Brain Insulin and Leptin Signaling in Metabolic Control. From Animal Research to Clinical Application

Endocrinology and Metabolism Clinics of North America

Volumn 42, Issue 1, 2013, Pages 109-125

  Scherer, Thomas ^a   Lehnert, Hendrik ^b   Hallschmid, Manfred ^c  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

^b UNIVERSITY OF LÜBECK   (Germany)

^c UNIVERSITY OF TÜBINGEN   (Germany)

Author keywords

Brain; Energy homeostasis; Insulin; Intranasal administration; Leptin; Metabolism

Indexed keywords

GLUCOSE; INSULIN; LEPTIN;

ADRENERGIC SYSTEM; CENTRAL NERVOUS SYSTEM; ENERGY BALANCE; ENERGY EXPENDITURE; FATTY LIVER; FOOD INTAKE; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; HORMONE ACTION; HUMAN; INSULIN BLOOD LEVEL; INSULIN RESISTANCE; INSULIN SENSITIVITY; METABOLIC REGULATION; NERVE CELL PLASTICITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN METABOLISM; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; BRAIN; ENERGY METABOLISM; HUMANS; INSULIN; LEPTIN; OBESITY; SIGNAL TRANSDUCTION;

EID: 84873254079     PISSN: 08898529     EISSN: 15584410     Source Type: Journal    
DOI: 10.1016/j.ecl.2012.11.002     Document Type: Review

References (139)

