Comprehensive Physiology Wiley Online Library

Autonomic Regulation of Hepatic Glucose Production

Full Article on Wiley Online Library


Glucose produced by the liver is a major energy source for the brain. Considering its critical dependence on glucose, it seems only natural that the brain is capable of monitoring and controlling glucose homeostasis. In addition to neuroendocrine pathways, the brain uses the autonomic nervous system to communicate with peripheral organs. Within the brain, the hypothalamus is the key region to integrate signals on energy status, including signals from lipid, glucose, and hormone sensing cells, with afferent neural signals from the internal and external milieu. In turn, the hypothalamus regulates metabolism in peripheral organs, including the liver, not only via the anterior pituitary gland but also via multiple neuropeptidergic pathways in the hypothalamus that have been identified as regulators of hepatic glucose metabolism. These pathways comprise preautonomic neurons projecting to nuclei in the brain stem and spinal cord, which relay signals from the hypothalamus to the liver via the autonomic nervous system. The neuroendocrine and neuronal outputs of the hypothalamus are not separate entities. They appear to act as a single integrated regulatory system, far more subtle, and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and neural influences. As a result, our endocrine‐based understanding of diseases such as diabetes and obesity should be expanded by integration of neural inputs into our concept of the pathophysiological process. © 2015 American Physiological Society. Compr Physiol 5:147‐165, 2015.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images

Figure 1. Figure 1. Sagittal scheme of the sympathetic and parasympathetic control of the liver. Brain areas providing first‐order projections are indicated in red, brain areas containing second‐order neurons are indicated in blue, and those containing third‐order neurons are indicated in yellow. It is clear by comparing the parasympathetic pattern against the sympathetic pattern that far more second‐order cell groups are in control of the first‐order parasympathetic (i.e., DMV) than first‐order sympathetic (i.e., IML) motor neurons. RVLM also includes the catecholaminergic A5, C1, and C3 areas. Abbreviations: Ace, Amygdala, central part; ARC, Arcuate nucleus; Ba, Barrington nucleus; BNST, Bed nucleus of the stria terminalis; DMH, Dorsomedial nucleus of the hypothalamus; DMV, Dorsal motor nucleus of the vagus nerve; IML, Intermediolateral column of the spinal cord; INS; Insular cortex; LH, Lateral hypothalamus; MPO, Medial preoptic area; NTS, Nucleus of the tractus solitaries; OVLT, Organum vasculosum of the lamina terminalis; P, Pineal gland; PVN, Paraventricular nucleus of the hypothalamus; vPVN, Ventral part of the PVN; dPVN, Dorsal part of the PVN; RA, Raphe nucleus; RCA, Retrochiasmatic area; RVLM, Rostroventrolateral medulla; SCN, Suprachiasmatic nucleus; SFO, Subfornical organ; VMH, Ventromedial nucleus of the hypothalamus; X, Nervus vagus; ZI, Zona incerta

