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Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?

Gene Therapy volume 18, pages 319–325 (2011)Cite this article

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Abstract

The incidence of diabetes mellitus has soared to epidemic proportion worldwide. The debilitating chronic hyperglycemia is caused by either lack of insulin as in diabetes type 1 or its ineffectiveness as in diabetes type 2. Frequent replacement of insulin with or without insulin analogs for optimum glycemic control are the conventional cumbersome therapies. Recent application of leptin gene transfer technology has uncovered the participation of adipocytes-derived leptin-dependent hypothalamic neural signaling in glucose homeostasis and demonstrated that a breakdown in this communication due to leptin insufficiency in the hypothalamus underlies the etiology of chronic hyperglycemia. Reinstatement of central leptin sufficiency by hyperleptinemia produced either by intravenous leptin infusion or a single systemic injection of recombinant adenovirus vector encoding leptin gene suppressed hyperglycemia and evoked euglycemia only transiently in rodent models of diabetes type 1. In contrast, stable restoration of leptin sufficiency, solely in the hypothalamus, with biologically active leptin transduced by an intracerebroventicular injection of recombinant adeno-associated virus vector encoding leptin gene (rAAV-lep) abolished hyperglycemia and imposed euglycemia through the extended duration of experiment by stimulating glucose disposal in the periphery in models of diabetes type 1. Further, similar hypothalamic leptin transgene expression abrogated chronic hyperglycemia and hyperinsulinemia, the predisposing risk factors of the age and environmentally acquired diabetes type 2, and instituted euglycemia by independently activating relays that stimulate glucose metabolism and repress hyperinsulinemia and improve insulin sensitivity in the periphery. Consequently, this durable antidiabetic efficacy of one time rAAV-lep neurotherapy offers a potential novel substitute for insulin therapy following preclinical trials in subhuman primates and humans.

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References

  1. Grundy SM . Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 2004; 89: 2595–2600.

    CAS  PubMed  Google Scholar 

  2. Kahn SE, Hull RL, Utzschneider KM . Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840–846.

    CAS  PubMed  Google Scholar 

  3. Lazar MA . How obesity causes diabetes: not a tall tale. Science 2005; 307: 373–375.

    CAS  PubMed  Google Scholar 

  4. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K . Central obesity and increased risk of dementia more than three decades later. Neurology 2008; 71: 1057–1064.

    CAS  PubMed  Google Scholar 

  5. Kalra SP . Increased leptin supply to hypothalamus by gene therapy confers life-long benefits on energy homeostasis, disease cluster of metabolic syndrome-diabetes type 1 and 2, dyslipidemia and cardiovascular ailments-and bone remodeling. In: Shioda S, Homma I, Kato N (eds). Transmitters and modulators in health and disease. Springer: Tokyo, 2009, pp 19–30.

    Google Scholar 

  6. Santamaria P . The long and winding road to understanding and conquering type 1 diabetes. Immunity 2010; 32: 437–445.

    CAS  PubMed  Google Scholar 

  7. Kalra SP . Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation. Peptides 2009; 30: 1957–1963.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Carr MC, Brunzell JD . Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab 2004; 89: 2601–2607.

    CAS  PubMed  Google Scholar 

  9. Lewis GF, Carpentier A, Adeli K, Giacca A . Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23: 201–229.

    CAS  PubMed  Google Scholar 

  10. Kalra SP, Kalra PS . Neuroendocrine control of energy homeostasis: update on new insights. Prog Brain Res 2010; 181: 17–33.

    CAS  PubMed  Google Scholar 

  11. Robertson RP, Kendall DM, Seaquist ER . Diabetes: strategies to prevent the type 2 diabetes mellitus epidemic. Nat Rev Endocrinol 2010; 6: 128–129.

