Impaired insulin action in the human brain: Causes and metabolic consequences

Nature Reviews Endocrinology

Volumn 11, Issue 12, 2015, Pages 701-711

  Heni, Martin ^a   Kullmann, Stephanie ^a   Preissl, Hubert ^a   Fritsche, Andreas ^a   Häring, Hans Ulrich ^a  

^a UNIVERSITY OF TÜBINGEN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPOCYTOKINE; INSULIN; INSULIN DERIVATIVE; SATURATED FATTY ACID;

AGE; AGING; BLOOD BRAIN BARRIER; BODY WEIGHT; BRAIN; BRAIN FUNCTION; COGNITION; FEEDING BEHAVIOR; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC VARIABILITY; HUMAN; INSULIN RESISTANCE; INSULIN RESPONSE; INSULIN SENSITIVITY; INSULIN TREATMENT; INTRAABDOMINAL FAT; METABOLIC DISORDER; METABOLISM; MOLECULAR PATHOLOGY; NONHUMAN; OBESITY; PRENATAL DISORDER; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; BRAIN CHEMISTRY; NON INSULIN DEPENDENT DIABETES MELLITUS; PHYSIOLOGY;

BODY WEIGHT; BRAIN CHEMISTRY; COGNITION; DIABETES MELLITUS, TYPE 2; FEEDING BEHAVIOR; HUMANS; INSULIN; INSULIN RESISTANCE;

EID: 84947614766     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2015.173     Document Type: Review

References (155)

1. Bernard, C. Leçons de physiologie expérimentale appliquées A la médecine. [French] (J. B. Baillière et fils, 1855).
2. Havrankova, J., Roth, J. & Brownstein, M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272, 827-829 (1978).
3. Hill, J. M., Lesniak, M. A., Pert, C. B. & Roth, J. Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience 17, 1127-1138 (1986).
4. Lesniak, M. A. et al. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin. Endocrinology 123, 2089-2099 (1988).
5. Hopkins, D. F. & Williams, G. Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet. Med. 14, 1044-1050 (1997).
6. Hom, F. G., Goodner, C. J. & Berrie, M. A. A (3H)2-deoxyglucose method for comparing rates of glucose metabolism and insulin responses among rat tissues in vivo: validation of the model and the absence of an insulin effect on brain. Diabetes 33, 141-152 (1984).
7. Seaquist, E. R., Damberg, G. S., Tkac, I. & Gruetter, R. The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Diabetes 50, 2203-2209 (2001).
8. Brüning, J. C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122-2125 (2000).
9. Kleinridders, A., Ferris, H. A., Cai, W. & Kahn, C. R. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63, 2232-2243 (2014).
10. Vogt, M. C. & Brüning, J. C. CNS insulin signaling in the control of energy homeostasis and glucose metabolism-from embryo to old age. Trends Endocrinol. Metab. 24, 76-84 (2013).
11. Fernandez, A. M. & Torres-Alemán, I. The many faces of insulin-like peptide signalling in the brain. Nat. Rev. Neurosci. 13, 225-239 (2012).
12. Tschritter, O. et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: A magnetoencephalographic study. Proc. Natl Acad. Sci. USA 103, 12103-12108 (2006).
13. Porubská, K. et al. Processing of food-relevant visual stimuli measured by magnetoencephalography and its modulation by insulin. Int. Congr. Ser. 1300, 516-519 (2007).
14. Benedict, L., Nelson, C. A., Schunk, E., Sullwold, K. & Seaquist, E. R. Effect of insulin on the brain activity obtained during visual and memory tasks in healthy human subjects. Neuroendocrinology 83, 20.26 (2006).
15. Hallschmid, M. et al. Transcortical direct current potential shift reflects immediate signaling of systemic insulin to the human brain. Diabetes 53, 2202.2208 (2004).
16. Anthony, K. et al. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: The cerebral basis for impaired control of food intake in metabolic syndrome? Diabetes 55, 2986.2992 (2006).