Figure 1. Sagittal scheme of the sympathetic and parasympathetic control of the liver. Brain areas providing first‐order projections are indicated in red, brain areas containing second‐order neurons are indicated in blue, and those containing third‐order neurons are indicated in yellow. It is clear by comparing the parasympathetic pattern against the sympathetic pattern that far more second‐order cell groups are in control of the first‐order parasympathetic (i.e., DMV) than first‐order sympathetic (i.e., IML) motor neurons. RVLM also includes the catecholaminergic A5, C1, and C3 areas. Abbreviations: Ace, Amygdala, central part; ARC, Arcuate nucleus; Ba, Barrington nucleus; BNST, Bed nucleus of the stria terminalis; DMH, Dorsomedial nucleus of the hypothalamus; DMV, Dorsal motor nucleus of the vagus nerve; IML, Intermediolateral column of the spinal cord; INS; Insular cortex; LH, Lateral hypothalamus; MPO, Medial preoptic area; NTS, Nucleus of the tractus solitaries; OVLT, Organum vasculosum of the lamina terminalis; P, Pineal gland; PVN, Paraventricular nucleus of the hypothalamus; vPVN, Ventral part of the PVN; dPVN, Dorsal part of the PVN; RA, Raphe nucleus; RCA, Retrochiasmatic area; RVLM, Rostroventrolateral medulla; SCN, Suprachiasmatic nucleus; SFO, Subfornical organ; VMH, Ventromedial nucleus of the hypothalamus; X, Nervus vagus; ZI, Zona incerta
 1.Agarwal A, Halvorson LM, Legradi G. Pituitary adenylate cyclase‐activating polypeptide (PACAP) mimics neuroendocrine and behavioral manifestations of stress: Evidence for PKA‐mediated expression of the corticotropin‐releasing hormone (CRH) gene. Brain Res Mol Brain Res 138: 45‐57, 2005.
 2.Akiyoshi H, Gonda T, Terada T. A comparative histochemical and immunohistochemical study of aminergic, cholinergic and peptidergic innervation in rat, hamster, guinea pig, dog and human livers. Liver 18: 352‐359, 1998.
 3.Alam MN, Kumar S, Bashir T, Suntsova N, Methippara MM, Szymusiak R, McGinty D. GABA‐mediated control of hypocretin‐ but not melanin‐concentrating hormone‐immunoreactive neurones during sleep in rats. J Physiol 563: 569‐582, 2005.
 4.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.
 5.Ao Y, Ko M, Chen A, Marvizon JC, Adelson D, Song MK, Go VL, Liu YY, Yang H. Potent hyperglycemic and hyperinsulinemic effects of thyrotropin‐releasing hormone microinjected into the rostroventrolateral medulla and abnormal responses in type 2 diabetic rats. Neuroscience 169: 706‐719, 2010.
 6.Aoyagi T, Birumachi J, Hiroyama M, Fujiwara Y, Sanbe A, Yamauchi J, Tanoue A. Alteration of glucose homeostasis in V1a vasopressin receptor‐deficient mice. Endocrinology 148: 2075‐2084, 2007.
 7.Arletti R, Benelli A, Bertolini A. Influence of oxytocin on feeding behavior in the rat. Peptides 10: 89‐93, 1989.
 8.Arvidsson U, Riedl M, Elde R, Meister B. Vesicular acetylcholine transporter (VAChT) protein: A novel and unique marker for cholinergic neurons in the central and peripheral nervous systems. J Comp Neurol 378: 454‐467, 1997.
 9.Athari A, Hanecke K, Jungermann K. Prostaglandin F2 alpha and D2 release from primary Ito cell cultures after stimulation with noradrenaline and ATP but not adenosine. Hepatology 20: 142‐148, 1994.
 10.Backman SB, Henry JL. Effects of oxytocin and vasopressin on thoracic sympathetic preganglionic neurones in the cat. Brain Res Bull 13: 679‐684, 1984.
 11.Baran K, Preston E, Wilks D, Cooney GJ, Kraegen EW, Sainsbury A. Chronic central melanocortin‐4 receptor antagonism and central neuropeptide‐Y infusion in rats produce increased adiposity by divergent pathways. Diabetes 51: 152‐158, 2002.
 12.Bechtold DA, Brown TM, Luckman SM, Piggins HD. Metabolic rhythm abnormalities in mice lacking VIP‐VPAC2 signaling. Am J Physiol Regul Integr Comp Physiol 294: R344‐R351, 2008.
 13.Beckh K, Fuchs E, Balle C, Jungermann K. Activation of glycogenolysis by stimulation of the hepatic nerves in perfused livers of guinea pig and tree shrew as compared to rat: Differences in the mode of action. Biol Chem Hoppe Seyler 371: 153‐158, 1990.
 14.Berthoud HR. Anatomy and function of sensory hepatic nerves. Anat Rec 280A: 827‐835, 2004.
 15.Berthoud HR, Kressel M, Neuhuber WL. An anterograde tracing study of the vagal innervation of rat liver, portal vein and biliary system. Anat Embryol (Berl) 186: 431‐442, 1992.
 16.Bjorkstrand E, Eriksson M, Uvnas‐Moberg K. Evidence of a peripheral and a central effect of oxytocin on pancreatic hormone release in rats. Neuroendocrinology 63: 377‐383, 1996.
 17.Blevins JE, Schwartz MW, Baskin DG. Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol 287: R87‐R96, 2004.
 18.Borg MA, Sherwin RS, Borg WP, Tamborlane WV, Shulman GI. Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. J Clin Invest 99: 361‐365, 1997.
 19.Borg MA, Tamborlane WV, Shulman GI, Sherwin RS. Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation. Diabetes 52: 663‐666, 2003.
 20.Borg WP, During MJ, Sherwin RS, Borg MA, Brines ML, Shulman GI. Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia. J Clin Invest 93: 1677‐1682, 1994.
 21.Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Müller‐Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 289: 2122‐2125, 2000.
 22.Bruinstroop E, La Fleur SE, Ackermans MT, Foppen E, Wortel J, Kooijman S, Berbee JF, Rensen PC, Fliers E, Kalsbeek A. The autonomic nervous system regulates postprandial hepatic lipid metabolism. Am J Physiol Endocrinol Metab 304: E1089‐E1096, 2013.
 23.Bruinstroop E, Pei L, Ackermans MT, Foppen E, Borgers AJ, Kwakkel J, Alkemade A, Fliers E, Kalsbeek A. Hypothalamic neuropeptide Y (NPY) controls hepatic VLDL‐triglyceride secretion in rats via the sympathetic nervous system. Diabetes 61: 1043‐1050, 2012.
 24.Buijs RM, Chun SJ, Niijima A, Romijn HJ, Nagai K. Parasympathetic and sympathetic control of the pancreas: A role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J Comp Neurol 431: 405‐423, 2001.
 25.Camerino C. Low sympathetic tone and obese phenotype in oxytocin‐deficient mice. Obesity (Silver Spring) 17: 980‐984, 2009.
 26.Chee MJ, Colmers WF. Y eat? Nutrition 24: 869‐877, 2008.
 27.Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation. Cell 98: 437‐451, 1999.
 28.Cintra A, Fuxe K, Härfstrand A, Agnati LF, Wikström AC, Okret S, Vale W, Gustafsson JÅ. Presence of glucocorticoid receptor immunoreactivity in corticotrophin releasing factor and in growth hormone releasing factor immunoreactive neurons of the rat di‐ and telencephalon. Neurosci Lett 77: 25‐30, 1987.
 29.Clegg DJ, Brown LM, Woods SC, Benoit SC. Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 55: 978‐987, 2006.
 30.Coomans CP, Geerling JJ, Guigas B, van den Hoek AM, Parlevliet ET, Ouwens DM, Pijl H, Voshol PJ, Rensen PC, Havekes LM, Romijn JA. 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.
 31.Cryer PE. Diverse causes of hypoglycemia‐associated autonomic failure in diabetes. N Engl J Med 350: 2272‐2279, 2004.
 32.Cusin I, Rouru J, Rohner‐Jeanrenaud F. Intracerebroventricular glucocorticoid infusion in normal rats: Induction of parasympathetic‐mediated obesity and insulin resistance. Obes Res 9: 401‐406, 2001.
 33.Dalvi PS, Nazarians‐Armavil A, Purser MJ, Belsham DD. Glucagon‐like peptide‐1 receptor agonist, exendin‐4, regulates feeding‐associated neuropeptides in hypothalamic neurons in vivo and in vitro. