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Central Regulation of Glucose Homeostasis

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ABSTRACT

The ability of the brain to directly control glucose levels in the blood independently of its effects on food intake and body weight has been known ever since 1854 when Claude Bernard, a French physiologist, discovered that lesioning the floor of the fourth ventricle in rabbits led to a rise of sugar in the blood. Despite this outstanding discovery at that time, it took more than 140 years before progress started to be made in identifying the underlying mechanisms of brain‐mediated control of glucose homeostasis. Technological advances including the generation of brain insulin receptor null mice revealed that insulin action specifically in the central nervous system is required for the regulation of glucose metabolism, particularly in the modulation of hepatic glucose production. Furthermore, it was established that the hormone leptin, known for its role in regulating food intake and body weight, actually exerts its most potent effects on glucose metabolism, and that this function of leptin is mediated centrally. Under certain circumstances, high levels of leptin can replicate the actions of insulin, thus challenging the idea that life without insulin is impossible. Disruptions of central insulin signaling and glucose metabolism not only lead to impairments in whole body glucose homeostasis, they also have other serious consequences, including the development of Alzheimer's disease which is sometimes referred to as type 3 diabetes reflecting its common etiology with type 2 diabetes. © 2017 American Physiological Society. Compr Physiol 7:471‐764, 2017.

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Figure 1. Figure 1. Central regulation of glucose homeostasis is hypothesised to be mediated via interaction of pancreatic insulin and adipose tissue‐derived leptin in the central nervous system. Both hormones bind to their respective receptors, expressed in the hypothalamic arcuate nucleus and appear to interact via convergence of intracellular signaling at the IRS‐PI3K‐AKT pathway. Leptin sensitizes insulin signaling by activating IRS1, resulting in a modification of this molecule to a higher affinity to insulin signal transduction. This allows the transduction of the insulin signal into a glycemic response. Besides IRS1 also IRS2 and 4 are expressed in the hypothalamus but sensitization by leptin remains to be established. LepR: Leptin receptor; IR: insulin receptor; JAK: Janus kinase, IRS: Insulin receptor substrate, Pi3K: Phosphatidylinositol 3‐kinase.
Figure 2. Figure 2. Model proposing that sensitization of insulin signaling in the hypothalamus is mediated via the WNT pathway. Leptin, similar to WNT 7a and 4 activates LRP‐6, resulting in inactivation of GSK3β (This inactivation can also be induced artificially by administration of a GSK3β inhibitor). Consequently, a positive feedback loop might be triggered in which the phosphorylation of inhibitory phosphorylation sites on IRS‐1 by GSK3β is reduced. This modification on IRS‐1 would result in activation of the IRS‐PI3K pathway by insulin, leading to an increase in phosphorylation of AKT. Phospho‐AKT, in turn, might enhance this mechanism by further inactivating GSK3β. Leptin induces activation of WNT target genes Axin‐2 and Cyclin‐D1, however, whether this increase is mediated by TCF7 and β‐Catenin and their respective role in central regulation of glucose homeostasis remains to be established (dotted arrows). LepR: Leptin receptor; IR: insulin receptor; JAK: Janus kinase, IRS: Insulin receptor substrate, Pi3K: Phosphatidylinositol 3‐kinase, TCF7: transcription factor 7.
Figure 3. Figure 3. Gene‐therapeutic inhibition of the pro‐inflammatory IKKβ/NFκB pathway in neurons in the ARC by overexpressing a mutated form of IκBα (IκBα‐mt) in an AAV2 vector, partially protects from metabolic alterations induced by high fat diet. The expression of IκBα‐mt was under the control of the human synapsin‐1 promoter to restrict the expression to neurons and WPRE (Woodchuck hepatitis virus post‐transcriptional regulatory element) to ensure long‐term expression of the transgene. When animals overexpressing this mutated gene were fed a high‐fat diet they gained less fat mass, had reduced basal blood glucose levels, improved glucose tolerance and were more insulin sensitive than control mice. For details, see ().
Figure 4. Figure 4. Central and peripheral diet of glucose homeostasis associated with obesity and type two diabetes mellitus leads to cognitive impairment. In rodents on a high fat diet, the hypothalamus and the hippocampus appear to be particularly affected illustrated by the loss of central control of peripheral glucose homeostasis and energy balance, and memory deficits respectively. Mechanisms underlying these effects are the rapid development of insulin and leptin insensitivity, increased central levels of glucose resulting in glucotoxicity and the formation of advanced glycation end products (AGEs). Inflammation and lipotoxic fatty acid metabolites are also detected.
Figure 5. Figure 5. Central regulation of glucose homeostasis is regulated by a coordinated action of nutrient absorption in the intestine and the crosstalk of leptin and insulin in the hypothalamus. Long chain saturated fatty acids, abundant in a Western diet, activate the the pro‐inflammatory IKKβ/NFκB pathway in neurons and microglia of the hypothalamus. This in turn disrupts the essential crosstalk of leptin and insulin signaling leading to an increase of centrally mediated hepatic glucose production and a reduction in insulin dependent glucose uptake in the muscle. Chronic consumption of a Western diet rich in long chain saturated fatty acids leads to an imbalance of glucose homeostasis and ultimately to the development of type 2 diabetes.


Figure 1. Central regulation of glucose homeostasis is hypothesised to be mediated via interaction of pancreatic insulin and adipose tissue‐derived leptin in the central nervous system. Both hormones bind to their respective receptors, expressed in the hypothalamic arcuate nucleus and appear to interact via convergence of intracellular signaling at the IRS‐PI3K‐AKT pathway. Leptin sensitizes insulin signaling by activating IRS1, resulting in a modification of this molecule to a higher affinity to insulin signal transduction. This allows the transduction of the insulin signal into a glycemic response. Besides IRS1 also IRS2 and 4 are expressed in the hypothalamus but sensitization by leptin remains to be established. LepR: Leptin receptor; IR: insulin receptor; JAK: Janus kinase, IRS: Insulin receptor substrate, Pi3K: Phosphatidylinositol 3‐kinase.


Figure 2. Model proposing that sensitization of insulin signaling in the hypothalamus is mediated via the WNT pathway. Leptin, similar to WNT 7a and 4 activates LRP‐6, resulting in inactivation of GSK3β (This inactivation can also be induced artificially by administration of a GSK3β inhibitor). Consequently, a positive feedback loop might be triggered in which the phosphorylation of inhibitory phosphorylation sites on IRS‐1 by GSK3β is reduced. This modification on IRS‐1 would result in activation of the IRS‐PI3K pathway by insulin, leading to an increase in phosphorylation of AKT. Phospho‐AKT, in turn, might enhance this mechanism by further inactivating GSK3β. Leptin induces activation of WNT target genes Axin‐2 and Cyclin‐D1, however, whether this increase is mediated by TCF7 and β‐Catenin and their respective role in central regulation of glucose homeostasis remains to be established (dotted arrows). LepR: Leptin receptor; IR: insulin receptor; JAK: Janus kinase, IRS: Insulin receptor substrate, Pi3K: Phosphatidylinositol 3‐kinase, TCF7: transcription factor 7.


Figure 3. Gene‐therapeutic inhibition of the pro‐inflammatory IKKβ/NFκB pathway in neurons in the ARC by overexpressing a mutated form of IκBα (IκBα‐mt) in an AAV2 vector, partially protects from metabolic alterations induced by high fat diet. The expression of IκBα‐mt was under the control of the human synapsin‐1 promoter to restrict the expression to neurons and WPRE (Woodchuck hepatitis virus post‐transcriptional regulatory element) to ensure long‐term expression of the transgene. When animals overexpressing this mutated gene were fed a high‐fat diet they gained less fat mass, had reduced basal blood glucose levels, improved glucose tolerance and were more insulin sensitive than control mice. For details, see ().


Figure 4. Central and peripheral diet of glucose homeostasis associated with obesity and type two diabetes mellitus leads to cognitive impairment. In rodents on a high fat diet, the hypothalamus and the hippocampus appear to be particularly affected illustrated by the loss of central control of peripheral glucose homeostasis and energy balance, and memory deficits respectively. Mechanisms underlying these effects are the rapid development of insulin and leptin insensitivity, increased central levels of glucose resulting in glucotoxicity and the formation of advanced glycation end products (AGEs). Inflammation and lipotoxic fatty acid metabolites are also detected.


