Skip to main content

Advertisement

SpringerLink
Log in

SOCS3 as a future target to treat metabolic disorders

  • Review Article
  • Published:
Hormones Aims and scope Submit manuscript

Abstract

The suppressors of cytokine signaling (SOCS) are a group of eight proteins responsible for preventing excessive cytokine signaling. Among this protein family, SOCS3 has received special attention. SOCS3 expression is important to control certain allergy autoimmune diseases. Furthermore, SOCS3 expression is elevated in obesity and it is involved in the inhibition of leptin and insulin signaling, two important hormones involved in the control of energy metabolism. Therefore, increased SOCS3 expression in obese individuals is associated with several metabolic disorders, including reduced energy expenditure, increased food intake and adiposity, and insulin and leptin resistance. In addition, recent studies found that SOCS3 expression regulates energy and glucose homeostasis in several metabolic conditions, such as pregnancy, caloric restriction, and refeeding. Importantly, attenuation of SOCS3 expression in most cases improves leptin and insulin sensitivity, leading to beneficial metabolic effects. This review aims to discuss the role of SOCS3 in the control of blood glucose levels as well as in energy homeostasis. The development of pharmacological compounds to inhibit SOCS3 activity and/or expression may represent a promising therapeutic approach to treat type 2 diabetes mellitus, obesity, and other metabolic imbalances.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7(6):454–465. https://doi.org/10.1038/nri2093

    Article  CAS  PubMed  Google Scholar 

  2. Krebs DL, Hilton DJ (2001) SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19(5):378–387. https://doi.org/10.1634/stemcells.19-5-378

    Article  CAS  PubMed  Google Scholar 

  3. Howard JK, Flier JS (2006) Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab 17(9):365–371. https://doi.org/10.1016/j.tem.2006.09.007

    Article  CAS  PubMed  Google Scholar 

  4. Yin Y, Liu W, Dai Y (2015) SOCS3 and its role in associated diseases. Hum Immunol 76(10):775–780. https://doi.org/10.1016/j.humimm.2015.09.037

    Article  CAS  PubMed  Google Scholar 

  5. Wong PK, Egan PJ, Croker BA, O'Donnell K, Sims NA, Drake S, Kiu H, McManus EJ, Alexander WS, Roberts AW, Wicks IP (2006) SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest 116(6):1571–1581. https://doi.org/10.1172/JCI25660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A (2001) Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 108(12):1781–1788. https://doi.org/10.1172/JCI13568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Calegari VC, Bezerra RM, Torsoni MA, Torsoni AS, Franchini KG, Saad MJ, Velloso LA (2003) Suppressor of cytokine signaling 3 is induced by angiotensin II in heart and isolated cardiomyocytes, and participates in desensitization. Endocrinology 144(10):4586–4596. https://doi.org/10.1210/en.2003-0046

    Article  CAS  PubMed  Google Scholar 

  8. Ferrario CM (2006) Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J Renin-Angiotensin-Aldosterone Syst 7(1):3–14. https://doi.org/10.3317/jraas.2006.003

    Article  CAS  PubMed  Google Scholar 

  9. Agha M, Agha R (2017) The rising prevalence of obesity: part a: impact on public health. International journal of surgery Oncology 2(7):e17. https://doi.org/10.1097/IJ9.0000000000000017

    Article  PubMed  PubMed Central  Google Scholar 

  10. Upadhyay J, Farr O, Perakakis N, Ghaly W, Mantzoros C (2018) Obesity as a disease. Med Clin North Am 102(1):13–33. https://doi.org/10.1016/j.mcna.2017.08.004

    Article  PubMed  Google Scholar 

  11. Palanivel R, Fullerton MD, Galic S, Honeyman J, Hewitt KA, Jorgensen SB, Steinberg GR (2012) Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance. Diabetologia 55(11):3083–3093. https://doi.org/10.1007/s00125-012-2665-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pedroso JA, Buonfiglio DC, Cardinali LI, Furigo IC, Ramos-Lobo AM, Tirapegui J, Elias CF, Donato J Jr (2014) Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity. Mol Metab 3(6):608–618. https://doi.org/10.1016/j.molmet.2014.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zampieri TT, da Silva TE, de Paula Romeu D, Torrao AS, Donato J Jr (2016) SOCS3 expression within leptin receptor-expressing cells regulates food intake and leptin sensitivity but does not affect weight gain in pregnant mice consuming a high-fat diet. Physiol Behav 157:109–115. https://doi.org/10.1016/j.physbeh.2016.01.039