    CAS  PubMed  Google Scholar 

  12. Bonow RO, Gheorghiade M . The diabetes epidemic: a national and global crisis. Am J Med 2004; 116: 2S–10S.

    PubMed  Google Scholar 

  13. Kahn BB, Flier JS . Obesity and insulin resistance. J Clin Invest 2000; 106: 473–481.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Kalra PS, Kalra SP . Obesity and metabolic syndrome: long-term benefits of central leptin gene therapy. In: Prous JR (ed). Drugs of Today. Prous Science: Barcelona, Spain, 2002, pp 745–757.

    Google Scholar 

  15. Smyth S, Heron A . Diabetes and obesity: the twin epidemics. Nat Med 2006; 12: 75–80.

    CAS  PubMed  Google Scholar 

  16. Friedman JM . Leptin at 14 y of age: an ongoing story. Am J Clin Nutr 2009; 89: 973S–979S.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Slyper AH . The pediatric obesity epidemic: causes and controversies. J Clin Endocrinol Metab 2004; 89: 2540–2547.

    CAS  PubMed  Google Scholar 

  18. Stein CJ, Colditz GA . The epidemic of obesity. J Clin Endocrinol Metab 2004; 89: 2522–2525.

    CAS  PubMed  Google Scholar 

  19. Olshansky SJ, Passaro DJ, Hershow RC, Layden J, Carnes BA, Brody J et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med 2005; 352: 1138–1145.

    CAS  PubMed  Google Scholar 

  20. Cummings DE, Overduin J, Foster-Schubert KE . Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution. J Clin Endocrinol Metab 2004; 89: 2608–2615.

    CAS  PubMed  Google Scholar 

  21. Clifton P . Diabetes: treatment of type 2 diabetes mellitus with bariatric surgery. Nat Rev Endocrinol 2010; 6: 191–193.

    PubMed  Google Scholar 

  22. McKnight SL . WAT-free mice: diabetes without obesity. Genes Dev 1998; 12: 3145–3148.

    CAS  PubMed  Google Scholar 

  23. Farooqi IS, O′Rahilly S . Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr 2009; 89: 980S–984S.

    CAS  PubMed  Google Scholar 

  24. Ogawa Y, Masuzaki H, Hosoda K, Aizawa-Abe M, Suga J, Suda M et al. Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin. Diabetes 1999; 48: 1822–1829.

    CAS  PubMed  Google Scholar 

  25. Paz-Filho G, Esposito K, Hurwitz B, Sharma A, Dong C, Andreev V et al. Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients. Am J Physiol Endocrinol Metab 2008; 295: E1401–E1408.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL . Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999; 401: 73–76.

    CAS  PubMed  Google Scholar 

  27. Ebihara K, Kusakabe T, Hirata M, Masuzaki H, Miyanaga F, Kobayashi N et al. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab 2007; 92: 532–541.

    CAS  PubMed  Google Scholar 

  28. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002; 109: 1345–1350.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Banting FG, Best CH . Pancreatic extracts 1922. J Lab Clin Med 1990; 115: 254–272.

    CAS  PubMed  Google Scholar 

  30. Owens DR, Zinman B, Bolli GB . Insulins today and beyond. Lancet 2001; 358: 739–746.

    CAS  PubMed  Google Scholar 

  31. Taubes G . Diabetes. paradoxical effects of tightly controlled blood sugar. Science 2008; 322: 365–367.

    CAS  PubMed  Google Scholar 

  32. Carrascosa JM, Ros M, Andres A, Fernandez-Agullo T, Arribas C . Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging. Exp Gerontol 2009; 44: 20–25.

    CAS  PubMed  Google Scholar 

  33. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS . Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999; 20: 68–100.

    CAS  PubMed  Google Scholar 

  34. Dietrich MO, Horvath TL . Feeding signals and brain circuitry. Eur J Neurosci 2009; 30: 1688–1696.

    PubMed  Google Scholar 

  35. Kalra SP, Bagnasco M, Otukonyong EE, Dube MG, Kalra PS . Rhythmic, reciprocal ghrelin and leptin signaling: new insight in the development of obesity. Regul Pept 2003; 111: 1–11.