Figure 5. Central regulation of glucose homeostasis is regulated by a coordinated action of nutrient absorption in the intestine and the crosstalk of leptin and insulin in the hypothalamus. Long chain saturated fatty acids, abundant in a Western diet, activate the the pro‐inflammatory IKKβ/NFκB pathway in neurons and microglia of the hypothalamus. This in turn disrupts the essential crosstalk of leptin and insulin signaling leading to an increase of centrally mediated hepatic glucose production and a reduction in insulin dependent glucose uptake in the muscle. Chronic consumption of a Western diet rich in long chain saturated fatty acids leads to an imbalance of glucose homeostasis and ultimately to the development of type 2 diabetes.
References
 1.Adachi A, Kobashi M, Funahashi M. Glucose‐responsive neurons in the brainstem. Obes Res 3(Suppl 5): 735S‐740S, 1995.
 2.Al‐Qassab H, Smith MA, Irvine EE, Guillermet‐Guibert J, Claret M, Choudhury AI, Selman C, Piipari K, Clements M, Lingard S, Chandarana K, Bell JD, Barsh GS, Smith AJ, Batterham RL, Ashford ML, Vanhaesebroeck B, Withers DJ. Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab 10: 343‐354, 2009.
 3.Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF‐1. EMBO J 15: 6541‐6551, 1996.
 4.Alosco ML, Cohen R, Spitznagel MB, Strain G, Devlin M, Crosby RD, Mitchell JE, Gunstad J. Older age does not limit postbariatric surgery cognitive benefits: A preliminary investigation. Surg Obes Relat Dis 10: 1196‐1201, 2014.
 5.Amaral AI. Effects of hypoglycaemia on neuronal metabolism in the adult brain: Role of alternative substrates to glucose. J Inherit Metab Dis 36: 621‐634, 2013.
 6.Anagnostou SH, Shepherd PR. Glucose induces an autocrine activation of the Wnt/beta‐catenin pathway in macrophage cell lines. Biochem J 416: 211‐218, 2008.
 7.Anand BK, Chhina GS, Sharma KN, Dua S, Singh B. Activity of single neurons in the hypothalamic feeding centers: Effect of glucose. Am J Physiol 207: 1146‐1154, 1964.
 8.Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, Tschop MH, Shanabrough M, Cline G, Shulman GI, Coppola A, Gao XB, Horvath TL, Diano S. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454: 846‐851, 2008.
 9.Apelt J, Mehlhorn G, Schliebs R. Insulin‐sensitive GLUT4 glucose transporters are colocalized with GLUT3‐expressing cells and demonstrate a chemically distinct neuron‐specific localization in rat brain. J Neurosci Res 57: 693‐705, 1999.
 10.Arbuckle MI, Kane S, Porter LM, Seatter MJ, Gould GW. Structure‐function analysis of liver‐type (GLUT2) and brain‐type (GLUT3) glucose transporters: Expression of chimeric transporters in Xenopus oocytes suggests an important role for putative transmembrane helix 7 in determining substrate selectivity. Biochemistry 35: 16519‐16527, 1996.
 11.Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw‐Boris A, Poli G, Olefsky J, Karin M. IKK‐beta links inflammation to obesity‐induced insulin resistance. Nat Med 11: 191‐198, 2005.
 12.Arluison M, Quignon M, Nguyen P, Thorens B, Leloup C, Penicaud L. Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain–‐an immunohistochemical study. J Chem Neuroanat 28: 117‐136, 2004.
 13.Arluison M, Quignon M, Thorens B, Leloup C, Penicaud L. Immunocytochemical localization of the glucose transporter 2 (GLUT2) in the adult rat brain. II. Electron microscopic study. J Chem Neuroanat 28: 137‐146, 2004.
 14.Ashford ML, Boden PR, Treherne JM. Glucose‐induced excitation of hypothalamic neurones is mediated by ATP‐sensitive K+ channels. Pflugers Arch 415: 479‐483, 1990.
 15.Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21: 1133‐1145, 2001.
 16.Awad N, Gagnon M, Messier C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol 26: 1044‐1080, 2004.
 17.Bady I, Marty N, Dallaporta M, Emery M, Gyger J, Tarussio D, Foretz M, Thorens B. Evidence from glut2‐null mice that glucose is a critical physiological regulator of feeding. Diabetes 55: 988‐995, 2006.
 18.Banks AS, Davis SM, Bates SH, Myers MG, Jr. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 275: 14563‐14572, 2000.
 19.Barnard ND, Bunner AE, Agarwal U. Saturated and trans fats and dementia: A systematic review. Neurobiol Aging 35(Suppl 2): S65‐S73, 2014.
 20.Barnett PA, Gonzalez RG, Chylack LT, Jr., Cheng HM. The effect of oxidation on sorbitol pathway kinetics. Diabetes 35: 426‐432, 1986.
 21.Baruch K, Deczkowska A, Rosenzweig N, Tsitsou‐Kampeli A, Sharif AM, Matcovitch‐Natan O, Kertser A, David E, Amit I, Schwartz M. PD‐1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med 22: 135‐137, 2016.
 22.Bates SH, Dundon TA, Seifert M, Carlson M, Maratos‐Flier E, Myers MG, Jr. LRb‐STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes 53: 3067‐3073, 2004.
 23.Beall C, Hamilton DL, Gallagher J, Logie L, Wright K, Soutar MP, Dadak S, Ashford FB, Haythorne E, Du Q, Jovanovic A, McCrimmon RJ, Ashford ML. Mouse hypothalamic GT1‐7 cells demonstrate AMPK‐dependent intrinsic glucose‐sensing behaviour. Diabetologia 55: 2432‐2444, 2012.
 24.Benedict C, Brede S, Schioth HB, Lehnert H, Schultes B, Born J, Hallschmid M. Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men. Diabetes 60: 114‐118, 2011.
 25.Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans: Superiority of insulin aspart. Neuropsychopharmacology 32: 239‐243, 2007.
 26.Benedict C, Hallschmid M, Schultes B, Born J, Kern W. Intranasal insulin to improve memory function in humans. Neuroendocrinology 86: 136‐142, 2007.
 27.Benzler J, Andrews ZB, Pracht C, Stohr S, Shepherd PR, Grattan DR, Tups A. Hypothalamic WNT signalling is impaired during obesity and reinstated by leptin treatment in male mice. Endocrinology 154: 4737‐4745, 2013.
 28.Benzler J, Ganjam GK, Kruger M, Pinkenburg O, Kutschke M, Stohr S, Steger J, Koch CE, Olkrug R, Schwartz MW, Shepherd PR, Grattan DR, Tups A. Hypothalamic glycogen synthase kinase 3beta has a central role in the regulation of food intake and glucose metabolism. Biochem J 447: 175‐184, 2012.
 29.Benzler J, Ganjam GK, Pretz D, Oelkrug R, Koch CE, Legler K, Stohr S, Culmsee C, Williams LM, Tups A. Central inhibition of IKKbeta/NF‐kappaB signaling attenuates high‐fat diet‐induced obesity and glucose intolerance. Diabetes 64: 2015‐2027, 2015.
 30.Berglund ED, Vianna CR, Donato J, Jr., Kim MH, Chuang JC, Lee CE, Lauzon DA, Lin P, Brule LJ, Scott MM, Coppari R, Elmquist JK. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest 122: 1000‐1009, 2012.
 31.Berkseth KE, Guyenet SJ, Melhorn SJ, Lee D, Thaler JP, Schur EA, Schwartz MW. Hypothalamic gliosis associated with high‐fat diet feeding is reversible in mice: A combined immunohistochemical and magnetic resonance imaging study. Endocrinology 155: 2858‐2867, 2014.
 32.Bernard C. Leçons de Ohysiologie Experimentale Appliqués á là Medecine. Paris, J‐B Baillière 1854.
 33.Best JD, Kahn SE, Ader M, Watanabe RM, Ni TC, Bergman RN. Role of glucose effectiveness in the determination of glucose tolerance. Diabetes care 19: 1018‐1030, 1996.
 34.Beydoun MA, Beydoun HA, Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: A systematic review and meta‐analysis. Obes Rev 9: 204‐218, 2008.
 35.Bingham EM, Hopkins D, Smith D, Pernet A, Hallett W, Reed L, Marsden PK, Amiel SA. The role of insulin in human brain glucose metabolism: An 18fluoro‐deoxyglucose positron emission tomography study. Diabetes 51: 3384‐3390, 2002.
 36.Bjorbaek C, El‐Haschimi K, Frantz JD, Flier JS. The role of SOCS‐3 in leptin signaling and leptin resistance. J Biol Chem 274: 30059‐30065, 1999.
 37.Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identification of SOCS‐3 as a potential mediator of central leptin resistance. Mol Cell 1: 619‐625, 1998.
 38.Blouet C, Schwartz GJ. Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding. Cell Metab 16: 579‐587, 2012.
 39.Boado RJ, Pardridge WM. The brain‐type glucose transporter mRNA is specifically expressed at the blood‐brain barrier. Biochem Biophys Res Commun 166: 174‐179, 1990.
 40.Bolborea M, Dale N. Hypothalamic tanycytes: Potential roles in the control of feeding and energy balance. Trends Neurosci 36: 91‐100, 2013.
 41.Bomfim TR, Forny‐Germano L, Sathler LB, Brito‐Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG. An anti‐diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease‐associated Abeta oligomers. J Clin Invest 122: 1339‐1353, 2012.
 42.Bondy CA, Lightman SL, Lightman SL. Developmental and physiological regulation of aldose reductase mRNA expression in renal medulla. Mol Endocrinol 3: 1409‐1416, 1989.
 43.Bourre JM. Effects of nutrients (in food) on the structure and function of the nervous system: Update on dietary requirements for brain. Part 2: macronutrients. J Nutr Health Aging 10: 386‐399, 2006.
 44.Braccini L, Ciraolo E, Martini M, Pirali T, Germena G, Rolfo K, Hirsch E. PI3K keeps the balance between metabolism and cancer. Adv Biol Regul 52: 389‐405, 2012.
 45.Brands AM, Van den Berg E, Manschot SM, Biessels GJ, Kappelle LJ, De Haan EH, Kessels RP. A detailed profile of cognitive dysfunction and its relation to psychological distress in patients with type 2 diabetes mellitus. J Int Neuropsychol Soc: JINS 13: 288‐297, 2007.
 46.Brown AM, Ransom BR. Astrocyte glycogen and brain energy metabolism. Glia 55: 1263‐1271, 2007.
 47.Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller‐Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 289: 2122‐2125, 2000.
 48.Burdakov D, Gerasimenko O, Verkhratsky A. Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin‐concentrating hormone and orexin neurons in situ. J Neurosci 25: 2429‐2433, 2005.