1. Gomez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci 2008, 9(7):568-578.
2. Crawford M.A., Bloom M., Broadhurst C.L., et al. Evidence for the unique function of docosahexaenoic acid during the evolution of the modern hominid brain. Lipids 1999, 34(Suppl):S39-S47.
3. McNay E.C. Insulin and ghrelin: peripheral hormones modulating memory and hippocampal function. Curr Opin Pharmacol 2007, 7(6):628-632.
4. Bernard C. Leçons de physiologie expérimentale appliquée à la médecine, faites au Collège de France, par m. Claude Bernard 1855, vol. 1. Paris, J.B. Baillière et fils, Paris, p. 1855-56.
5. Hetherington A.W., Ranson S.W. Hypothalamic lesions and adiposity in the rat. Anat Rec 1940, 78(2):149-172.
6. Halaas J.L., Gajiwala K.S., Maffei M., et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995, 269(5223):543-546.
7. Schwartz M.W., Peskind E., Raskind M., et al. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med 1996, 2(5):589-593.
8. Caro J.F., Kolaczynski J.W., Nyce M.R., et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996, 348(9021):159-161.
9. Schwartz M.W., Woods S.C., Porte D., et al. Central nervous system control of food intake. Nature 2000, 404(6778):661-671.
10. Pelleymounter M.A., Cullen M.J., Baker M.B., et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995, 269(5223):540-543.
11. Farooqi I.S., Matarese G., Lord G.M., et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002, 110(8):1093-1103.
12. Liu L., Karkanias G.B., Morales J.C., et al. Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J Biol Chem 1998, 273(47):31160-31167.
13. Buettner C., Muse E.D., Cheng A., et al. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat Med 2008, 14(6):667-675.
14. Davis J.F., Choi D.L., Benoit S.C. Insulin, leptin and reward. Trends Endocrinol Metab 2010, 21(2):68-74.
15. Domingos A.I., Vaynshteyn J., Voss H.U., et al. Leptin regulates the reward value of nutrient. Nat Neurosci 2011, 14(12):1562-1568.
16. Watanobe H., Suda T., Wikberg J.E., et al. Evidence that physiological levels of circulating leptin exert a stimulatory effect on luteinizing hormone and prolactin surges in rats. Biochem Biophys Res Commun 1999, 263(1):162-165.
17. Buettner C., Pocai A., Muse E.D., et al. Critical role of STAT3 in leptin's metabolic actions. Cell Metab 2006, 4(1):49-60.
18. Mantzoros C.S. Role of leptin in reproduction. Ann N Y Acad Sci 2000, 900:174-183.
19. Shanley L.J., Irving A.J., Harvey J. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J Neurosci 2001, 21(24):RC186.
20. Lu X.Y., Kim C.S., Frazer A., et al. Leptin: a potential novel antidepressant. Proc Natl Acad Sci U S A 2006, 103(5):1593-1598.
21. Yamada N., Katsuura G., Ochi Y., et al. Impaired CNS leptin action is implicated in depression associated with obesity. Endocrinology 2011, 152(7):2634-2643.
22. Bagdade J.D., Bierman E.L., Porte D. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest 1967, 46(10):1549-1557.
23. Porte D., Woods S.C. Regulation of food intake and body weight in insulin. Diabetologia 1981, 20(Suppl):274-280.
24. Devaskar S.U., Giddings S.J., Rajakumar P.A., et al. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J Biol Chem 1994, 269(11):8445-8454.
25. Schwartz M.W., Bergman R.N., Kahn S.E., et al. Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport. J Clin Invest 1991, 88(4):1272-1281.
26. Banks W.A., Jaspan J.B., Kastin A.J. Selective, physiological transport of insulin across the blood-brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides 1997, 18(8):1257-1262.
27. Obici S., Zhang B.B., Karkanias G., et al. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 2002, 8(12):1376-1382.
28. Scherer T., O'Hare J., Diggs-Andrews K., et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 2011, 13(2):183-194.
29. Figlewicz D.P., Bennett J., Evans S.B., et al. Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats. Behav Neurosci 2004, 118(3):479-487.
30. Figlewicz D.P., Bennett J.L., Naleid A.M., et al. Intraventricular insulin and leptin decrease sucrose self-administration in rats. Physiol Behav 2006, 89(4):611-616.
31. Benedict C., Hallschmid M., Hatke A., et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 2004, 29(10):1326-1334.
32. Chiu S.L., Chen C.M., Cline H.T. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 2008, 58(5):708-719.
33. Bruning J.C., Gautam D., Burks D.J., et al. Role of brain insulin receptor in control of body weight and reproduction. Science 2000, 289(5487):2122-2125.
34. Rulifson E.J., Kim S.K., Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 2002, 296(5570):1118-1120.
35. Schubert M., Gautam D., Surjo D., et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A 2004, 101(9):3100-3105.
36. Muzumdar R., Ma X., Yang X., et al. Physiologic effect of leptin on insulin secretion is mediated mainly through central mechanisms. FASEB J 2003, 17(9):1130-1132.
37. Chen M., Woods S.C., Porte D. Effect of cerebral intraventricular insulin on pancreatic insulin secretion in the dog. Diabetes 1975, 24(10):910-914.
38. Wallum B.J., Taborsky G.J., Porte D., et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 1987, 64(1):190-194.
39. Ott V., Benedict C., Schultes B., et al. Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes Metab 2012, 14(3):214-221.
40. Thorne R.G., Emory C.R., Ala T.A., et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res 1995, 692(1-2):278-282.
41. Born J., Lange T., Kern W., et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002, 5(6):514-516.
42. Schulz C., Paulus K., Johren O., et al. Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO). Endocrinology 2012, 153(1):143-153.
43. Schulz C., Paulus K., Lehnert H. Central nervous and metabolic effects of intranasally applied leptin. Endocrinology 2004, 145(6):2696-2701.
44. Shimizu H., Oh I.S., Okada S., et al. Inhibition of appetite by nasal leptin administration in rats. Int J Obes 2005, 29(7):858-863.
45. Degerman E., Landström T.R., Holst L.S., et al. Role for phosphodiesterase 3b in regulation of lipolysis and insulin secretion. Diabetes mellitus: a fundamental and clinical text 2003, 374-381. Lippincott Williams & Wilkins, Philadelphia. 3rd edition. D. LeRoith, J.M. Olefsky, S.I. Taylor (Eds.).
46. Assimacopoulos-Jeannet F., Brichard S., Rencurel F., et al. In vivo effects of hyperinsulinemia on lipogenic enzymes and glucose transporter expression in rat liver and adipose tissues. Metabolism 1995, 44(2):228-233.
47. Grefhorst A., Hoekstra J., Derks T.G., et al. Acute hepatic steatosis in mice by blocking beta-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production. Am J Physiol Gastrointest Liver Physiol 2005, 289(3):G592-G598.
48. Buettner C., Camacho R.C. Hypothalamic control of hepatic glucose production and its potential role in insulin resistance. Endocrinol Metab Clin North Am 2008, 37(4):825-840.
49. Pocai A., Lam T.K., Gutierrez-Juarez R., et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 2005, 434(7036):1026-1031.
50. Okamoto H., Obici S., Accili D., et al. Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J Clin Invest 2005, 115(5):1314-1322.
51. Ramnanan C.J., Saraswathi V., Smith M.S., et al. Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. J Clin Invest 2011, 121(9):3713-3723.
52. Konner A.C., Janoschek R., Plum L., et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 2007, 5(6):438-449.
53. Ramnanan C.J., Edgerton D.S., Cherrington A.D. Evidence against a physiologic role for acute changes in CNS insulin action in the rapid regulation of hepatic glucose production. Cell Metab 2012, 15(5):656-664.
54. Kishore P., Boucai L., Zhang K., et al. Activation of K(ATP) channels suppresses glucose production in humans. J Clin Invest 2011, 121(12):4916-4920.
55. Heni M., Kullmann S., Ketterer C., et al. Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions. Diabetologia 2012, 55(6):1773-1782.
56. Stockhorst U., de Fries D., Steingrueber H.J., et al. Unconditioned and conditioned effects of intranasally administered insulin vs placebo in healthy men: a randomised controlled trial. Diabetologia 2011, 54(6):1502-1506.
57. Benedict C., Brede S., Schioth H.B., et al. Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men. Diabetes 2010, 60(1):114-118.
58. Jauch-Chara K., Friedrich A., Rezmer M., et al. Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans. Diabetes 2012, 61(9):2261-2268.
59. Benedict C., Dodt C., Hallschmid M., et al. Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings. Metabolism 2005, 54(10):1356-1361.
60. Clegg D.J., Riedy C.A., Smith K.A., et al. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 2003, 52(3):682-687.
61. McGowan M.K., Andrews K.M., Grossman S.P. Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiol Behav 1992, 51(4):753-766.
62. Brief D.J., Davis J.D. Reduction of food intake and body weight by chronic intraventricular insulin infusion. Brain Res Bull 1984, 12(5):571-575.
63. Menendez J.A., Atrens D.M. Insulin and the paraventricular hypothalamus: modulation of energy balance. Brain Res 1991, 555(2):193-201.
64. Rahmouni K., Morgan D.A., Morgan G.M., et al. Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest 2004, 114(5):652-658.
65. Benedict C., Kern W., Schultes B., et al. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab 2008, 93(4):1339-1344.
66. Hallschmid M., Benedict C., Schultes B., et al. Intranasal insulin reduces body fat in men but not in women. Diabetes 2004, 53(11):3024-3029.
67. Guthoff M., Grichisch Y., Canova C., et al. Insulin modulates food-related activity in the central nervous system. J Clin Endocrinol Metab 2010, 95(2):748-755.
68. Hallschmid M., Higgs S., Thienel M., et al. Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women. Diabetes 2012, 61(4):782-789.
69. Higgs S., Williamson A.C., Attwood A.S. Recall of recent lunch and its effect on subsequent snack intake. Physiol Behav 2008, 94(3):454-462.