    Article  CAS  PubMed  Google Scholar 

  14. Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS (1998) Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1(4):619–625

    Article  CAS  PubMed  Google Scholar 

  15. Santillan-Benitez JG, Mendieta-Zeron H, Gomez-Olivan LM, Quiroz AO, Torres-Juarez JJ, Gonzalez-Banales JM (2014) JAK2, STAT3 and SOCS3 gene expression in women with and without breast cancer. Gene 547(1):70–76. https://doi.org/10.1016/j.gene.2014.06.025

    Article  CAS  PubMed  Google Scholar 

  16. Ahima RS, Stanley TL, Khor VK, Zanni MV, Grinspoon SK (2011) Estrogen sulfotransferase is expressed in subcutaneous adipose tissue of obese humans in association with TNF-alpha and SOCS3. J Clin Endocrinol Metab 96(7):E1153–E1158. https://doi.org/10.1210/jc.2010-2903

    Article  PubMed  PubMed Central  Google Scholar 

  17. Xu K, Zhang X, Wang Z, Hu Y, Sinha R (2018) Epigenome-wide association analysis revealed that SOCS3 methylation influences the effect of cumulative stress on obesity. Biol Psychol 131:63–71. https://doi.org/10.1016/j.biopsycho.2016.11.001

    Article  PubMed  Google Scholar 

  18. Zhou Y, Rui L (2013) Leptin signaling and leptin resistance. Front Med 7(2):207–222. https://doi.org/10.1007/s11684-013-0263-5

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lubis AR, Widia F, Soegondo S, Setiawati A (2008) The role of SOCS-3 protein in leptin resistance and obesity. Acta Med Indones 40(2):89–95

    PubMed  Google Scholar 

  20. Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS, Van Obberghen E (2001) SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 276(51):47944–47949. https://doi.org/10.1074/jbc.M104602200

    Article  CAS  PubMed  Google Scholar 

  21. Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E (2000) SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275(21):15985–15991

    Article  CAS  PubMed  Google Scholar 

  22. Klok MD, Jakobsdottir S, Drent ML (2007) The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev 8(1):21–34. https://doi.org/10.1111/j.1467-789X.2006.00270.x

    Article  CAS  PubMed  Google Scholar 

  23. Shimizu H, Oh IS, Okada S, Mori M (2007) Leptin resistance and obesity. Endocr J 54(1):17–26

    Article  CAS  PubMed  Google Scholar 

  24. El-Haschimi K, Lehnert H (2003) Leptin resistance - or why leptin fails to work in obesity. Exp Clin Endocrinol Diabetes 111(1):2–7. https://doi.org/10.1055/s-2003-37492

    Article  CAS  PubMed  Google Scholar 

  25. Guo S (2014) Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol 220(2):T1–T23. https://doi.org/10.1530/JOE-13-0327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rui L, Yuan M, Frantz D, Shoelson S, White MF (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 277(44):42394–42398. https://doi.org/10.1074/jbc.C200444200

    Article  CAS  PubMed  Google Scholar 

  27. Zampieri TT, Ramos-Lobo AM, Furigo IC, Pedroso JA, Buonfiglio DC, Donato J Jr (2015) SOCS3 deficiency in leptin receptor-expressing cells mitigates the development of pregnancy-induced metabolic changes. Molecular metabolism 4(3):237–245. https://doi.org/10.1016/j.molmet.2014.12.005

    Article  CAS  PubMed  Google Scholar 

  28. Pedroso JA, Silveira MA, Lima LB, Furigo IC, Zampieri TT, Ramos-Lobo AM, Buonfiglio DC, Teixeira PD, Frazao R, Donato J Jr (2016) Changes in leptin signaling by SOCS3 modulate fasting-induced Hyperphagia and weight regain in mice. Endocrinology 157(10):3901–3914. https://doi.org/10.1210/en.2016-1038

    Article  CAS  PubMed  Google Scholar 

  29. Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H, Yoshimura A (2004) Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10(7):739–743. https://doi.org/10.1038/nm1071