 49.Burdakov D, Gonzalez JA. Physiological functions of glucose‐inhibited neurones. Acta Physiol 195: 71‐78, 2009.
 50.Burdakov D, Luckman SM, Verkhratsky A. Glucose‐sensing neurons of the hypothalamus. Philos Trans R Soc Lond B Biol Sci 360: 2227‐2235, 2005.
 51.Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK‐beta and NF‐kappaB. Nat Med 11: 183‐190, 2005.
 52.Cameron NE, Cotter MA. Effects of protein kinase Cbeta inhibition on neurovascular dysfunction in diabetic rats: Interaction with oxidative stress and essential fatty acid dysmetabolism. Diabetes Metab Res Rev 18: 315‐323, 2002.
 53.Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science 269: 546‐549, 1995.
 54.Cantley LC. The phosphoinositide 3‐kinase pathway. Science 296: 1655‐1657, 2002.
 55.Chang GQ, Karatayev O, Davydova Z, Leibowitz SF. Circulating triglycerides impact on orexigenic peptides and neuronal activity in hypothalamus. Endocrinology 145: 3904‐3912, 2004.
 56.Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice. Cell 84: 491‐495, 1996.
 57.Choi SJ, Kim F, Schwartz MW, Wisse BE. Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids. Am J Physiol Endocrinol Metab 298: E1122‐E1130, 2010.
 58.Chua SC, Jr., Chung WK, Wu‐Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271: 994‐996, 1996.
 59.Chuang CC, McIntosh MK. Potential mechanisms by which polyphenol‐rich grapes prevent obesity‐mediated inflammation and metabolic diseases. Annu Rev Nutr 31: 155‐176, 2011.
 60.Cintra DE, Ropelle ER, Moraes JC, Pauli JR, Morari J, Souza CT, Grimaldi R, Stahl M, Carvalheira JB, Saad MJ, Velloso LA. Unsaturated fatty acids revert diet‐induced hypothalamic inflammation in obesity. PloS One 7: e30571, 2012.
 61.Citron M. Alzheimer's disease: Strategies for disease modification. Nat Rev Drug Discov 9: 387‐398, 2010.
 62.Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LG, Clements M, Al‐Qassab H, Heffron H, Xu AW, Speakman JR, Barsh GS, Viollet B, Vaulont S, Ashford ML, Carling D, Withers DJ. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 117: 2325‐2336, 2007.
 63.Cline GW, Johnson K, Regittnig W, Perret P, Tozzo E, Xiao L, Damico C, Shulman GI. Effects of a novel glycogen synthase kinase‐3 inhibitor on insulin‐stimulated glucose metabolism in Zucker diabetic fatty (fa/fa) rats. Diabetes 51: 2903‐2910, 2002.
 64.Coppari R, Bjorbaek C. Leptin revisited: Its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 11: 692‐708, 2012.
 65.Copps KD, Hancer NJ, Opare‐Ado L, Qiu W, Walsh C, White MF. Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab 11: 84‐92, 2010.
 66.Cordner ZA, Tamashiro KL. Effects of high‐fat diet exposure on learning and memory. Physiol Behav 152: 363‐371, 2015.
 67.Cotero VE, Routh VH. Insulin blunts the response of glucose‐excited neurons in the ventrolateral‐ventromedial hypothalamic nucleus to decreased glucose. Am J Physiol Endocrinol Metab 296: E1101‐E1109, 2009.
 68.Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411: 480‐484, 2001.
 69.Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch Neurol 69: 29‐38, 2012.
 70.Croset M, Rajas F, Zitoun C, Hurot JM, Montano S, Mithieux G. Rat small intestine is an insulin‐sensitive gluconeogenic organ. Diabetes 50: 740‐746, 2001.
 71.Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase‐3 by insulin mediated by protein kinase B. Nature 378: 785‐789, 1995.
 72.Dali‐Youcef N, Ricci R. Signalling networks governing metabolic inflammation. Handb Exp Pharmacol 233: 195‐220, 2016.
 73.de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes‐evidence reviewed. J Diabetes Sci Technol 2: 1101‐1113, 2008.
 74.De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA. Consumption of a fat‐rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146: 4192‐4199, 2005.
 75.de Vries MG, Arseneau LM, Lawson ME, Beverly JL. Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia. Diabetes 52: 2767‐2773, 2003.
 76.Denner LA, Rodriguez‐Rivera J, Haidacher SJ, Jahrling JB, Carmical JR, Hernandez CM, Zhao Y, Sadygov RG, Starkey JM, Spratt H, Luxon BA, Wood TG, Dineley KT. Cognitive enhancement with rosiglitazone links the hippocampal PPARgamma and ERK MAPK signaling pathways. J Neurosci 32: 16725‐16735, 2012.
 77.Devaskar SU, Giddings SJ, Rajakumar PA, Carnaghi LR, Menon RK, Zahm DS. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J Biol Chem 269: 8445‐8454, 1994.
 78.Devaskar SU, Singh BS, Carnaghi LR, Rajakumar PA, Giddings SJ. Insulin II gene expression in rat central nervous system. Regul Pept 48: 55‐63, 1993.
 79.Diano S, Liu ZW, Jeong JK, Dietrich MO, Ruan HB, Kim E, Suyama S, Kelly K, Gyengesi E, Arbiser JL, Belsham DD, Sarruf DA, Schwartz MW, Bennett AM, Shanabrough M, Mobbs CV, Yang X, Gao XB, Horvath TL. Peroxisome proliferation‐associated control of reactive oxygen species sets melanocortin tone and feeding in diet‐induced obesity. Nat Med 17: 1121‐1127, 2011.
 80.Dienel GA. Brain lactate metabolism: The discoveries and the controversies. J Cereb Blood Flow Metab 32: 1107‐1138, 2012.
 81.Dienel GA, Ball KK, Cruz NF. A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: Implications for glycogen turnover. J Neurochem 102: 466‐478, 2007.
 82.Dou JT, Chen M, Dufour F, Alkon DL, Zhao WQ. Insulin receptor signaling in long‐term memory consolidation following spatial learning. Learn Mem 12: 646‐655, 2005.
 83.Dringen R HH, Minich T, Ruedig C. 1.3 Pentose Phosphate Pathway and NADPH Metabolism. Handbook of Neurochemistry and Molecular Neurobiology, 3rd Edition. Springer, 2007, pp. 264‐266.
 84.Du X, Edelstein D, Obici S, Higham N, Zou MH, Brownlee M. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 116: 1071‐1080, 2006.
 85.Dunn‐Meynell AA, Rawson NE, Levin BE. Distribution and phenotype of neurons containing the ATP‐sensitive K+ channel in rat brain. Brain Res 814: 41‐54, 1998.
 86.Dunn‐Meynell AA, Routh VH, Kang L, Gaspers L, Levin BE. Glucokinase is the likely mediator of glucosensing in both glucose‐excited and glucose‐inhibited central neurons. Diabetes 51: 2056‐2065, 2002.
 87.Dunn‐Meynell AA, Sanders NM, Compton D, Becker TC, Eiki J, Zhang BB, Levin BE. Relationship among brain and blood glucose levels and spontaneous and glucoprivic feeding. J Neurosci 29: 7015‐7022, 2009.
 88.Eldar‐Finkelman H. Glycogen synthase kinase 3: An emerging therapeutic target. Trends Mol Med 8: 126‐132, 2002.
 89.Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 493: 63‐71, 2005.
 90.Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3‐kinases as regulators of growth and metabolism. Nat Rev Genet 7: 606‐619, 2006.
 91.Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341: 879‐884, 1999.
 92.Fioramonti X, Contie S, Song Z, Routh VH, Lorsignol A, Penicaud L. Characterization of glucosensing neuron subpopulations in the arcuate nucleus: Integration in neuropeptide Y and pro‐opio melanocortin networks? Diabetes 56: 1219‐1227, 2007.
 93.Fioramonti X, Marsollier N, Song Z, Fakira KA, Patel RM, Brown S, Duparc T, Pica‐Mendez A, Sanders NM, Knauf C, Valet P, McCrimmon RJ, Beuve A, Magnan C, Routh VH. Ventromedial hypothalamic nitric oxide production is necessary for hypoglycemia detection and counterregulation. Diabetes 59: 519‐528, 2010.
 94.Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D, Diabetes Prevention Program Research G. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355: 241‐250, 2006.
 95.Frederich RC, Lollmann B, Hamann A, Napolitano‐Rosen A, Kahn BB, Lowell BB, Flier JS. Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest 96: 1658‐1663, 1995.
 96.Freiherr J, Hallschmid M, Frey WH, 2nd, Brunner YF, Chapman CD, Holscher C, Craft S, De Felice FG, Benedict C. Intranasal insulin as a treatment for Alzheimer's disease: A review of basic research and clinical evidence. CNS Drugs 27: 505‐514, 2013.
 97.Frolich L, Blum‐Degen D, Riederer P, Hoyer S. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease. Ann N Y Acad Sci 893: 290‐293, 1999.
 98.Fujikawa T, Berglund ED, Patel VR, Ramadori G, Vianna CR, Vong L, Thorel F, Chera S, Herrera PL, Lowell BB, Elmquist JK, Baldi P, Coppari R. Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin. Cell Metab 18: 431‐444, 2013.
 99.Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R. Leptin therapy improves insulin‐deficient type 1 diabetes by CNS‐dependent mechanisms in mice. Proc Natl Acad Sci U S A 107: 17391‐17396, 2010.
 100.Fujikawa T, Coppari R. Living without insulin: The role of leptin signaling in the hypothalamus. Front Neurosci 9: 108, 2015.
 101.Gabbay KH, Merola LO, Field RA. Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 151: 209‐210, 1966.
 102.Galioto R, Alosco ML, Spitznagel MB, Strain G, Devlin M, Cohen R, Crosby RD, Mitchell JE, Gunstad J. Glucose regulation and cognitive function after bariatric surgery. J Clin Exp Neuropsychol 37: 402‐413, 2015.
 103.Gao Q, Wolfgang MJ, Neschen S, Morino K, Horvath TL, Shulman GI, Fu XY. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc Natl Acad Sci U S A 101: 4661‐4666, 2004.
 104.Gao Y, Ottaway N, Schriever SC, Legutko B, Garcia‐Caceres C, de la Fuente E, Mergen C, Bour S, Thaler JP, Seeley RJ, Filosa J, Stern JE, Perez‐Tilve D, Schwartz MW, Tschop MH, Yi CX. Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia 62: 17‐25, 2014.
 105.Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, Xu H. Stimulation of beta‐amyloid precursor protein trafficking by insulin reduces intraneuronal beta‐amyloid and requires mitogen‐activated protein kinase signaling. J Neurosci 21: 2561‐2570, 2001.