    CAS  PubMed  Google Scholar 

  36. Chinookoswong N, Wang JL, Shi ZQ . Leptin restores euglycemia and normalizes glucose turnover in insulin- deficient diabetes in the rat. Diabetes 1999; 48: 1487–1492.

    CAS  PubMed  Google Scholar 

  37. Hidaka S, Yoshimatsu H, Kondou S, Tsuruta Y, Oka K, Noguchi H et al. Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. FASEB J 2002; 16: 509–518.

    CAS  PubMed  Google Scholar 

  38. Lin CY, Higginbotham DA, Judd RL, White BD . Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 2002; 282: E1084–E1091.

    CAS  PubMed  Google Scholar 

  39. Otukonyong EE, Dube MG, Torto R, Kalra PS, Kalra SP . Central leptin differentially modulates ultradian secretory patterns of insulin, leptin and ghrelin independent of effects on food intake and body weight. Peptides 2005; 26: 2559–2566.

    CAS  PubMed  Google Scholar 

  40. Otukonyong EE, Dube MG, Torto R, Kalra PS, Kalra SP . High fat diet-induced ultradian leptin and insulin hypersecretion and ghrelin is absent in obesity-resistant rats. Obes Res 2005; I13: 991–999.

    Google Scholar 

  41. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425–432.

    CAS  PubMed  Google Scholar 

  42. Kalra SP . Central leptin insufficiency syndrome: an interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions. Peptides 2008; 29: 127–138.

    CAS  PubMed  Google Scholar 

  43. Kastin AJ, Pan W . Dynamic regulation of leptin entry into brain by the blood-brain barrier. Regul Pept 2000; 92: 37–43.

    CAS  PubMed  Google Scholar 

  44. Kastin AJ, Pan W, Maness LM, Koletsky RJ, Ernsberger P . Decreased transport of leptin across the blood-brain barrier in rats lacking the short form of the leptin receptor. Peptides 1999; 20: 1449–1453.

    CAS  PubMed  Google Scholar 

  45. Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF, Friedman JM et al. Leptin targets in the mouse brain. J Comp Neurol 2009; 514: 518–532.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Kalra SP . Disruption in the leptin-NPY link underlies the pandemic of diabetes and metabolic syndrome:new therapeutic approaches. Nutrition 2008; 24: 820–826.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Bartness TJ, Kay Song C, Shi H, Bowers RR, Foster MT . Brain-adipose tissue cross talk. Proc Nutr Soc 2005; 64: 53–64.

    CAS  PubMed  Google Scholar 

  48. Kreier F, Kap YS, Mettenleiter TC, van Heijningen C, van der Vliet J, Kalsbeek A et al. Tracing from fat tissue, liver, and pancreas: a neuroanatomical framework for the role of the brain in type 2 diabetes. Endocrinology 2006; 147: 1140–1147.

    CAS  PubMed  Google Scholar 

  49. Uyama N, Geerts A, Reynaert H . Neural connections between the hypothalamus and the liver. Anat Rec A Discov Mol Cell Evol Biol 2004; 280: 808–820.

    PubMed  Google Scholar 

  50. Buijs RM, Chun SJ, Niijima A, Romijn HJ, Nagai K . Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J Comp Neurol 2001; 431: 405–423.

    CAS  PubMed  Google Scholar 

  51. Pu S, Dube MG, Kalra SP, Kalra PS . Permanent interruption of information flow between hypothalamus and hindbrain produces obesity accompanied by a selective dark-phase hyperphagia and hyperinsulinemia. 33rd Annual Society for Neuroscience Meeting. Society for Neuroscience: New Orleans, LA, 2003, pp W-33, Abstract no. 831.837.

    Google Scholar 

  52. Lee JH, Chan JL, Sourlas E, Raptopoulos V, Mantzoros CS . Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. J Clin Endocrinol Metab 2006; 91: 2605–2611.