17. Bingham, E. M. et al. The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes 51, 3384.3390 (2002).
18. Rotte, M. et al. Insulin affects the neuronal response in the medial temporal lobe in humans. Neuroendocrinology 81, 49.55 (2005).
19. Seaquist, E. R. et al. Insulin reduces the BOLD response but is without effect on the VEP during presentation of a visual task in humans. J. Cereb. Blood Flow Metab. 27, 154.160 (2007).
20. Born, J. et al. Sniffing neuropeptides: A transnasal approach to the human brain. Nat. Neurosci. 5, 514.516 (2002).
21. Stingl, K. T. et al. Insulin modulation of magnetoencephalographic resting state dynamics in lean and obese subjects. Front. Syst. Neurosci. 4, 157 (2010).
22. Kern, W., Born, J., Schreiber, H. & Fehm, H. L. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes 48, 557.563 (1999).
23. Guthoff, M. et al. The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects. PLoS ONE 6, e19482 (2011).
24. Renner, D. B. et al. Intranasal delivery of insulin via the olfactory nerve pathway. J. Pharm. Pharmacol. 64, 1709.1714 (2012).
25. Heni, M. et al. Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions. Diabetologia 55, 1773.1782 (2012).
26. Spetter, M. & Hallschmid, M. Intranasal neuropeptide administration to target the human brain in health and disease. Mol. Pharm. 12, 2767.2780 (2015).
27. Havrankova, J., Schmechel, D., Roth, J. & Brownstein, M. Identification of insulin in rat brain. Proc. Natl Acad. Sci. USA 75, 5737.5741 (1978).
28. Woods, S. C., Seeley, R. J., Baskin, D. G. & Schwartz, M. W. Insulin and the blood.brain barrier. Curr. Pharm. Des. 9, 795.800 (2003).
29. Banks, W. A. The source of cerebral insulin. Eur. J. Pharmacol. 490, 5.12 (2004).
30. Wallum, B. J. et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J. Clin. Endocrinol. Metab. 64, 190.194 (1987).
31. Kern, W. et al. Low cerebrospinal fluid insulin levels in obese humans. Diabetologia 49, 2790.2792 (2006).
32. Heni, M. et al. Evidence for altered transport of insulin across the blood.brain barrier in insulin-resistant humans. Acta Diabetol. 51, 679.681 (2014).
33. Bromander, S. et al. Cerebrospinal fluid insulin during non-neurological surgery. J. Neural Transm. 117, 1167.1170 (2010).
34. Pardridge, W. M., Eisenberg, J. & Yang, J. Human blood.brain barrier insulin receptor. J. Neurochem. 44, 1771.1778 (1985).
35. Frolich, L. et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J. Neural Transm. 105, 423.438 (1998).
36. Sartorius, T. et al. The brain response to peripheral insulin declines with age: A contribution of the blood.brain barrier? PLoS ONE 10, e0126804 (2015).
37. Craft, S. et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 50, 164.168 (1998).
38. Gray, S. M., Meijer, R. I. & Barrett, E. J. Insulin regulates brain function, but how does it get there? Diabetes 63, 3992.3997 (2014).
39. Kullmann, S., Heni, M., Fritsche, A. & Preissl, H. Insulin action in the human brain: evidence from neuroimaging studies. J. Neuroendocrinol. 27, 419.423 (2015).
40. Matsuda, M. et al. Altered hypothalamic function in response to glucose ingestion in obese humans. Diabetes 48, 1801.1806 (1999).
41. Little, T. J. et al. Mapping glucose-mediated gut.to.brain signalling pathways in humans. Neuroimage 96, 1.11 (2014).
42. Heni, M. et al. Differential effect of glucose ingestion on the neural processing of food stimuli in lean and overweight adults. Hum. Brain Mapp. 35, 918.928 (2014).
