118. 118. 
    Linnemann AK, Baan M, Davis DB. 2014. Pancreatic β-cell proliferation in obesity. Adv. Nutr. 5:278–88
     [Google Scholar]
  119. 119. 
    Cerf ME. 2006. Transcription factors regulating β-cell function. Eur. J. Endocrinol. 155:671–79
     [Google Scholar]
  120. 120. 
    Bernardo AS, Hay CW, Docherty K. 2008. Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell. Mol. Cell. Endocrinol. 294:1–9
     [Google Scholar]
  121. 121. 
    Kaneto H, Miyatsuka T, Kawamori D, Yamamoto K, Kato K et al. 2008. PDX-1 and MafA play a crucial role in pancreatic β-cell differentiation and maintenance of mature β-cell function. Endocr. J. 55:235–52
     [Google Scholar]
  122. 122. 
    Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR 2004. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J. Clin. Investig. 114:828–36
     [Google Scholar]
  123. 123. 
    Brissova M, Blaha M, Spear C, Nicholson W, Radhika A et al. 2005. Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis. Am. J. Physiol. Endocrinol. Metab. 288:E707–14
     [Google Scholar]
  124. 124. 
    Tsonkova VG, Sand FW, Wolf XA, Grunnet LG, Kirstine Ringgaard A et al. 2018. The EndoC-βH1 cell line is a valid model of human β cells and applicable for screenings to identify novel drug target candidates. Mol. Metab. 8:144–57
     [Google Scholar]
  125. 125. 
    Thiebaud D, Jacot E, DeFronzo RA, Maeder E, Jequier E, Felber JP 1982. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 31:957–63
     [Google Scholar]
  126. 126. 
    DeFronzo RA, Tripathy D. 2009. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32:Suppl. 2S157–63
     [Google Scholar]
  127. 127. 
    Meister J, Bone DBJ, Godlewski G, Liu Z, Lee RJ et al. 2019. Metabolic effects of skeletal muscle-specific deletion of β-arrestin-1 and -2 in mice. PLOS Genet 15:e1008424
     [Google Scholar]
  128. 128. 
    Lee AD, Hansen PA, Schluter J, Gulve EA, Gao J, Holloszy JO. 1997. Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle. Am. J. Physiol. 273:C1082–87
     [Google Scholar]
  129. 129. 
    Opie LH. 1985. Effect of β-adrenergic blockade on biochemical and metabolic response to exercise. Am. J. Cardiol. 55:95D–100D
     [Google Scholar]
  130. 130. 
    Sato M, Dehvari N, Öberg AI, Dallner OS, Sandström AL et al. 2014. Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle. Diabetes 63:4115–29
     [Google Scholar]
  131. 131. 
    Mobbs CV. 2016. Orphaned no more? Glucose-sensing hypothalamic neurons control insulin secretion. Diabetes 65:2473–75
     [Google Scholar]
  132. 132. 
    Ruud J, Steculorum SM, Bruning JC. 2017. Neuronal control of peripheral insulin sensitivity and glucose metabolism. Nat. Commun. 8:15259
     [Google Scholar]
  133. 133. 
    Arble DM, Sandoval DA. 2013. CNS control of glucose metabolism: response to environmental challenges. Front. Neurosci. 7:20
     [Google Scholar]
  134. 134. 
    Lam CK, Chari M, Lam TK. 2009. CNS regulation of glucose homeostasis. Physiology 24:159–70
     [Google Scholar]
  135. 135. 
    Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC et al. 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Investig. 121:1424–28
     [Google Scholar]
  136. 136. 
    Krashes MJ, Shah BP, Koda S, Lowell BB 2013. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab 18:588–95
     [Google Scholar]
  137. 137. 
    Morton GJ, Meek TH, Schwartz MW. 2014. Neurobiology of food intake in health and disease. Nat. Rev. Neurosci. 15:367–78
     [Google Scholar]
  138. 138. 
    Morton GJ. 2007. Hypothalamic leptin regulation of energy homeostasis and glucose metabolism. J. Physiol. 583:437–43
     [Google Scholar]
  139. 139. 
    Kleinridders A, Könner AC, Brüning JC. 2009. CNS-targets in control of energy and glucose homeostasis. Curr. Opin. Pharmacol. 9:794–804
     [Google Scholar]
  140. 140. 
    Loh K, Zhang L, Brandon A, Wang Q, Begg D et al. 2017. Insulin controls food intake and energy balance via NPY neurons. Mol. Metabol. 6:574–84
     [Google Scholar]
  141. 141. 
    Cavalcanti-de-Albuquerque JP, Bober J, Zimmer MR, Dietrich MO. 2019. Regulation of substrate utilization and adiposity by Agrp neurons. Nat. Commun. 10:311
     [Google Scholar]
  142. 142. 
    Pydi SP, Cui Z, He Z, Barella LF, Pham J et al. 2020. Beneficial metabolic role of β-arrestin-1 expressed by AgRP neurons. Sci. Adv. 6:eaaz1341
     [Google Scholar]
  143. 143. 
    Scherer T, O'Hare J, Diggs-Andrews K, Schweiger M, Cheng B et al. 2011. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 13:183–94
     [Google Scholar]
  144. 144. 
    Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ et al. 2005. Hypothalamic KATP channels control hepatic glucose production. Nature 434:1026–31
     [Google Scholar]
  145. 145. 
    Pocai A, Obici S, Schwartz GJ, Rossetti L. 2005. A brain-liver circuit regulates glucose homeostasis. Cell Metab 1:53–61
     [Google Scholar]
  146. 146. 
    Konner AC, Janoschek R, Plum L, Jordan SD, Rother E et al. 2007. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5:438–49
     [Google Scholar]
  147. 147. 
    Huang Y, He Z, Gao Y, Lieu L, Yao T et al. 2018. PI3K is integral for the acute activity of leptin and insulin in arcuate NPY/AgRP neurons in males. J. Endocr. Soc. 2:6518–532
     [Google Scholar]
  148. 148. 
    Mayer CM, Belsham DD. 2009. Insulin directly regulates NPY and AgRP gene expression via the MAPK MEK/ERK signal transduction pathway in mHypoE-46 hypothalamic neurons. Mol. Cell. Endocrinol. 307:99–108
     [Google Scholar]
  149. 149. 
    Usui I, Imamura T, Huang J, Satoh H, Shenoy SK et al. 2004. β-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1. Mol. Cell. Biol. 24:8929–37
     [Google Scholar]
/content/journals/10.1146/annurev-physiol-060721-092948
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β-Arrestins as Important Regulators of Glucose and Energy Homeostasis
Annual Review of Physiology 84, 17 (2022); https://doi.org/10.1146/annurev-physiol-060721-092948
/content/journals/10.1146/annurev-physiol-060721-092948
/content/journals/10.1146/annurev-physiol-060721-092948
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