    CAS  PubMed  Google Scholar 

  53. Park JY, Chong AY, Cochran EK, Kleiner DE, Haller MJ, Schatz DA et al. Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. J Clin Endocrinol Metab 2008; 93: 26–31.

    CAS  PubMed  Google Scholar 

  54. Boghossian S, Dube MG, Torto R, Kalra PS, Kalra SP . Hypothalamic clamp on insulin release by leptin-transgene expression. Peptides 2006; 27: 3245–3254.

    CAS  PubMed  Google Scholar 

  55. Ueno N, Dube MG, Inui A, Kalra PS, Kalra SP . Leptin modulates orexigenic effects of ghrelin and attenuates adiponectin and insulin levels and selectively the dark-phase feeding as revealed by central leptin gene therapy. Endocrinology 2004; 145: 4176–4184.

    CAS  PubMed  Google Scholar 

  56. Ueno N, Inui A, Kalra SP, Kalra PS . Leptin transgene expression in the hypothalamus enforces euglycemia in diabetic, insulin-deficient nonobese Akita mice and leptin-deficient obese ob/ob mice. Peptides 2006; 27: 2332–2342.

    CAS  PubMed  Google Scholar 

  57. Bluher S, Shah S, Mantzoros CS . Leptin deficiency: clinical implications and opportunities for therapeutic interventions. J Investig Med 2009; 57: 784–788.

    PubMed Central  PubMed  Google Scholar 

  58. Brennan AM, Lee JH, Tsiodras S, Chan JL, Doweiko J, Chimienti SN et al. r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans. Eur J Endocrinol 2009; 160: 173–176.

    CAS  PubMed  Google Scholar 

  59. Mulligan K, Khatami H, Schwarz JM, Sakkas GK, DePaoli AM, Tai VW et al. The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab 2009; 94: 1137–1144.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Cohen P, Zhao C, Cai X, Montez JM, Rohani SC, Feinstein P et al. Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 2001; 108: 1113–1121.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Keen-Rhinehart E, Kalra SP, Kalra PS . AAV mediated leptin receptor installation improves energy balance and the reproductive status of obese female Koletsky rats. Peptides 2005; 26: 2567–2578.

    CAS  PubMed  Google Scholar 

  62. Banks WA, DiPalma CR, Farrell CL . Impaired transport of leptin across the blood-brain barrier in obesity. Peptides 1999; 20: 1341–1345.

    CAS  PubMed  Google Scholar 

  63. Banks WA, Farr SA, Morley JE . The effects of high fat diets on the blood-brain barrier transport of leptin: failure or adaptation? Physiol Behav 2006; 88: 244–248.

    CAS  PubMed  Google Scholar 

  64. Banks WA, Farrell CL . Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab 2003; 285: E10–E15.

    CAS  PubMed  Google Scholar 

  65. Burguera B, Couce ME, Curran GL, Jensen MD, Lloyd RV, Cleary MP et al. Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Diabetes 2000; 49: 1219–1223.

    CAS  PubMed  Google Scholar 

  66. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996; 348: 159–161.

    CAS  PubMed  Google Scholar 

  67. Ziylan YZ, Baltaci AK, Mogulkoc R . Leptin transport in the central nervous system. Cell Biochem Funct 2009; 27: 63–70.

    CAS  PubMed  Google Scholar 

  68. Kastin AJ, Pan W . Intranasal leptin: blood-brain barrier bypass (BBBB) for obesity? Endocrinology 2006; 147: 2086–2087.

    CAS  PubMed  Google Scholar 

  69. Kalra SP . Circumventing leptin resistance for weight control. Proc Natl Acad Sci USA 2001; 98: 4279–4281.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kalra SP, Kalra PS . Gene transfer technology: a preventive neurotherapy to curb obesity, ameliorate metabolic syndrome and extend life-expectancy. Trends Pharmacol Sci 2005; 26: 488–495.