43. Smeets, P. A., de Graaf, C., Stafleu, A., van Osch, M. J. & van der Grond, J. Functional MRI of human hypothalamic responses following glucose ingestion. Neuroimage 24, 363.368 (2005).
44. Teeuwisse, W. M. et al. Short-term caloric restriction normalizes hypothalamic neuronal responsiveness to glucose ingestion in patients with type 2 diabetes. Diabetes 61, 3255.3259 (2012).
45. Page, K. A. et al. Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA 309, 63.70 (2013).
46. Vidarsdottir, S. et al. Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes. Diabetes 56, 2547.2550 (2007).
47. Kullmann, S. et al. Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women. Neuroendocrinology 97, 176.182 (2013).
48. Kullmann, S. et al. Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care 38, 1044.1050 (2015).
49. Guthoff, M. et al. Insulin modulates food-related activity in the central nervous system. J. Clin. Endocrinol. Metab. 95, 748.755 (2010).
50. Kroemer, N. B. et al. (Still) longing for food: insulin reactivity modulates response to food pictures. Hum. Brain Mapp. 34, 2367.2380 (2012).
51. Zhang, H. et al. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes 64, 1025.1034 (2015).
52. Winocur, G., Moscovitch, M. & Bontempi, B. Memory formation and long-term retention in humans and animals: convergence towards a transformation account of hippocampal.neocortical interactions. Neuropsychologia 48, 2339.2356 (2010).
53. Kern, W. et al. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology 74, 270.280 (2001).
54. Benedict, C. et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29, 1326.1334 (2004).
55. Benedict, C. et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology 32, 239.243 (2007).
56. Benedict, C., Kern, W., Schultes, B., Born, J. & Hallschmid, M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J. Clin. Endocrinol. Metab. 93, 1339.1344 (2008).
57. Ott, V., Benedict, C., Schultes, B., Born, J. & Hallschmid, M. Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes. Metab. 14, 214.221 (2012).
58. Novak, V. et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 37, 751.759 (2014).
59. Craft, S., Cholerton, B. & Baker, L. D. Insulin and Alzheimer's disease: untangling the web. J. Alzheimer's Dis. 33, S263.S275 (2013).
60. Freiherr, J. et al. Intranasal insulin as a treatment for Alzheimer's disease: A review of basic research and clinical evidence. CNS Drugs 27, 505.514 (2013).
61. Yarchoan, M. & Arnold, S. E. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 63, 2253.2261 (2014).
62. Wallner-Liebmann, S. et al. Insulin and hippocampus activation in response to images of high-calorie food in normal weight and obese adolescents. Obes. (Silver Spring) 18, 1552.1557 (2010).
63. Ketterer, C. et al. Acute, short-term hyperinsulinemia increases olfactory threshold in healthy subjects. Int. J. Obes. (Lond.) 35, 1135.1138 (2011).
64. Brunner, Y. F., Benedict, C. & Freiherr, J. Intranasal insulin reduces olfactory sensitivity in normosmic humans. J. Clin. Endocrinol. Metab. 98, E1626.E1630 (2013).
65. Flint, A. et al. Associations between postprandial insulin and blood glucose responses, appetite sensations and energy intake in normal weight and overweight individuals: A meta-analysis of test meal studies. Br. J. Nutr. 98, 17.25 (2007).
66. Hallschmid, M., Higgs, S., Thienel, M., Ott, V. & Lehnert, H. Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women. Diabetes 61, 782.789 (2012).
67. Jauch-Chara, K. et al. Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans. Diabetes 61, 2261.2268 (2012).
68. Hallschmid, M. et al. Intranasal insulin reduces body fat in men but not in women. Diabetes 53, 3024.3029 (2004).
69. Tschritter, O. et al. High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention. Diabetologia 55, 175.182 (2012).
70. Pontiroli, A. E., Miele, L. & Morabito, A. Increase of body weight during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis. Diabetes Obes. Metab. 13, 1008.1019 (2011).