 106.Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res 106: 1319‐1331, 2010.
 107.Gerhart DZ, Leino RL, Taylor WE, Borson ND, Drewes LR. GLUT1 and GLUT3 gene expression in gerbil brain following brief ischemia: An in situ hybridization study. Brain Res Mol Brain Res 25: 313‐322, 1994.
 108.German JP, Wisse BE, Thaler JP, Oh IS, Sarruf DA, Ogimoto K, Kaiyala KJ, Fischer JD, Matsen ME, Taborsky GJ, Jr., Schwartz MW, Morton GJ. Leptin deficiency causes insulin resistance induced by uncontrolled diabetes. Diabetes 59: 1626‐1634, 2010.
 109.Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: Sources, localization and functions. Mol Neurobiol 47: 145‐171, 2013.
 110.Gonzalez RG, Miglior S, Von Saltza I, Buckley L, Neuringer LJ, Cheng HM. 31P NMR studies of the diabetic lens. Magn Reson Med 6: 435‐444, 1988.
 111.Gould GW, Holman GD. The glucose transporter family: Structure, function and tissue‐specific expression. Biochem J 295 (Pt 2): 329‐341, 1993.
 112.Gould GW, Thomas HM, Jess TJ, Bell GI. Expression of human glucose transporters in Xenopus oocytes: Kinetic characterization and substrate specificities of the erythrocyte, liver, and brain isoforms. Biochemistry 30: 5139‐5145, 1991.
 113.Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K. Variant of transcription factor 7‐like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38: 320‐323, 2006.
 114.Gunstad J, Strain G, Devlin MJ, Wing R, Cohen RA, Paul RH, Crosby RD, Mitchell JE. Improved memory function 12 weeks after bariatric surgery. Surg Obes Relat Dis 7: 465‐472, 2011.
 115.Guo YF, Xiong DH, Shen H, Zhao LJ, Xiao P, Guo Y, Wang W, Yang TL, Recker RR, Deng HW. Polymorphisms of the low‐density lipoprotein receptor‐related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family‐based association study. J Med Genet 43: 798‐803, 2006.
 116.Haas CB, Kalinine E, Zimmer ER, Hansel G, Brochier AW, Oses JP, Portela LV, Muller AP. Brain insulin administration triggers distinct cognitive and neurotrophic responses in young and aged rats. Mol Neurobiol 53: 5807‐5817, 2016.
 117.Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM, Mattson MP. Intermittent fasting and caloric restriction ameliorate age‐related behavioral deficits in the triple‐transgenic mouse model of Alzheimer's disease. Neurobiol Dis 26: 212‐220, 2007.
 118.Hall CN, Klein‐Flugge MC, Howarth C, Attwell D. Oxidative phosphorylation, not glycolysis, powers presynaptic and postsynaptic mechanisms underlying brain information processing. J Neurosci 32: 8940‐8951, 2012.
 119.Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, Gout I, Downes CP, Lamb RF. The TSC1‐2 tumor suppressor controls insulin‐PI3K signaling via regulation of IRS proteins. J Cell Biol 166: 213‐223, 2004.
 120.Hasselbalch SG, Knudsen GM, Videbaek C, Pinborg LH, Schmidt JF, Holm S, Paulson OB. No effect of insulin on glucose blood‐brain barrier transport and cerebral metabolism in humans. Diabetes 48: 1915‐1921, 1999.
 121.Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad Sci U S A 75: 5737‐5741, 1978.
 122.Hayden MS, Ghosh S. Shared principles in NF‐kappaB signaling. Cell 132: 344‐362, 2008.
 123.Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, Friedman JM. Antidiabetic effects of IGFBP2, a leptin‐regulated gene. Cell Metab 11: 11‐22, 2010.
 124.Heidenrich KA, Gilmore PR, Garvey WT. Glucose transport in primary cultured neurons. J Neurosci Res 22: 397‐407, 1989.
 125.Hertz L, Peng L, Dienel GA. Energy metabolism in astrocytes: High rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27: 219‐249, 2007.
 126.Hidaka S, Yoshimatsu H, Kondou S, Tsuruta Y, Oka K, Noguchi H, Okamoto K, Sakino H, Teshima Y, Okeda T, Sakata T. Chronic central leptin infusion restores hyperglycemia independent of food intake and insulin level in streptozotocin‐induced diabetic rats. FASEB J 16: 509‐518, 2002.
 127.Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED, Holland WL, Cho YR, Chuang JC, Xu Y, Choi M, Lauzon D, Lee CE, Coppari R, Richardson JA, Zigman JM, Chua S, Scherer PE, Lowell BB, Bruning JC, Elmquist JK. Direct insulin and leptin action on pro‐opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab 11: 286‐297, 2010.
 128.Hill JW, Williams KW, Ye C, Luo J, Balthasar N, Coppari R, Cowley MA, Cantley LC, Lowell BB, Elmquist JK. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest 118: 1796‐1805, 2008.
 129.Hirtz D, Thurman DJ, Gwinn‐Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the “common” neurologic disorders? Neurology 68: 326‐337, 2007.
 130.Hom FG, Goodner CJ, Berrie MA. 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.
 131.Howarth C, Gleeson P, Attwell D. Updated energy budgets for neural computation in the neocortex and cerebellum. J Cereb Blood Flow Metab 32: 1222‐1232, 2012.
 132.Hur EM, Zhou FQ. GSK3 signalling in neural development. Nat Rev Neurosci 11: 539‐551, 2010.
 133.Ido Y, McHowat J, Chang KC, Arrigoni‐Martelli E, Orfalian Z, Kilo C, Corr PB, Williamson JR. Neural dysfunction and metabolic imbalances in diabetic rats. Prevention by acetyl‐L‐carnitine. Diabetes 43: 1469‐1477, 1994.
 134.Ikeda H, West DB, Pustek JJ, Figlewicz DP, Greenwood MR, Porte D, Jr., Woods SC. Intraventricular insulin reduces food intake and body weight of lean but not obese Zucker rats. Appetite 7: 381‐386, 1986.
 135.Irani BG, Le Foll C, Dunn‐Meynell A, Levin BE. Effects of leptin on rat ventromedial hypothalamic neurons. Endocrinology 149: 5146‐5154, 2008.
 136.Ivannikov MV, Sugimori M, Llinas RR. Calcium clearance and its energy requirements in cerebellar neurons. Cell calcium 47: 507‐513, 2010.
 137.Jacob RJ, Fan X, Evans ML, Dziura J, Sherwin RS. Brain glucose levels are elevated in chronically hyperglycemic diabetic rats: No evidence for protective adaptation by the blood brain barrier. Metabolism 51: 1522‐1524, 2002.
 138.Johnston DG, Pernet A, McCulloch A, Blesa‐Malpica G, Burrin JM, Alberti KG. Some hormonal influences on glucose and ketone body metabolism in normal human subjects. Ciba Found Symp 87: 168‐191, 1982.
 139.Kaidanovich‐Beilin O, Eldar‐Finkelman H. Long‐term treatment with novel glycogen synthase kinase‐3 inhibitor improves glucose homeostasis in ob/ob mice: Molecular characterization in liver and muscle. J Pharmacol Exp Ther 316: 17‐24, 2006.
 140.Kang L, Dunn‐Meynell AA, Routh VH, Gaspers LD, Nagata Y, Nishimura T, Eiki J, Zhang BB, Levin BE. Glucokinase is a critical regulator of ventromedial hypothalamic neuronal glucosensing. Diabetes 55: 412‐420, 2006.
 141.Kang L, Routh VH, Kuzhikandathil EV, Gaspers LD, Levin BE. Physiological and molecular characteristics of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes 53: 549‐559, 2004.
 142.Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding BA, Virtanen K, Oikonen V, Kemppainen J, Viljanen T, Guiducci L, Haaparanta‐Solin M, Nagren K, Solin O, Nuutila P. Increased brain fatty acid uptake in metabolic syndrome. Diabetes 59: 2171‐2177, 2010.
 143.Kaushik S, Rodriguez‐Navarro JA, Arias E, Kiffin R, Sahu S, Schwartz GJ, Cuervo AM, Singh R. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab 14: 173‐183, 2011.
 144.Kiessling A, Ehrhart‐Bornstein M. Transcription factor 7‐like 2 (TCFL2)—a novel factor involved in pathogenesis of type 2 diabetes. Comment on: Grant et al., Nature Genetics 2006, Published online 15 January 2006. Horm Metab Res 38: 137‐138, 2006.
 145.Kievit P, Howard JK, Badman MK, Balthasar N, Coppari R, Mori H, Lee CE, Elmquist JK, Yoshimura A, Flier JS. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling‐3 in POMC‐expressing cells. Cell Metab 4: 123‐132, 2006.
 146.Kim EK, Miller I, Landree LE, Borisy‐Rudin FF, Brown P, Tihan T, Townsend CA, Witters LA, Moran TH, Kuhajda FP, Ronnett GV. Expression of FAS within hypothalamic neurons: A model for decreased food intake after C75 treatment. Am J Physiol Endocrinol Metab 283: E867‐E879, 2002.
 147.Kleinridders A, Ferris HA, Cai W, Kahn CR. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63: 2232‐2243, 2014.
 148.Kleinridders A, Lauritzen HP, Ussar S, Christensen JH, Mori MA, Bross P, Kahn CR. Leptin regulation of Hsp60 impacts hypothalamic insulin signaling. J Clin Invest 123: 4667‐4680, 2013.
 149.Kloek C, Haq AK, Dunn SL, Lavery HJ, Banks AS, Myers MG, Jr. Regulation of Jak kinases by intracellular leptin receptor sequences. J Biol Chem 277: 41547‐41555, 2002.
 150.Kobayashi M, Nikami H, Morimatsu M, Saito M. Expression and localization of insulin‐regulatable glucose transporter (GLUT4) in rat brain. Neurosci Lett 213: 103‐106, 1996.
 151.Koch C, Augustine RA, Steger J, Ganjam GK, Benzler J, Pracht C, Lowe C, Schwartz MW, Shepherd PR, Anderson GM, Grattan DR, Tups A. Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J Neurosci 30: 16180‐16187, 2010.
 152.Koch CE, Lowe C, Legler K, Benzler J, Boucsein A, Bottiger G, Grattan DR, Williams LM, Tups A. Central adiponectin acutely improves glucose tolerance in male mice. Endocrinology 155: 1806‐1816, 2014.
 153.Komatsu T, Chiba T, Yamaza H, Yamashita K, Shimada A, Hoshiyama Y, Henmi T, Ohtani H, Higami Y, de Cabo R, Ingram DK, Shimokawa I. Manipulation of caloric content but not diet composition, attenuates the deficit in learning and memory of senescence‐accelerated mouse strain P8. Exp Gerontol 43: 339‐346, 2008.