    CAS  PubMed  Google Scholar 

  71. Carter BJ, Burstein H . Adeno-associated virus and AAV vectors for gene delivery. In: Templeton-Smith N (ed). Theruapeutics Mechanisms and Strategies. Marcel Dekker: New York, NY, 2004, pp 71–1011.

    Google Scholar 

  72. Dhillon H, Ge Y, Minter RM, Prima V, Moldawer LL, Muzyczka N et al. Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice. Relationship with body weight change. Regul Pept 2000; 92: 97–105.

    CAS  PubMed  Google Scholar 

  73. Dhillon H, Kalra SP, Kalra PS . Dose-dependent effects of central leptin gene therapy on genes that regulate body weight and appetite in the hypothalamus. Mol Ther 2001; 4: 139–145.

    CAS  PubMed  Google Scholar 

  74. Dhillon H, Kalra SP, Prima V, Zolotukhin S, Scarpace PJ, Moldawer LL et al. Central leptin gene therapy suppresses body weight gain, adiposity and serum insulin without affecting food consumption in normal rats: a long-term study. Regul Pept 2001; 99: 69–77.

    CAS  PubMed  Google Scholar 

  75. Miyanaga F, Ogawa Y, Ebihara K, Hidaka S, Tanaka T, Hayashi S et al. Leptin as an adjunct of insulin therapy in insulin-deficient diabetes. Diabetologia 2003; 46: 1329–1337.

    CAS  PubMed  Google Scholar 

  76. Briley LP, Szczech LA . Leptin and renal disease. Semin Dial 2006; 19: 54–59.

    PubMed  Google Scholar 

  77. Correia MLG, Rahmouni K . Role of leptin in the cardiovascular and endocrine complications of metabolic syndrome. Diabetes, Obes Metab 2006; 8: 603–610.

    CAS  Google Scholar 

  78. Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O′Doherty R et al. Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci USA 1996; 93: 14795–14799.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Koyama K, Shimabukuro M, Chen G, Wang MY, Lee Y, Kalra PS et al. Resistance to adenovirally induced hyperleptinemia in rats. Comparison of ventromedial hypothalamic lesions and mutated leptin receptors. J Clin Invest 1998; 102: 728–733.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Muzzin P, Cusin I, Charnay Y, Rohner-Jeanrenaud F . Single intracerebroventricular bolus injection of a recombinant adenovirus expressing leptin results in reduction of food intake and body weight in both lean and obese Zucker fa/fa rats. Regul Pept 2000; 92: 57–64.

    CAS  PubMed  Google Scholar 

  81. Murphy JE, Zhou S, Giese K, Williams LT, Escobedo JA, Dwarki VJ . Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin. Proc Natl Acad Sci USA 1997; 94: 13921–13926.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Bagnasco M, Dube MG, Kalra PS, Kalra SP . Evidence for the existence of distinct central appetite and energy expenditure pathways and stimulation of ghrelin as revealed by hypothalamic site-specific leptin gene therapy. Endocrinology 2002; 143: 4409–4421.

    CAS  PubMed  Google Scholar 

  83. Bagnasco M, Dube MG, Katz A, Kalra PS, Kalra SP . Leptin expression in hypothalamic PVN reverses dietary obesity and hyperinsulinemia but stimulates ghrelin. Obes Res 2003; 11: 1463–1470.

    CAS  PubMed  Google Scholar 

  84. Gao G, Vandenberghe LH, Wilson JM . New recombinant serotypes of AAV vectors. Curr Gene Ther 2005; 5: 285–297.

    CAS  PubMed  Google Scholar 

  85. Taymans JM, Vandenberghe LH, Haute CV, Thiry I, Deroose CM, Mortelmans L et al. Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum Gene Ther 2007; 18: 195–206.