71. Scherer, T. & Buettner, C. Yin and yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism. Rev. Endocr. Metab. Disord. 12, 235.243 (2011).
72. Benedict, C. et al. Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men. Diabetes 60, 114.118 (2011).
73. Scherer, T. et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab. 13, 183.194 (2011).
74. Koch, L. et al. Central insulin action regulates peripheral glucose and fat metabolism in mice. J. Clin. Invest. 118, 2132.2147 (2008).
75. Coomans, C. P. et al. Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice. J. Lipid Res. 52, 1712.1722 (2011).
76. Iwen, K. A. et al. Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J. Clin. Endocrinol. Metab. 99, E246.E251 (2014).
77. Jensen, M. D., Caruso, M., Heiling, V. & Miles, J. M. Insulin regulation of lipolysis in nondiabetic and IDDM subjects. Diabetes 38, 1595.1601 (1989).
78. Heni, M. et al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes 63, 4083.4088 (2014).
79. Gancheva, S. et al. Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans. Diabetes 64, 1966.1975 (2015).
80. Dash, S., Xiao, C., Morgantini, C., Koulajian, K. & Lewis, G. F. Intranasal insulin suppresses endogenous glucose production in humans compared to placebo, in the presence of similar venous insulin concentration. Diabetes 64, 766.774 (2015).
81. Heni, M., Wagner, R., Kullmann, S., Preissl, H. & Fritsche, A. Response to Comment on Heni. et al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes 2014;63:4083.4088. Diabetes 64, e8.e9 (2015).
82. Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376.1382 (2002).
83. Macedo, M. P. et al. Risk of postprandial insulin resistance: The liver/vagus rapport. Rev. Endocr. Metab. Disord. 15, 67.77 (2014).
84. Filippi, B. M., Yang, C. S., Tang, C. & Lam, T. K. T. Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab. 16, 500.510 (2012).
85. Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain.liver circuit regulates glucose homeostasis. Cell Metab. 1, 53.61 (2005).
86. Konner, A. C. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438.449 (2007).
87. Coomans, C. P. et al. Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice. Diabetes 60, 3132.3140 (2011).
88. 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. 15, 656.664 (2012).
89. Girard, J. Insulins effect on the liver: direct or indirect? continues to be the question. J. Clin. Invest. 116, 302.304 (2006).
90. Kishore, P. et al. Activation of KATP channels suppresses glucose production in humans. J. Clin. Invest. 121, 4916.4920 (2011).
91. Matthews, D. R. et al. Homeostasis model assessment: insulin resistance and A-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412.419 (1985).
92. Wallace, T. M., Levy, J. C. & Matthews, D. R. Use and abuse of HOMA modeling. Diabetes Care 27, 1487.1495 (2004).
93. Nolan, J. J. & Farch, K. Estimating insulin sensitivity and A cell function: perspectives from the modern pandemics of obesity and type 2 diabetes. Diabetologia 55, 2863.2867 (2012).
94. Edgerton, D. S. & Cherrington, A. D. Is brain insulin action relevant to the control of plasma glucose in humans? Diabetes 64, 696.699 (2015).
95. Ott, V. et al. Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia. Diabetes 64, 760.765 (2015).
96. Scarlett, J. M. & Schwartz, M. W. Gut.brain mechanisms controlling glucose homeostasis. F1000Prime Rep. 7, 12 (2015).
97. Stockhorst, U., de Fries, D., Steingrueber, H..J. & Scherbaum, W. A. Unconditioned and conditioned effects of intranasally administered insulin vs placebo in healthy men: A randomised controlled trial. Diabetologia 54, 1502.1506 (2011).
98. Benedict, C. et al. Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings. Metabolism 54, 1356.1361 (2005).
99. Bohringer, A., Schwabe, L., Richter, S. & Schachinger, H. Intranasal insulin attenuates the hypothalamic.pituitary.adrenal axis response to psychosocial stress. Psychoneuroendocrinology 33, 1394.1400 (2008).