 154.Konner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley MA, Ashcroft FM, Bruning JC. Insulin action in AgRP‐expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5: 438‐449, 2007.
 155.Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi M, Sugi K, Noda T, Ebinuma H, Ueta Y, Kondo T, Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y, Ueki K, Minokoshi Y, Kadowaki T. Adiponectin stimulates AMP‐activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6: 55‐68, 2007.
 156.Ladyman SR, Grattan DR. Central effects of leptin on glucose homeostasis are modified during pregnancy in the rat. J Neuroendocrinol 28: 2016.
 157.Lam TK, Schwartz GJ, Rossetti L. Hypothalamic sensing of fatty acids. Nat Neurosci 8: 579‐584, 2005.
 158.Langlet F, Levin BE, Luquet S, Mazzone M, Messina A, Dunn‐Meynell AA, Balland E, Lacombe A, Mazur D, Carmeliet P, Bouret SG, Prevot V, Dehouck B. Tanycytic VEGF‐A boosts blood‐hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab 17: 607‐617, 2013.
 159.Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: Specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 285: R277‐R297, 2003.
 160.Lattanzio S, Santilli F, Liani R, Vazzana N, Ueland T, Di Fulvio P, Formoso G, Consoli A, Aukrust P, Davi G. Circulating dickkopf‐1 in diabetes mellitus: Association with platelet activation and effects of improved metabolic control and low‐dose aspirin. J Am Heart Assoc 3: 1‐10, 2014.
 161.Lee CC, Huang CC, Hsu KS. Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology 61: 867‐879, 2011.
 162.Lee CC, Huang CC, Wu MY, Hsu KS. Insulin stimulates postsynaptic density‐95 protein translation via the phosphoinositide 3‐kinase‐Akt‐mammalian target of rapamycin signaling pathway. J Biol Chem 280: 18543‐18550, 2005.
 163.Lee WH, Bondy CA. Ischemic injury induces brain glucose transporter gene expression. Endocrinology 133: 2540‐2544, 1993.
 164.Lehning EJ, LoPachin RM, Mathew J, Eichberg J. Changes in Na‐K ATPase and protein kinase C activities in peripheral nerve of acrylamide‐treated rats. J Toxicol Environ Health 42: 331‐342, 1994.
 165.Lenzen S. The mechanisms of alloxan‐ and streptozotocin‐induced diabetes. Diabetologia 51: 216‐226, 2008.
 166.Levin BE, Routh VH, Kang L, Sanders NM, Dunn‐Meynell AA. Neuronal glucosensing: What do we know after 50 years? Diabetes 53: 2521‐2528, 2004.
 167.Li M, Quan C, Toth R, Campbell DG, MacKintosh C, Wang HY, Chen S. Fasting and systemic insulin signaling regulate phosphorylation of brain proteins that modulate cell morphology and link to neurological disorders. J Biol Chem 290: 30030‐30041, 2015.
 168.Li X, Shan J, Chang W, Kim I, Bao J, Lee HJ, Zhang X, Samuel VT, Shulman GI, Liu D, Zheng JJ, Wu D. Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism. Proc Natl Acad Sci U S A 109: 11402‐11407, 2012.
 169.Li Z, Shen J, Wu WK, Yu X, Liang J, Qiu G, Liu J. Leptin induces cyclin D1 expression and proliferation of human nucleus pulposus cells via JAK/STAT, PI3K/Akt and MEK/ERK pathways. PloS One 7: e53176, 2012.
 170.Liu Z, Habener JF. Glucagon‐like peptide‐1 activation of TCF7L2‐dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem 283: 8723‐8735, 2008.
 171.Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288: 2379‐2381, 2000.
 172.Lopez M, Lage R, Saha AK, Perez‐Tilve D, Vazquez MJ, Varela L, Sangiao‐Alvarellos S, Tovar S, Raghay K, Rodriguez‐Cuenca S, Deoliveira RM, Castaneda T, Datta R, Dong JZ, Culler M, Sleeman MW, Alvarez CV, Gallego R, Lelliott CJ, Carling D, Tschop MH, Dieguez C, Vidal‐Puig A. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 7: 389‐399, 2008.
 173.Lopez M, Lelliott CJ, Tovar S, Kimber W, Gallego R, Virtue S, Blount M, Vazquez MJ, Finer N, Powles TJ, O'Rahilly S, Saha AK, Dieguez C, Vidal‐Puig AJ. Tamoxifen‐induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl‐CoA. Diabetes 55: 1327‐1336, 2006.
 174.Lopez M, Varela L, Vazquez MJ, Rodriguez‐Cuenca S, Gonzalez CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, Martinez de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Oresic M, Chatterjee K, Saha AK, Rahmouni K, Dieguez C, Vidal‐Puig A. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 16: 1001‐1008, 2010.
 175.Lutas A, Yellen G. The ketogenic diet: Metabolic influences on brain excitability and epilepsy. Trends Neurosci 36: 32‐40, 2013.
 176.Lynch RM, Tompkins LS, Brooks HL, Dunn‐Meynell AA, Levin BE. Localization of glucokinase gene expression in the rat brain. Diabetes 49: 693‐700, 2000.
 177.MacDonald BT, Tamai K, He X. Wnt/beta‐catenin signaling: Components, mechanisms, and diseases. Dev Cell 17: 9‐26, 2009.
 178.Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight‐reduced subjects. Nat Med 1: 1155‐1161, 1995.
 179.Magistretti PJ, Pellerin L. Metabolic coupling during activation. A cellular view. Adv Exp Med Biol 413: 161‐166, 1997.
 180.Maher F, Davies‐Hill TM, Lysko PG, Henneberry RC, Simpson IA. Expression of two glucose transporters, GLUT1 and GLUT3, in cultured cerebellar neurons: Evidence for neuron‐specific expression of GLUT3. Mol Cell Neurosci 2: 351‐360, 1991.
 181.Malone JI, Hanna S, Saporta S, Mervis RF, Park CR, Chong L, Diamond DM. Hyperglycemia not hypoglycemia alters neuronal dendrites and impairs spatial memory. Pediatr Diabetes 9: 531‐539, 2008.
 182.Mangia S, DiNuzzo M, Giove F, Carruthers A, Simpson IA, Vannucci SJ. Response to ‘comment on recent modeling studies of astrocyte‐neuron metabolic interactions’: Much ado about nothing. J Cereb Blood Flow Metab 31: 1346‐1353, 2011.
 183.Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson‐Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315: 1278‐1282, 2007.
 184.Manolescu AR, Witkowska K, Kinnaird A, Cessford T, Cheeseman C. Facilitated hexose transporters: New perspectives on form and function. Physiology 22: 234‐240, 2007.
 185.Manschot SM, Brands AM, van der Grond J, Kessels RP, Algra A, Kappelle LJ, Biessels GJ, Utrecht Diabetic Encephalopathy Study G. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 55: 1106‐1113, 2006.
 186.Margolis RU, Altszuler N. Insulin in the cerebrospinal fluid. Nature 215: 1375‐1376, 1967.
 187.Marks JL, King MG, Baskin DG. Localization of insulin and type 1 IGF receptors in rat brain by in vitro autoradiography and in situ hybridization. Adv Exp Med Biol 293: 459‐470, 1991.
 188.Marks JL, Porte D, Jr., Stahl WL, Baskin DG. Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127: 3234‐3236, 1990.
 189.Mattson MP. The impact of dietary energy intake on cognitive aging. Front Aging Neurosci 2: 5, 2010.
 190.Mauvais‐Jarvis F, Ueki K, Fruman DA, Hirshman MF, Sakamoto K, Goodyear LJ, Iannacone M, Accili D, Cantley LC, Kahn CR. Reduced expression of the murine p85alpha subunit of phosphoinositide 3‐kinase improves insulin signaling and ameliorates diabetes. J Clin Invest 109: 141‐149, 2002.
 191.McEwen BS, Reagan LP. Glucose transporter expression in the central nervous system: Relationship to synaptic function. Eur J Pharmacol 490: 13‐24, 2004.
 192.McNay EC, Fries TM, Gold PE. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci U S A 97: 2881‐2885, 2000.
 193.McNay EC, Gold PE. Extracellular glucose concentrations in the rat hippocampus measured by zero‐net‐flux: effects of microdialysis flow rate, strain, and age. J Neurochem 72: 785‐790, 1999.
 194.Melnick IV, Price CJ, Colmers WF. Glucosensing in parvocellular neurons of the rat hypothalamic paraventricular nucleus. Eur J Neurosci 34: 272‐282, 2011.
 195.Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. Localization of leptin receptor mRNA and the long form splice variant (Ob‐Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 387: 113‐116, 1996.
 196.Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: The role of glucose in physiological and pathological brain function. Trends Neurosci 36: 587‐597, 2013.
 197.Messier C. Glucose improvement of memory: A review. Eur J Pharmacol 490: 33‐57, 2004.
 198.Migrenne S, Magnan C, Cruciani‐Guglielmacci C. Fatty acid sensing and nervous control of energy homeostasis. Diabetes Metab 33: 177‐182, 2007.
 199.Mistry AM, Swick AG, Romsos DR. Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J Nutr 127: 2065‐2072, 1997.
 200.Mitton KP, Linklater HA, Dzialoszynski T, Sanford SE, Starkey K, Trevithick JR. Modelling cortical cataractogenesis 21: In diabetic rat lenses taurine supplementation partially reduces damage resulting from osmotic compensation leading to osmolyte loss and antioxidant depletion. Exp Eye Res 69: 279‐289, 1999.
 201.Moon RT, Brown JD, Torres M. WNTs modulate cell fate and behavior during vertebrate development. Trends in genetics: TIG 13: 157‐162, 1997.
 202.Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Dietary fat intake and 6‐year cognitive change in an older biracial community population. Neurology 62: 1573‐1579, 2004.
 203.Morris MC, Tangney CC. Dietary fat composition and dementia risk. Neurobiol Aging 35(Suppl 2): S59‐64, 2014.
 204.Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol‐3‐OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2: 411‐420, 2005.
 205.Morton GJ, Matsen ME, Bracy DP, Meek TH, Nguyen HT, Stefanovski D, Bergman RN, Wasserman DH, Schwartz MW. FGF19 action in the brain induces insulin‐independent glucose lowering. J Clin Invest 123: 4799‐4808, 2013.
 206.Mullier A, Bouret SG, Prevot V, Dehouck B. Differential distribution of tight junction proteins suggests a role for tanycytes in blood‐hypothalamus barrier regulation in the adult mouse brain. J Comp Neurol 518: 943‐962, 2010.
 207.Munzberg H, Myers MG, Jr. Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 8: 566‐570, 2005.