    Article  CAS  PubMed  Google Scholar 

  30. Jorgensen SB, O'Neill HM, Sylow L, Honeyman J, Hewitt KA, Palanivel R, Fullerton MD, Oberg L, Balendran A, Galic S, van der Poel C, Trounce IA, Lynch GS, Schertzer JD, Steinberg GR (2013) Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes 62(1):56–64. https://doi.org/10.2337/db12-0443

    Article  CAS  PubMed  Google Scholar 

  31. Ortega FB, Lavie CJ, Blair SN (2016) Obesity and cardiovascular disease. Circ Res 118(11):1752–1770. https://doi.org/10.1161/CIRCRESAHA.115.306883

    Article  CAS  PubMed  Google Scholar 

  32. Lipek T, Igel U, Gausche R, Kiess W, Grande G (2015) Obesogenic environments: environmental approaches to obesity prevention. J Pediatr Endocrinol Metab 28(5–6):485–495. https://doi.org/10.1515/jpem-2015-0127

    Article  PubMed  Google Scholar 

  33. Myers MG Jr, Olson DP (2012) Central nervous system control of metabolism. Nature 491(7424):357–363. https://doi.org/10.1038/nature11705

    Article  CAS  PubMed  Google Scholar 

  34. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671. https://doi.org/10.1038/35007534

    Article  CAS  PubMed  Google Scholar 

  35. Munzberg H, Myers MG, Jr. (2005) Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 8 (5):566–570. doi:https://doi.org/10.1038/nn1454

  36. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395(6704):763–770. https://doi.org/10.1038/27376

    Article  CAS  PubMed  Google Scholar 

  37. Zhang YY, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homolog. Nature 372(6505):425–432. https://doi.org/10.1038/372425a0

    Article  CAS  PubMed  Google Scholar 

  38. Kwon O, Kim KW, Kim MS (2016) Leptin signalling pathways in hypothalamic neurons. Cell Mol Life Sci 73(7):1457–1477. https://doi.org/10.1007/s00018-016-2133-1

    Article  CAS  PubMed  Google Scholar 

  39. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM (1997) Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A 94(16):8878–8883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Reed AS, Unger EK, Olofsson LE, Piper ML, Myers MG Jr, Xu AW (2010) Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes 59(4):894–906. https://doi.org/10.2337/db09-1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A (1999) The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J 18 (5):1309–1320. doi:DOI 10.1093/emboj/18.5.1309

  42. Fruhbeck G (2006) Intracellular signalling pathways activated by leptin. Biochem. J. 393(Pt 1):7–20. https://doi.org/10.1042/BJ20051578

    Article  CAS  PubMed  Google Scholar 

  43. Krol E, Speakman JR (2007) Regulation of body mass and adiposity in the field vole, Microtus agrestis: a model of leptin resistance. J Endocrinol 192(2):271–278. https://doi.org/10.1677/JOE-06-0074

    Article  CAS  PubMed  Google Scholar 

  44. Norman JE, Reynolds RM (2011) The consequences of obesity and excess weight gain in pregnancy. Proc Nutr Soc 70(4):450–456. https://doi.org/10.1017/S0029665111003077

    Article  CAS  PubMed  Google Scholar 

  45. Ladyman SR, Fieldwick DM, Grattan DR (2012) Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse. Reproduction 144(1):83–90. https://doi.org/10.1530/REP-12-0112

    Article  CAS  PubMed  Google Scholar 

  46. Nagaishi VS, Cardinali LI, Zampieri TT, Furigo IC, Metzger M, Donato J Jr (2014) Possible crosstalk between leptin and prolactin during pregnancy. Neuroscience 259:71–83. https://doi.org/10.1016/j.neuroscience.2013.11.050

    Article  CAS  PubMed  Google Scholar 

  47. Ayyad C, Andersen T (2000) Long-term efficacy of dietary treatment of obesity: a systematic review of studies published between 1931 and 1999. Obes Rev 1(2):113–119

    Article  CAS  PubMed  Google Scholar 

  48. Mann T, Tomiyama AJ, Westling E, Lew AM, Samuels B, Chatman J (2007) Medicare's search for effective obesity treatments: diets are not the answer. Am Psychol 62(3):220–233. https://doi.org/10.1037/0003-066X.62.3.220

    Article  PubMed  Google Scholar 

  49. Hambly C, Duncan JS, Archer ZA, Moar KM, Mercer JG, Speakman JR (2012) Repletion of TNFalpha or leptin in calorically restricted mice suppresses post-restriction hyperphagia. Dis Model Mech 5(1):83–94. https://doi.org/10.1242/dmm.007781