100. Hallschmid, M., Benedict, C., Schultes, B., Born, J. & Kern, W. Obese men respond to cognitive but not to catabolic brain insulin signaling. Int. J. Obes. (Lond.) 32, 275.282 (2008).
101. Chong, A. C., Vogt, M. C., Hill, A. S., Bruning, J. C. & Zeltser, L. M. Central insulin signaling modulates hypothalamus.pituitary.adrenal axis responsiveness. Mol. Metab. 4, 83.92 (2015).
102. Fekete, C. et al. Differential effects of central leptin, insulin, or glucose administration during fasting on the hypothalamic.pituitary.thyroid axis and feeding-related neurons in the arcuate nucleus. Endocrinology 147, 520.529 (2006).
103. Ketterer, C. et al. Insulin sensitivity of the human brain. Diabetes Res. Clin. Pract. 93, S47.S51 (2011).
104. Hallschmid, M. & Schultes, B. Central nervous insulin resistance: A promising target in the treatment of metabolic and cognitive disorders? Diabetologia 52, 2264.2269 (2009).
105. Kullmann, S. et al. The obese brain: association of body mass index and insulin sensitivity with resting state network functional connectivity. Hum. Brain Mapp. 33, 1052.1061 (2012).
106. Tuulari, J. J. et al. Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese. Diabetes 62, 2747.2751 (2013).
107. Tschritter, O. et al. Cerebrocortical A activity in overweight humans responds to insulin detemir. PLoS ONE 2, e1196 (2007).
108. Hirvonen, J. et al. Effects of insulin on brain glucose metabolism in impaired glucose tolerance. Diabetes 60, 443.447 (2011).
109. Tschritter, O. et al. Insulin effects on A and activity in the human brain are differentially affected by ageing. Diabetologia 52, 169.171 (2009).
110. Sobngwi, E. et al. Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet 361, 1861.1865 (2003).
111. Dabelea, D. et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: A study of discordant sibships. Diabetes 49, 2208.2211 (2000).
112. Gupta, A., Srinivasan, M., Thamadilok, S. & Patel, M. S. Hypothalamic alterations in fetuses of high fat diet-fed obese female rats. J. Endocrinol. 200, 293.300 (2009).
113. Vogt, M. C. et al. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 156, 495.509 (2014).
114. Linder, K. et al. Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity. Diabetologia 57, 1192.1198 (2014).
115. Tschritter, O. et al. The insulin effect on cerebrocortical activity is associated with serum concentrations of saturated nonesterified fatty acids. J. Clin. Endocrinol. Metab. 94, 4600.4607 (2009).
116. Krogmann, A. et al. Inflammatory response of human coronary artery endothelial cells to saturated long-chain fatty acids. Microvasc. Res. 81, 52.59 (2011).
117. Stefan, N., Wahl, H. G., Fritsche, A., Haring, H. & Stumvoll, M. Effect of the pattern of elevated free fatty acids on insulin sensitivity and insulin secretion in healthy humans. Horm. Metab. Res. 33, 432.438 (2001).
118. Boden, G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46, 3.10 (1997).
119. Konner, A. C. & Bruning, J. C. Toll-like receptors: linking inflammation to metabolism. Trends Endocrinol. Metab. 22, 16.23 (2011).
120. Hennige, A. M. et al. Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity. Diabetologia 52, 2416.2424 (2009).
121. Sartorius, T. et al. Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin.6 and osteopontin and alter sleep architecture. FASEB J. 26, 1799.1809 (2012).
122. Staiger, H. et al. Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans. Obes. Res. 11, 368.372 (2003).
123. Konner, A. C. & Bruning, J. C. Selective insulin and leptin resistance in metabolic disorders. Cell Metab. 16, 144.152 (2012).
124. Williams, K. W. & Elmquist, J. K. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat. Neurosci. 15, 1350.1355 (2012).