    CAS  PubMed  Google Scholar 

  86. Beretta E, Dube MG, Kalra PS, Kalra SP . Long-term suppression of weight gain, adiposity, and serum insulin by central leptin gene therapy in prepubertal rats: effects on serum ghrelin and appetite-regulating genes. Pediatr Res 2002; 52: 189–198.

    CAS  PubMed  Google Scholar 

  87. Boghossian S, Lecklin AH, Torto R, Kalra PS, Kalra SP . Suppression of fat deposition for the life time of rodents with gene therapy. Peptides 2005; 26: 1512–1519.

    CAS  PubMed  Google Scholar 

  88. Boghossian S, Ueno N, Dube MG, Kalra P, Kalra S . Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin. Neurobiol Aging 2007; 28: 1594–1604.

    CAS  PubMed  Google Scholar 

  89. Wang J, Takeuchi T, Tanaka S, Kubo SK, Kayo T, Lu D et al. A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. J Clin Invest 1999; 103: 27–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Malhotra A, Vashistha H, Yadav VS, Dube MG, Kalra SP, Abdellatif M et al. Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis. Am J Physiol Heart Circ Physiol 2009; 296: H380–H388.

    CAS  PubMed  Google Scholar 

  91. Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ . Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 1997; 389: 374–377.

    CAS  PubMed  Google Scholar 

  92. Wang JL, Chinookoswong N, Scully S, Qi M, Shi ZQ . Differential effects of leptin in regulation of tissue glucose utilization in vivo. Endocrinology 1999; 140: 2117–2124.

    CAS  PubMed  Google Scholar 

  93. Yu X, Park BH, Wang MY, Wang ZV, Unger RH . Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci USA 2008; 105: 14070–14075.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR et al. Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci USA 2010; 107: 4813–4819.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kraus D, Herman MA, Kahn BB . Leveraging leptin for type I diabetes? Proc Natl Acad Sci USA 2010; 107: 4793–4794.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kojima S, Asakawa A, Amitani H, Sakoguchi T, Ueno N, Inui A et al. Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides 2009; 30: 962–966.

    CAS  PubMed  Google Scholar 

  97. Dube MG, Beretta E, Dhillon H, Ueno N, Kalra PS, Kalra SP . Central leptin gene therapy blocks high fat diet-induced weight gain, hyperleptinemia and hyperinsulinemia: effects on serum ghrelin levels. Diabetes 2002; 51: 1729–1736.

    CAS  PubMed  Google Scholar 

  98. Lecklin AH, Dube MG, Torto R, Kalra PS, Kalra SP . Perigestational suppression of weight gain with central leptin gene therapy results in lower weight F1 generation. Peptides 2005; 26: 1176–1187.

    CAS  PubMed  Google Scholar 

  99. Dube MG, Torto R, Kalra SP . Increased leptin expression selectively in the hypothalamus suppresses inflammatory markers CRP and IL-6 in leptin-deficient diabetic obese mice. Peptides 2008; 29: 593–598.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Iwaniec UT, Boghossian S, Lapke PD, Turner RT, Kalra SP . Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice. Peptides 2007; 28: 1012–1019.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Kalra SP, Dube MG, Iwaniec UT . Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay. Peptides 2009; 30: 967–973.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson′s disease: an open label, phase I trial. Lancet 2007; 369: 2097–2105.

    CAS  PubMed  Google Scholar 

  103. Mandel RJ, Burger C . Clinical trials in neurological disorders using AAV vectors: promises and challenges. Curr Opin Mol Ther 2004; 6: 482–490.

    CAS  PubMed  Google Scholar 

  104. Mueller C, Flotte TR . Clinical gene therapy using recombinant adeno-associated virus vectors. Gene Therapy 2008; 15: 858–863.

    CAS  PubMed  Google Scholar 

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Acknowledgements

The research embodied in this review was supported by National Institute of Health, grant DK 37273 and NS32727.

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  1. Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA

    S P Kalra

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Kalra, S. Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention?. Gene Ther 18, 319–325 (2011). https://doi.org/10.1038/gt.2010.164

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