 208.Murphy BA, Fakira KA, Song Z, Beuve A, Routh VH. AMP‐activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose‐inhibited neurons. Am J Physiol Cell Physiol 297: C750‐C758, 2009.
 209.Muzzin P, Eisensmith RC, Copeland KC, Woo SL. Correction of obesity and diabetes in genetically obese mice by leptin gene therapy. Proc Natl Acad Sci U S A 93: 14804‐14808, 1996.
 210.Nagamatsu S, Sawa H, Kamada K, Nakamichi Y, Yoshimoto K, Hoshino T. Neuron‐specific glucose transporter (NSGT): CNS distribution of GLUT3 rat glucose transporter (RGT3) in rat central neurons. FEBS Lett 334: 289‐295, 1993.
 211.Navarro M, Rodriquez de Fonseca F, Alvarez E, Chowen JA, Zueco JA, Gomez R, Eng J, Blazquez E. Colocalization of glucagon‐like peptide‐1 (GLP‐1) receptors, glucose transporter GLUT‐2, and glucokinase mRNAs in rat hypothalamic cells: Evidence for a role of GLP‐1 receptor agonists as an inhibitory signal for food and water intake. J Neurochem 67: 1982‐1991, 1996.
 212.Nikoulina SE, Ciaraldi TP, Mudaliar S, Carter L, Johnson K, Henry RR. Inhibition of glycogen synthase kinase 3 improves insulin action and glucose metabolism in human skeletal muscle. Diabetes 51: 2190‐2198, 2002.
 213.Nishimura H, Pallardo FV, Seidner GA, Vannucci S, Simpson IA, Birnbaum MJ. Kinetics of GLUT1 and GLUT4 glucose transporters expressed in Xenopus oocytes. J Biol Chem 268: 8514‐8520, 1993.
 214.Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258: 607‐614, 1992.
 215.Nistico R, Cavallucci V, Piccinin S, Macri S, Pignatelli M, Mehdawy B, Blandini F, Laviola G, Lauro D, Mercuri NB, D'Amelio M. Insulin receptor beta‐subunit haploinsufficiency impairs hippocampal late‐phase LTP and recognition memory. Neuromol Med 14: 262‐269, 2012.
 216.Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG, Jr., Schwartz MW. Intracellular signalling. Key enzyme in leptin‐induced anorexia. Nature 413: 794‐795, 2001.
 217.Oates PJ. Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol 50: 325‐392, 2002.
 218.Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase‐1 decreases food intake and glucose production. Nat Med 9: 756‐761, 2003.
 219.Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5: 566‐572, 2002.
 220.Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51: 271‐275, 2002.
 221.Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8: 1376‐1382, 2002.
 222.Ono H, Pocai A, Wang Y, Sakoda H, Asano T, Backer JM, Schwartz GJ, Rossetti L. Activation of hypothalamic S6 kinase mediates diet‐induced hepatic insulin resistance in rats. J Clin Invest 118: 2959‐2968, 2008.
 223.Oomura Y, Kimura K, Ooyama H, Maeno T, Iki M, Kuniyoshi M. Reciprocal activities of the ventromedial and lateral hypothalamic areas of cats. Science 143: 484‐485, 1964.
 224.Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD, Hotamisligil GS. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29: 541‐551, 2008.
 225.Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, Xu C, Vianna CR, Balthasar N, Lee CE, Elmquist JK, Cowley MA, Lowell BB. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449: 228‐232, 2007.
 226.Patel NJ, Llewelyn JG, Wright DW, Thomas PK. Glucose and leucine uptake by rat dorsal root ganglia is not insulin sensitive. J Neurol Sci 121: 159‐162, 1994.
 227.Patterson CM, Leshan RL, Jones JC, Myers MG, Jr. Molecular mapping of mouse brain regions innervated by leptin receptor‐expressing cells. Brain Res 1378: 18‐28, 2011.
 228.Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus. Science 287: 1606‐1609, 2000.
 229.Pellerin L, Magistretti PJ. Food for thought: challenging the dogmas. J Cereb Blood Flow Metab 23: 1282‐1286, 2003.
 230.Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32: 1152‐1166, 2012.
 231.Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269: 540‐543, 1995.
 232.Piroli GG, Grillo CA, Hoskin EK, Znamensky V, Katz EB, Milner TA, McEwen BS, Charron MJ, Reagan LP. Peripheral glucose administration stimulates the translocation of GLUT8 glucose transporter to the endoplasmic reticulum in the rat hippocampus. J Comp Neurol 452: 103‐114, 2002.
 233.Pocai A, Lam TK, Gutierrez‐Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar‐Bryan L, Rossetti L. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434: 1026‐1031, 2005.
 234.Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan‐Giri A, Pennathur S, Baskin DG, Heinecke JW, Woods SC, Schwartz MW, Niswender KD. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high‐fat diet. Am J Physiol Endocrinol Metab 296: E1003‐E1012, 2009.
 235.Prickett C, Brennan L, Stolwyk R. Examining the relationship between obesity and cognitive function: A systematic literature review. Obes Rese Clin Pract 9: 93‐113, 2015.
 236.Puzziferri N, Roshek TB, 3rd, Mayo HG, Gallagher R, Belle SH, Livingston EH. Long‐term follow‐up after bariatric surgery: A systematic review. JAMA 312: 934‐942, 2014.
 237.Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 362: 329‐344, 2010.
 238.Rao R, Hao CM, Redha R, Wasserman DH, McGuinness OP, Breyer MD. Glycogen synthase kinase 3 inhibition improves insulin‐stimulated glucose metabolism but not hypertension in high‐fat‐fed C57BL/6J mice. Diabetologia 50: 452‐460, 2007.
 239.Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH, 2nd, Craft S. Intranasal insulin administration dose‐dependently modulates verbal memory and plasma amyloid‐beta in memory‐impaired older adults. J Alzheimer Dis 13: 323‐331, 2008.
 240.Rodriguez‐Rivera J, Denner L, Dineley KT. Rosiglitazone reversal of Tg2576 cognitive deficits is independent of peripheral gluco‐regulatory status. Behav Brain Res 216: 255‐261, 2011.
 241.Roland AV, Moenter SM. Glucosensing by GnRH neurons: Inhibition by androgens and involvement of AMP‐activated protein kinase. Mol Endocrinol 25: 847‐858, 2011.
 242.Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322: 1551‐1555, 2008.
 243.Routh VH. Glucose sensing neurons in the ventromedial hypothalamus. Sensors 10: 9002‐9025, 2010.
 244.Routh VH, Hao L, Santiago AM, Sheng Z, Zhou C. Hypothalamic glucose sensing: Making ends meet. Front Syst Neurosci 8: 236, 2014.
 245.Saarinen A, Saukkonen T, Kivela T, Lahtinen U, Laine C, Somer M, Toiviainen‐Salo S, Cole WG, Lehesjoki AE, Makitie O. Low density lipoprotein receptor‐related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin Endocrinol 72: 481‐488, 2010.
 246.Sahu A, Koshinaka K, Sahu M. Phosphatidylinositol 3‐kinase is an upstream regulator of the phosphodiesterase 3B pathway of leptin signalling that may not involve activation of Akt in the rat hypothalamus. J Neuroendocrinol 25: 168‐179, 2013.
 247.Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor‐mTOR complex. Science 307: 1098‐1101, 2005.
 248.Scarlett JM, Rojas JM, Matsen ME, Kaiyala KJ, Stefanovski D, Bergman RN, Nguyen HT, Dorfman MD, Lantier L, Wasserman DH, Mirzadeh Z, Unterman TG, Morton GJ, Schwartz MW. Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med 22: 800‐806, 2016.
 249.Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Kustermann E, Arndt S, Jacobs AH, Krone W, Kahn CR, Bruning JC. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A 101: 3100‐3105, 2004.
 250.Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, Prunkard DE, Porte D, Jr., Woods SC, Seeley RJ, Weigle DS. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45: 531‐535, 1996.
 251.Schwartz MW, Seeley RJ, Tschop MH, Woods SC, Morton GJ, Myers MG, D'Alessio D. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503: 59‐66, 2013.
 252.Schwartz MW, Woods SC, Porte D, Jr., Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 404: 661‐671, 2000.
 253.Scott MM, Lachey JL, Sternson SM, Lee CE, Elias CF, Friedman JM, Elmquist JK. Leptin targets in the mouse brain. J Comp Neurol 514: 518‐532, 2009.
 254.Seaquist ER, Damberg GS, 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.
 255.Shepherd PR. Mechanisms regulating phosphoinositide 3‐kinase signalling in insulin‐sensitive tissues. Acta Physiol Scand 183: 3‐12, 2005.
 256.Shian LR, Lin MT. Insulin acts on the hypothalamic glucose‐facilitated neurons to induce hyperglycemia and hyperinsulinemia in the rat. Experientia 47: 942‐944, 1991.
 257.Shpilman M, Niv‐Spector L, Katz M, Varol C, Solomon G, Ayalon‐Soffer M, Boder E, Halpern Z, Elinav E, Gertler A. Development and characterization of high affinity leptins and leptin antagonists. J Biol Chem 286: 4429‐4442, 2011.
 258.Shu L, Sauter NS, Schulthess FT, Matveyenko AV, Oberholzer J, Maedler K. Transcription factor 7‐like 2 regulates beta‐cell survival and function in human pancreatic islets. Diabetes 57: 645‐653, 2008.
 259.Simpson IA, Carruthers A, Vannucci SJ. Supply and demand in cerebral energy metabolism: The role of nutrient transporters. J Cereb Blood Flow Metab 27: 1766‐1791, 2007.
 260.Simpson IA, Davies P. Reduced glucose transporter concentrations in brains of patients with Alzheimer's disease. Ann Neurol 36: 800‐801, 1994.
 261.Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ. The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 295: E242‐E253, 2008.
 262.Solinas G, Karin M. JNK1 and IKKbeta: Molecular links between obesity and metabolic dysfunction. FASEB J 24: 2596‐2611, 2010.
 263.Song Z, Levin BE, McArdle JJ, Bakhos N, Routh VH. Convergence of pre‐ and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 50: 2673‐2681, 2001.
 264.Song Z, Routh VH. Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54: 15‐22, 2005.