    Article  CAS  PubMed  Google Scholar 

  50. Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C, Flier JS (2004) Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 10(7):734–738. https://doi.org/10.1038/nm1072

    Article  CAS  PubMed  Google Scholar 

  51. Briancon N, McNay DE, Maratos-Flier E, Flier JS (2010) Combined neural inactivation of suppressor of cytokine signaling-3 and protein-tyrosine phosphatase-1B reveals additive, synergistic, and factor-specific roles in the regulation of body energy balance. Diabetes 59(12):3074–3084. https://doi.org/10.2337/db10-0481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu ZJ, Bian J, Zhao YL, Zhang X, Zou N, Li D (2011) Lentiviral vector-mediated knockdown of SOCS3 in the hypothalamus protects against the development of diet-induced obesity in rats. Diabetes Obes Metab 13(10):885–892. https://doi.org/10.1111/j.1463-1326.2011.01419.x

    Article  CAS  PubMed  Google Scholar 

  53. de Backer MW, Brans MA, van Rozen AJ, van der Zwaal EM, Luijendijk MC, Garner KG, de Krom M, van Beekum O, la Fleur SE, Adan RA (2010) Suppressor of cytokine signaling 3 knockdown in the mediobasal hypothalamus: counterintuitive effects on energy balance. J Mol Endocrinol 45(5):341–353. https://doi.org/10.1677/JME-10-0057

    Article  CAS  PubMed  Google Scholar 

  54. Matarazzo V, Schaller F, Nedelec E, Benani A, Penicaud L, Muscatelli F, Moyse E, Bauer S (2012) Inactivation of Socs3 in the hypothalamus enhances the hindbrain response to endogenous satiety signals via oxytocin signaling. J Neurosci 32(48):17097–17107. https://doi.org/10.1523/JNEUROSCI.1669-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kievit P, Howard JK, Badman MK, Balthasar N, Coppari R, Mori H, Lee CE, Elmquist JK, Yoshimura A, Flier JS (2006) Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab 4(2):123–132. https://doi.org/10.1016/j.cmet.2006.06.010

    Article  CAS  PubMed  Google Scholar 

  56. Zhang R, Dhillon H, Yin H, Yoshimura A, Lowell BB, Maratos-Flier E, Flier JS (2008) Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight. Endocrinology 149(11):5654–5661. https://doi.org/10.1210/en.2008-0805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pedroso JAB, de Mendonca POR, Fortes MAS, Tomaz I, Pecorali VL, Auricino TB, Costa IC, Lima LB, Furigo IC, Bueno DN, Ramos-Lobo AM, Lotfi CFP, Donato J Jr (2017) SOCS3 expression in SF1 cells regulates adrenal differentiation and exercise performance. J Endocrinol 235(3):207–222. https://doi.org/10.1530/JOE-17-0255

    Article  CAS  PubMed  Google Scholar 

  58. Ramos-Lobo AM, Teixeira PDS, Furigo IC, Donato J Jr (2017) SOCS3 ablation in SF1 cells causes modest metabolic effects during pregnancy and lactation. Neuroscience 365:114–124. https://doi.org/10.1016/j.neuroscience.2017.09.048

    Article  CAS  PubMed  Google Scholar 

  59. Ramos-Lobo AM, Furigo IC, Teixeira PDS, Zampieri TT, Wasinski F, Buonfiglio DC, Donato J Jr (2018) Maternal metabolic adaptations are necessary for normal offspring growth and brain development. Phys. Rep. 6(5). https://doi.org/10.14814/phy2.13643

  60. Torisu T, Sato N, Yoshiga D, Kobayashi T, Yoshioka T, Mori H, Iida M, Yoshimura A (2007) The dual function of hepatic SOCS3 in insulin resistance in vivo. Genes Cells 12(2):143–154. https://doi.org/10.1111/j.1365-2443.2007.01044.x

    Article  CAS  PubMed  Google Scholar 

  61. Sachithanandan N, Fam BC, Fynch S, Dzamko N, Watt MJ, Wormald S, Honeyman J, Galic S, Proietto J, Andrikopoulos S, Hevener AL, Kay TW, Steinberg GR (2010) Liver-specific suppressor of cytokine signaling-3 deletion in mice enhances hepatic insulin sensitivity and lipogenesis resulting in fatty liver and obesity. Hepatology 52(5):1632–1642. https://doi.org/10.1002/hep.23861