125. Sartorius, T. et al. Leptin affects insulin action in astrocytes and impairs insulin-mediated physical activity. Cell. Physiol. Biochem. 30, 238.246 (2012).
126. Argente-Arizon, P., Freire-Regatillo, A., Argente, J. & Chowen, J. A. Role of non-neuronal cells in body weight and appetite control. Front. Endocrinol. 6, 42 (2015).
127. Farooqi, I. S. et al. Leptin regulates striatal regions and human eating behavior. Science 317, (2007).
128. Frank, S. et al. Leptin therapy in a congenital leptin-deficient patient leads to acute and long-term changes in homeostatic, reward, and food-related brain areas. J. Clin. Endocrinol. Metab. 96, E1283.E1287 (2011).
129. Frank, S. et al. Long-term stabilization effects of leptin on brain functions in a leptin-deficient patient. PLoS ONE 8, (2013).
130. Schwartz, M. W. et al. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503, 59.66 (2013).
131. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85-96 (2006).
132. Tschritter, O. et al. Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. Diabetologia 50, 2602-2603 (2007).
133. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889-894 (2007).
134. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724-726 (2007).
135. Haupt, A. et al. Variation in the FTO gene influences food intake but not energy expenditure. Exp. Clin. Endocrinol. Diabetes 117, 194-197 (2009).
136. Heni, M. et al. Variation in the obesity risk gene FTO determines the postprandial cerebral processing of food stimuli in the prefrontal cortex. Mol. Metab. 3, 109-113 (2013).
137. Tschritter, O. et al. An obesity risk SNP (rs17782313) near the MC4R gene is associated with cerebrocortical insulin resistance in humans. J. Obes. 2011, 283153 (2011).
138. Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S. & Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 443, 289-295 (2006).
139. Ketterer, C. et al. Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action. Obesity (Silver Spring) 22, 925-931(2014).
140. Di Marzo, V. & Matias, I. Endocannabinoid control of food intake and energy balance. Nat. Neurosci. 8, 585-589 (2005).
141. Yeo, G. S. H. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111-112 (1998).
142. Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113-114 (1998).
143. Reger, M. A. et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol. Aging 27, 451-458 (2006).
144. Jastreboff, A. M. et al. Neural correlates of stress-and food cue-induced food craving in obesity: association with insulin levels. Diabetes Care 36, 394-402 (2013).
145. de la Monte, S. M. & Tong, M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem. Pharmacol. 88, 548-559 (2014).
146. Craft, S. Alzheimer disease: insulin resistance and AD-extending the translational path. Nat. Rev. Neurol. 8, 360-362 (2012).
147. Hennige, A. M. et al. Tissue selectivity of insulin detemir action in vivo. Diabetologia 49, 1274-1282 (2006).
148. Begg, D. P. et al. Insulin detemir is transported from blood to cerebrospinal fluid and has prolonged central anorectic action relative to NPH insulin. Diabetes 64, 2457-2466 (2015).
149. Hallschmid, M. et al. Euglycemic infusion of insulin detemir compared with human insulin appears to increase direct current brain potential response and reduces food intake while inducing similar systemic effects. Diabetes 59, 1101-1107 (2010).
150. Frier, B. M., Russell-Jones, D. & Heise, T. A comparison of insulin detemir and neutral protamine Hagedorn (isophane) insulin in the treatment of diabetes: A systematic review. Diabetes Obes. Metab. 15, 978-986 (2013).
151. Claxton, A. et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J. Alzheimer's Dis. 44, 897-906 (2015).
152. Labuzek, K. et al. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol. Rep. 62, 956-965 (2010).
153. Begg, D. P. et al. Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats. Endocrinology 154, 1047-1054 (2013).
154. Gallwitz, B. Anorexigenic effects of GLP-1 and its analogues. Handb. Exp. Pharmacol. 209, 185-207 (2012).
155. Ferrannini, E. & Solini, A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat. Rev. Endocrinol. 8, 495-502 (2012).