 265.Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML. Leptin inhibits hypothalamic neurons by activation of ATP‐sensitive potassium channels. Nature 390: 521‐525, 1997.
 266.Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP‐sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 3: 757‐758, 2000.
 267.Sredy J, Sawicki DR, Notvest RR. Polyol pathway activity in nervous tissues of diabetic and galactose‐fed rats: Effect of dietary galactose withdrawal or tolrestat intervention therapy. J Diabet Complications 5: 42‐47, 1991.
 268.Stambolic V, Woodgett JR. Mitogen inactivation of glycogen synthase kinase‐3 beta in intact cells via serine 9 phosphorylation. Biochem J 303(Pt 3): 701‐704, 1994.
 269.Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin‐like growth factor expression and signaling mechanisms in Alzheimer's disease–‐is this type 3 diabetes? J Alzheimer Dis 7: 63‐80, 2005.
 270.Stohr O, Schilbach K, Moll L, Hettich MM, Freude S, Wunderlich FT, Ernst M, Zemva J, Bruning JC, Krone W, Udelhoven M, Schubert M. Insulin receptor signaling mediates APP processing and beta‐amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer's disease. Age 35: 83‐101, 2013.
 271.Sutherland C, Leighton IA, Cohen P. Inactivation of glycogen synthase kinase‐3 beta by phosphorylation: New kinase connections in insulin and growth‐factor signalling. Biochem J 296 (Pt 1): 15‐19, 1993.
 272.Szwergold BS, Kappler F, Brown TR. Identification of fructose 3‐phosphate in the lens of diabetic rats. Science 247: 451‐454, 1990.
 273.Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317: 369‐372, 2007.
 274.Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF‐1 resistance, IRS‐1 dysregulation, and cognitive decline. J Clin Invest 122: 1316‐1338, 2012.
 275.Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint‐Jeannet JP, He X. LDL‐receptor‐related proteins in Wnt signal transduction. Nature 407: 530‐535, 2000.
 276.Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB‐R. Cell 83: 1263‐1271, 1995.
 277.Thaler JP, Choi SJ, Schwartz MW, Wisse BE. Hypothalamic inflammation and energy homeostasis: Resolving the paradox. Front Neuroendocrinol 31: 79‐84, 2010.
 278.Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschop MH, Schwartz MW. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122: 153‐162, 2012.
 279.Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci 9: 36‐45, 2008.
 280.Tups A. Physiological models of leptin resistance. J Neuroendocrinol 21: 961‐971, 2009.
 281.Tups A, Anderson GM, Rizwan M, Augustine RA, Chaussade C, Shepherd PR, Grattan DR. Both p110alpha and p110beta isoforms of phosphatidylinositol 3‐OH‐kinase are required for insulin signalling in the hypothalamus. J Neuroendocrinol 22: 534‐542, 2010.
 282.Tuulari JJ, Karlsson HK, Hirvonen J, Hannukainen JC, Bucci M, Helmio M, Ovaska J, Soinio M, Salminen P, Savisto N, Nummenmaa L, Nuutila P. Weight loss after bariatric surgery reverses insulin‐induced increases in brain glucose metabolism of the morbidly obese. Diabetes 62: 2747‐2751, 2013.
 283.Uemura E, Greenlee HW. Insulin regulates neuronal glucose uptake by promoting translocation of glucose transporter GLUT3. Exp Neurol 198: 48‐53, 2006.
 284.Valerio A, Ghisi V, Dossena M, Tonello C, Giordano A, Frontini A, Ferrario M, Pizzi M, Spano P, Carruba MO, Nisoli E. Leptin increases axonal growth cone size in developing mouse cortical neurons by convergent signals inactivating glycogen synthase kinase‐3beta. J Biol Chem 281: 12950‐12958, 2006.
 285.van Hall G, Stromstad M, Rasmussen P, Jans O, Zaar M, Gam C, Quistorff B, Secher NH, Nielsen HB. Blood lactate is an important energy source for the human brain. J Cereb Blood Flow Metab 29: 1121‐1129, 2009.
 286.Van Heyningen R. Formation of polyols by the lens of the rat with ‘sugar’ cataract. Nature 184: 194‐195, 1959.
 287.Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD. Phosphoinositide 3‐kinases: A conserved family of signal transducers. Trends Biochem Sci 22: 267‐272, 1997.
 288.Vannucci SJ, Koehler‐Stec EM, Li K, Reynolds TH, Clark R, Simpson IA. GLUT4 glucose transporter expression in rodent brain: Effect of diabetes. Brain Res 797: 1‐11, 1998.
 289.Vannucci SJ, Reinhart R, Maher F, Bondy CA, Lee WH, Vannucci RC, Simpson IA. Alterations in GLUT1 and GLUT3 glucose transporter gene expression following unilateral hypoxia‐ischemia in the immature rat brain. Brain Res Dev Brain Res 107: 255‐264, 1998.
 290.Walls AB, Heimburger CM, Bouman SD, Schousboe A, Waagepetersen HS. Robust glycogen shunt activity in astrocytes: Effects of glutamatergic and adrenergic agents. Neuroscience 158: 284‐292, 2009.
 291.Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH. Leptin therapy in insulin‐deficient type I diabetes. Proc Natl Acad Sci U S A 107: 4813‐4819, 2010.
 292.Wang R, Liu X, Hentges ST, Dunn‐Meynell AA, Levin BE, Wang W, Routh VH. The regulation of glucose‐excited neurons in the hypothalamic arcuate nucleus by glucose and feeding‐relevant peptides. Diabetes 53: 1959‐1965, 2004.
 293.Wang X, Ge A, Cheng M, Guo F, Zhao M, Zhou X, Liu L, Yang N. Increased hypothalamic inflammation associated with the susceptibility to obesity in rats exposed to high‐fat diet. Exp Diabetes Res 2012: 847246, 2012.
 294.Watford M. Is the small intestine a gluconeogenic organ. Nutr Rev 63: 356‐360, 2005.
 295.Weissmann L, Quaresma PG, Santos AC, de Matos AH, Pascoal VD, Zanotto TM, Castro G, Guadagnini D, da Silva JM, Velloso LA, Bittencourt JC, Lopes‐Cendes I, Saad MJ, Prada PO. IKKepsilon is key to induction of insulin resistance in the hypothalamus, and its inhibition reverses obesity. Diabetes 63: 3334‐3345, 2014.
 296.Wellhauser L, Belsham DD. Activation of the omega‐3 fatty acid receptor GPR120 mediates anti‐inflammatory actions in immortalized hypothalamic neurons. J Neuroinflammation 11: 60, 2014.
 297.Werner H, Raizada MK, Mudd LM, Foyt HL, Simpson IA, Roberts CT, Jr., LeRoith D. Regulation of rat brain/HepG2 glucose transporter gene expression by insulin and insulin‐like growth factor‐I in primary cultures of neuronal and glial cells. Endocrinology 125: 314‐320, 1989.
 298.White DW, Kuropatwinski KK, Devos R, Baumann H, Tartaglia LA. Leptin receptor (OB‐R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo‐oligomerization. J Biol Chem 272: 4065‐4071, 1997.
 299.WHO. http://www.who.int/mediacentre/factsheets/fs311/en/.
 300.Wickelgren I. Tracking insulin to the mind. Science 280: 517‐519, 1998.
 301.Williams RH, Alexopoulos H, Jensen LT, Fugger L, Burdakov D. Adaptive sugar sensors in hypothalamic feeding circuits. Proc Natl Acad Sci U S A 105: 11975‐11980, 2008.
 302.Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T, Nyengaard JR, van den Enden M, Kilo C, Tilton RG. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 42: 801‐813, 1993.
 303.Winocur G, Greenwood CE. The effects of high fat diets and environmental influences on cognitive performance in rats. Behav Brain Res 101: 153‐161, 1999.
 304.Wisse BE, Ogimoto K, Tang J, Harris MK, Jr., Raines EW, Schwartz MW. Evidence that lipopolysaccharide‐induced anorexia depends upon central, rather than peripheral, inflammatory signals. Endocrinology 148: 5230‐5237, 2007.
 305.Wong RH, Scholey A, Howe PR. Assessing premorbid cognitive ability in adults with type 2 diabetes mellitus–‐a review with implications for future intervention studies. Curr Diabetes Rep 14: 547, 2014.
 306.Woods SC, Lotter EC, McKay LD, Porte D, Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282: 503‐505, 1979.
 307.Wu P, Shen Q, Dong S, Xu Z, Tsien JZ, Hu Y. Calorie restriction ameliorates neurodegenerative phenotypes in forebrain‐specific presenilin‐1 and presenilin‐2 double knockout mice. Neurobiol Aging 29: 1502‐1511, 2008.
 308.Xu AW, Kaelin CB, Takeda K, Akira S, Schwartz MW, Barsh GS. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115: 951‐958, 2005.
 309.Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzman M, Brownlee M. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein‐1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 276: 25096‐25100, 2001.
 310.Yi CX, Al‐Massadi O, Donelan E, Lehti M, Weber J, Ress C, Trivedi C, Muller TD, Woods SC, Hofmann SM. Exercise protects against high‐fat diet‐induced hypothalamic inflammation. Physiol Behav 106: 485‐490, 2012.
 311.Yi CX, Habegger KM, Chowen JA, Stern J, Tschop MH. A role for astrocytes in the central control of metabolism. Neuroendocrinology 93: 143‐149, 2011.
 312.Yi CX, Tschop MH, Woods SC, Hofmann SM. High‐fat‐diet exposure induces IgG accumulation in hypothalamic microglia. Dis Model Mech 5: 686‐690, 2012.
 313.Yu X, Park BH, Wang MY, Wang ZV, Unger RH. Making insulin‐deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A 105: 14070‐14075, 2008.
 314.Yu Y, Wu Y, Szabo A, Wu Z, Wang H, Li D, Huang XF. Teasaponin reduces inflammation and central leptin resistance in diet‐induced obese male mice. Endocrinology 154: 3130‐3140, 2013.
 315.Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF‐kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135: 61‐73, 2008.
 316.Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425‐432, 1994.
 317.Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274: 34893‐34902, 1999.
 318.Zvelebil MJ, MacDougall L, Leevers S, Volinia S, Vanhaesebroeck B, Gout I, Panayotou G, Domin J, Stein R, Pages F, et al. Structural and functional diversity of phosphoinositide 3‐kinases. Philos Trans R Soc Lond B Biol Sci 351: 217‐223, 1996.