70. Higgs S., Williamson A.C., Rotshtein P., et al. Sensory-specific satiety is intact in amnesics who eat multiple meals. Psychol Sci 2008, 19(7):623-628.
71. Rozin P., Dow S., Moscovitch M., et al. What causes humans to begin and end a meal? A role for memory for what has been eaten, as evidenced by a study of multiple meal eating in amnesic patients. Psychol Sci 1998, 9(5):392-396.
72. Diekelmann S., Born J. The memory function of sleep. Nat Rev Neurosci 2010, 11(2):114-126.
73. Moult P.R., Harvey J. Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity. Cell Adh Migr 2008, 2(4):269-275.
74. Craft S., Watson G.S. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 2004, 3(3):169-178.
75. Seaquist E.R., Damberg G.S., Tkac I., et al. The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Diabetes 2001, 50(10):2203-2209.
76. Hasselbalch S.G., Knudsen G.M., Videbaek C., et al. No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans. Diabetes 1999, 48(10):1915-1921.
77. Doyle P., Cusin I., Rohner-Jeanrenaud F., et al. Four-day hyperinsulinemia in euglycemic conditions alters local cerebral glucose utilization in specific brain nuclei of freely moving rats. Brain Res 1995, 684(1):47-55.
78. Benedict C., Hallschmid M., Schmitz K., et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology 2007, 32(1):239-243.
79. Reger M.A., Watson G.S., Green P.S., et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008, 70(6):440-448.
80. Reger M.A., Watson G.S., Green P.S., et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 2008, 13(3):323-331.
81. Craft S., Baker L.D., Montine T.J., et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012, 69(1):29-38.
82. Grillo C.A., Piroli G.G., Kaigler K.F., et al. Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats. Behav Brain Res 2011, 222(1):230-235.
83. Tschritter O., Preissl H., Hennige A.M., et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc Natl Acad Sci U S A 2006, 103(32):12103-12108.
84. Hallschmid M., Benedict C., Schultes B., et al. Obese men respond to cognitive but not to catabolic brain insulin signaling. Int J Obes (Lond) 2008, 32(2):275-282.
85. Wang J., Obici S., Morgan K., et al. Overfeeding rapidly induces leptin and insulin resistance. Diabetes 2001, 50(12):2786-2791.
86. Ono H., Pocai A., Wang Y., et al. Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest 2008, 118(8):2959-2968.
87. Scherer T., Lindtner C., Zielinski E., et al. Short-term voluntary overfeeding disrupts brain insulin control of adipose tissue lipolysis. J Biol Chem 2012, 287(39):33061-33069.
88. Cornier M.A., Bergman B.C., Bessesen D.H. The effects of short-term overfeeding on insulin action in lean and reduced-obese individuals. Metabolism 2006, 55(9):1207-1214.
89. Brons C., Jensen C.B., Storgaard H., et al. Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J Physiol 2009, 587(Pt 10):2387-2397.
90. Thaler J.P., Yi C.X., Schur E.A., et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012, 122(1):153-162.
91. Zhang X., Zhang G., Zhang H., et al. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008, 135(1):61-73.
92. McCrimmon R.J., Ryan C.M., Frier B.M. Diabetes and cognitive dysfunction. Lancet 2012, 379(9833):2291-2299.
93. Gold S.M., Dziobek I., Sweat V., et al. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 2007, 50(4):711-719.
94. Kodl C.T., Seaquist E.R. Cognitive dysfunction and diabetes mellitus. Endocr Rev 2008, 29(4):494-511.
95. Tschritter O., Preissl H., Hennige A.M., et al. High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention. Diabetologia 2012, 55(1):175-182.
96. Scherer T., Buettner C. Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism. Rev Endocr Metab Disord 2011, 12(3):235-243.
97. Gutierrez-Juarez R., Obici S., Rossetti L. Melanocortin-independent effects of leptin on hepatic glucose fluxes. J Biol Chem 2004, 279(48):49704-49715.
98. de Luca C., Kowalski T.J., Zhang Y., et al. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest 2005, 115(12):3484-3493.
99. Guo K., McMinn J.E., Ludwig T., et al. Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities. Endocrinology 2007, 148(8):3987-3997.
100. Baicy K., London E.D., Monterosso J., et al. Leptin replacement alters brain response to food cues in genetically leptin-deficient adults. Proc Natl Acad Sci U S A 2007, 104(46):18276-18279.
101. DelParigi A., Chen K., Salbe A.D., et al. Successful dieters have increased neural activity in cortical areas involved in the control of behavior. Int J Obes 2007, 31(3):440-448.
102. Farooqi I.S., Bullmore E., Keogh J., et al. Leptin regulates striatal regions and human eating behavior. Science 2007, 317(5843):1355.
103. Tataranni P.A., Gautier J.F., Chen K., et al. Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc Natl Acad Sci U S A 1999, 96(8):4569-4574.