    Article  CAS  PubMed  Google Scholar 

  62. Bjorbaek C, El-Haschimi K, Frantz JD, Flier JS (1999) The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 274(42):30059–30065

    Article  CAS  PubMed  Google Scholar 

  63. Ladyman SR, Augustine RA, Grattan DR (2010) Hormone interactions regulating energy balance during pregnancy. J Neuroendocrinol 22(7):805–817. https://doi.org/10.1111/j.1365-2826.2010.02017.x

    Article  CAS  PubMed  Google Scholar 

  64. Ladyman SR, Grattan DR (2005) Suppression of leptin receptor messenger ribonucleic acid and leptin responsiveness in the ventromedial nucleus of the hypothalamus during pregnancy in the rat. Endocrinology 146(9):3868–3874. https://doi.org/10.1210/en.2005-0194

    Article  CAS  PubMed  Google Scholar 

  65. Ladyman SR, Grattan DR (2016) Central effects of leptin on glucose homeostasis are modified during pregnancy in the rat. J Neuroendocrinol 28(10). https://doi.org/10.1111/jne.12431

  66. Beauloye V, Willems B, de Coninck V, Frank SJ, Edery M, Thissen JP (2002) Impairment of liver GH receptor signaling by fasting. Endocrinology 143(3):792–800. https://doi.org/10.1210/endo.143.3.8692

    Article  CAS  PubMed  Google Scholar 

  67. Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24(12):5434–5446. https://doi.org/10.1128/MCB.24.12.5434-5446.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA (2003) Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 278(16):13740–13746. https://doi.org/10.1074/jbc.M210689200

    Article  CAS  PubMed  Google Scholar 

  69. Shi H, Tzameli I, Bjorbaek C, Flier JS (2004) Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. J Biol Chem 279(33):34733–34740. https://doi.org/10.1074/jbc.M403886200

    Article  CAS  PubMed  Google Scholar 

  70. Yang Z, Hulver M, McMillan RP, Cai L, Kershaw EE, Yu L, Xue B, Shi H (2012) Regulation of insulin and leptin signaling by muscle suppressor of cytokine signaling 3 (SOCS3). PLoS One 7(10):e47493. https://doi.org/10.1371/journal.pone.0047493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tups A, Benzler J, Sergi D, Ladyman SR, Williams LM (2017) Central regulation of glucose homeostasis. Compr Physiol 7(2):741–764. https://doi.org/10.1002/cphy.c160015

    Article  PubMed  Google Scholar 

  72. Donato J Jr (2012) The central nervous system as a promising target to treat diabetes mellitus. Curr Top Med Chem 12(19):2070–2081

    Article  CAS  PubMed  Google Scholar 

  73. Havrankova J, Roth J, Brownstein M (1978) Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272(5656):827–829

    Article  CAS  PubMed  Google Scholar 

  74. Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8(12):1376–1382. https://doi.org/10.1038/nm798

    Article  CAS  PubMed  Google Scholar 

  75. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D, Kahn CR (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289(5487):2122–2125

    Article  CAS  PubMed  Google Scholar 

  76. Denroche HC, Huynh FK, Kieffer TJ (2012) The role of leptin in glucose homeostasis. J Diabetes Investig 3(2):115–129. https://doi.org/10.1111/j.2040-1124.2012.00203.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F (1995) Effects of the obese gene product on body weight regulation in Ob/Ob mice. Science 269(5223):540–543

    Article  CAS  PubMed  Google Scholar 

  78. Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, Friedman JM (2010) Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metab 11(1):11–22. https://doi.org/10.1016/j.cmet.2009.11.007

    Article  CAS  PubMed  Google Scholar 

  79. Hidaka S, Yoshimatsu H, Kondou S, Tsuruta Y, Oka K, Noguchi H, Okamoto K, Sakino H, Teshima Y, Okeda T, Sakata T (2002) Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. FASEB J 16(6):509–518. https://doi.org/10.1096/fj.01-0164com

    Article  CAS  PubMed  Google Scholar 

  80. Meek TH, Morton GJ (2012) Leptin, diabetes, and the brain Indian journal of endocrinology and metabolism. 16(Suppl 3):S534–S542. https://doi.org/10.4103/2230-8210.105568

  81. Pocai A, Morgan K, Buettner C, Gutierrez-Juarez R, Obici S, Rossetti L (2005) Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes 54(11):3182–3189. https://doi.org/10.2337/diabetes.54.11.3182

    Article  CAS  PubMed  Google Scholar 

  82. Seufert J (2004) Leptin effects on pancreatic beta-cell gene expression and function. Diabetes 53(Suppl 1):S152–S158

    Article  CAS  PubMed  Google Scholar 

  83. Scheller EL, Hankenson KD, Reuben JS, Krebsbach PH (2011) Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production. J Cell Biochem 112(11):3364–3372. https://doi.org/10.1002/jcb.23267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Whitaker M, Guo J, Kehoe T, Benson G (2012) Bisphosphonates for osteoporosis--where do we go from here? N Engl J Med 366(22):2048–2051. https://doi.org/10.1056/NEJMp1202619

    Article  CAS  PubMed  Google Scholar 

  85. He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5(7):522–531. https://doi.org/10.1038/nrg1379

    Article  CAS  PubMed  Google Scholar 

  86. Soriano A, Jubierre L, Almazan-Moga A, Molist C, Roma J, de Toledo JS, Gallego S, Segura MF (2013) microRNAs as pharmacological targets in cancer. Pharmacol Res 75:3–14. https://doi.org/10.1016/j.phrs.2013.03.006

    Article  CAS  PubMed  Google Scholar 

  87. Li Y, Luo T, Wang L, Wu J, Guo S (2016) MicroRNA-19a-3p enhances the proliferation and insulin secretion, while it inhibits the apoptosis of pancreatic beta cells via the inhibition of SOCS3. Int J Mol Med 38(5):1515–1524. https://doi.org/10.3892/ijmm.2016.2748

    Article  CAS  PubMed  Google Scholar 

  88. Bao L, Fu X, Si M, Wang Y, Ma R, Ren X, Lv H (2015) MicroRNA-185 targets SOCS3 to inhibit beta-cell dysfunction in diabetes. PLoS One 10(2):e0116067. https://doi.org/10.1371/journal.pone.0116067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Davalos A, Suarez Y (2013) MiRNA-based therapy: from bench to bedside. Pharmacol Res 75:1–2. https://doi.org/10.1016/j.phrs.2013.06.010

    Article  PubMed  Google Scholar 

  90. Nybo L (2003) CNS fatigue and prolonged exercise: effect of glucose supplementation. Med Sci Sports Exerc 35(4):589–594. https://doi.org/10.1249/01.MSS.0000058433.85789.66

    Article  CAS  PubMed  Google Scholar 

  91. Fujikawa T, Castorena CM, Lee S, Elmquist JK (2017) The hypothalamic regulation of metabolic adaptations to exercise. J Neuroendocrinol 29(10). https://doi.org/10.1111/jne.12533

  92. Beltowski J, Wojcicka G, Marciniak A, Jamroz A (2004) Oxidative stress, nitric oxide production, and renal sodium handling in leptin-induced hypertension. Life Sci 74(24):2987–3000. https://doi.org/10.1016/j.lfs.2003.10.029

    Article  CAS  PubMed  Google Scholar 

  93. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI (1997) Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 100(2):270–278. https://doi.org/10.1172/JCI119532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang DY, Anderson AS (2014) The sympathetic nervous system and heart failure. Cardiol Clin 32(1):33–45, vii. https://doi.org/10.1016/j.ccl.2013.09.010

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the São Paulo Research Foundation (FAPESP, Brazil) for supporting this study (grant numbers: 2013/25032-2, 2014/11752-6 and 2017/02983-2).

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, 05508-000, Brazil

    João A.B. Pedroso, Angela M. Ramos-Lobo & Jose Donato Jr

Authors
  1. João A.B. Pedroso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angela M. Ramos-Lobo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jose Donato Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to João A.B. Pedroso.

Ethics declarations

Disclosures

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pedroso, J.A., Ramos-Lobo, A.M. & Donato, J. SOCS3 as a future target to treat metabolic disorders. Hormones 18, 127–136 (2019). https://doi.org/10.1007/s42000-018-0078-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42000-018-0078-5

Keywords

Search

Navigation