Teaching Material

Tups A, Benzler J, Sergi D, Ladyman SR, Williams LM. Central regulation of glucose homeostasis. Compr Physiol 2017, 7: 741-764. doi: 10.1002/cphy.c160015

Didactic Synopsis

Major Teaching Points:

  • Peripherally produced metabolic hormones can act centrally to regulate whole body glucose homeostasis.
    • The satiety hormone leptin is able to centrally regulate glucose homeostasis at doses lower than that required to suppress food intake.
    • Insulin, produced by pancreatic beta-cells can act centrally to regulate glucose homeostasis, particularly through modulation of hepatic glucose production, as well as is well-known peripheral effects on glucose homeostasis.
  • Obesity is associated with an inability of leptin and insulin to signal in the brain, termed leptin and insulin insensitivity, respectively. The central insensitivity to these two hormones contributes to dysregulation of glucose homeostasis. Central inflammation may underlie central insensitivity to leptin and insulin in obesity.
  • Long-term dysregulation of glucose homeostasis resulting in high glucose levels and insulin resistance are contributing to impairments in memory and cognition.

 

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: The peripherally produced hormones, leptin and insulin, can act in the brain, particularly the hypothalamus to regulate glucose homeostasis. These hormones bind to their receptors that are located on the cell membrane and this leads to the activation of intracellular signaling pathways that can then influence the activity of the cells leading to downstream effects such as regulating peripheral glucose levels. Leptin signaling can positively influence the ability of a cell to respond to insulin, called ‘sensitizing the cell to insulin signaling’, and this has been proposed to involve an intracellular signaling molecule called IRS1.

Figure 2. Teaching points: One intracellular signaling pathway that is proposed to play a role in leptin’s ability to sensitize cells to insulin signaling in the hypothalamus is called the WNT signaling pathway. GSK-3 β plays a key role in the WNT signaling pathway. Leptin has been found to reduce the activity of GSK-3β resulting in removal of inhibition of the molecule IRS1. Thus, insulin signaling via IRS1 can be increased, leading to increased pAKT and further downstream effects. The increase in pAKT can further suppress GSK-3β generating a positive feedback loop to further increase insulin signaling within the cell.

Figure 3. Teaching points: Inflammation in the hypothalamus may play a key role in insulin and leptin insensitivity in the hypothalamus in diet-induced obesity. Injecting a specially made virus, which is designed to decreases inflammation in the arcuate nucleus, a key site of insulin and leptin action in the hypothalamus, can prevent mice from some of the effects of eating a high fat diet. When these virus-treated mice eat a high fat diet they have better regulation of blood glucose levels and are not as fat as mice that eat a high fat diet and did not get treated with this virus.

Figure 4. Teaching points: Dysfunction of glucose homeostasis in the body can lead to impaired memory and cognition. The proposed causes of which include exposure to constant high levels of glucose, insulin, and leptin insensitivity, and toxicity due to increased levels of long-chain saturated fatty acid metabolites.

Figure 5. Teaching points: Leptin and insulin can act in the hypothalamus to centrally regulate glucose homeostasis. Long chain saturated fatty acids, abundant in a Western diet, activate the proinflammatory IKKβ/NFκB pathway in cells of the hypothalamus. Activation of this pathway can disrupt the interaction of leptin and insulin intracellular signaling and therefore impair the normal regulation of glucose homeostasis by these two hormones and this can contribute to the development of type 2 diabetes.


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Alexander Tups, Jonas Benzler, Domenico Sergi, Sharon R. Ladyman, Lynda M. Williams. Central Regulation of Glucose Homeostasis. Compr Physiol 2017, 7: 741-764. doi: 10.1002/cphy.c160015