104. Scarpace P.J., Matheny M., Pollock B.H., et al. Leptin increases uncoupling protein expression and energy expenditure. Am J Physiol 1997, 273(1 Pt 1):E226-E230.
105. Ahima R.S., Prabakaran D., Mantzoros C., et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996, 382(6588):250-252.
106. Rosenbaum M., Nicolson M., Hirsch J., et al. Effects of weight change on plasma leptin concentrations and energy expenditure. J Clin Endocrinol Metab 1997, 82(11):3647-3654.
107. Rosenbaum M., Goldsmith R., Bloomfield D., et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 2005, 115(12):3579-3586.
108. Sumithran P., Prendergast L.A., Delbridge E., et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011, 365(17):1597-1604.
109. Leibel R.L., Rosenbaum M., Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med 1995, 332(10):621-628.
110. Rosenbaum M., Sy M., Pavlovich K., et al. Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J Clin Invest 2008, 118(7):2583-2591.
111. Koyama K., Chen G., Wang M.Y., et al. beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy. Diabetes 1997, 46(8):1276-1280.
112. Rossetti L., Massillon D., Barzilai N., et al. Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J Biol Chem 1997, 272(44):27758-27763.
113. Chinookoswong N., Wang J.L., Shi Z.Q. Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 1999, 48(7):1487-1492.
114. Yu X., Park B.H., Wang M.Y., et al. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A 2008, 105(37):14070-14075.
115. Wang M.Y., Chen L., Clark G.O., et al. Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci U S A 2010, 107(11):4813-4819.
116. Hidaka S., Yoshimatsu H., Kondou S., et al. Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin-induced diabetic rats. FASEB J 2002, 16(6):509-518.
117. Lin C.Y., Higginbotham D.A., Judd R.L., et al. Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 2002, 282(5):E1084-E1091.
118. Fujikawa T., Chuang J.C., Sakata I., et al. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 2010, 107(40):17391-17396.
119. Denroche H.C., Levi J., Wideman R.D., et al. Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 2011, 60(5):1414-1423.
120. Mittendorfer B., Horowitz J.F., DePaoli A.M., et al. Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes 2011, 60(5):1474-1477.
121. Moon H.S., Matarese G., Brennan A.M., et al. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes 2011, 60(6):1647-1656.
122. Mantzoros C.S., Magkos F., Brinkoetter M., et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 2011, 301(4):E567-E584.
123. Szczepaniak L.S., Nurenberg P., Leonard D., et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005, 288(2):E462-E468.
124. Warne J.P., Alemi F., Reed A.S., et al. Impairment of central leptin-mediated PI3K signaling manifested as hepatic steatosis independent of hyperphagia and obesity. Cell Metab 2011, 14(6):791-803.
125. Singh A., Wirtz M., Parker N., et al. Leptin-mediated changes in hepatic mitochondrial metabolism, structure, and protein levels. Proc Natl Acad Sci U S A 2009, 106(31):13100-13105.
126. Cohen P., Zhao C., Cai X., et al. Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 2001, 108(8):1113-1121.
127. Petersen K.F., Oral E.A., Dufour S., et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002, 109(10):1345-1350.
128. Ebihara K., Kusakabe T., Hirata M., 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(2):532-541.
129. Heymsfield S.B., Greenberg A.S., Fujioka K., et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999, 282(16):1568-1575.
130. Pocai A., Morgan K., Buettner C., et al. Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes 2005, 54(11):3182-3189.
131. El-Haschimi K., Pierroz D.D., Hileman S.M., et al. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 2000, 105(12):1827-1832.
132. Banks W.A., DiPalma C.R., Farrell C.L. Impaired transport of leptin across the blood-brain barrier in obesity. Peptides 1999, 20(11):1341-1345.
133. Burguera B., Couce M.E., Curran G.L., et al. Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Diabetes 2000, 49(7):1219-1223.
134. Ceccarini G., Flavell R.R., Butelman E.R., et al. PET imaging of leptin biodistribution and metabolism in rodents and primates. Cell Metab 2009, 10(2):148-159.
135. Fliedner S., Schulz C., Lehnert H. Brain uptake of intranasally applied radioiodinated leptin in Wistar rats. Endocrinology 2006, 147(5):2088-2094.
136. Kern W., Benedict C., Schultes B., et al. Low cerebrospinal fluid insulin levels in obese humans. Diabetologia 2006, 49(11):2790-2792.
137. Fishel M.A., Watson G.S., Montine T.J., et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol 2005, 62(10):1539-1544.
138. Mayer C.M., Belsham D.D. Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation. Endocrinology 2010, 151(1):75-84.
139. Bohringer A., Schwabe L., Richter S., et al. Intranasal insulin attenuates the hypothalamic-pituitary-adrenal axis response to psychosocial stress. Psychoneuroendocrinology 2008, 33(10):1394-1400.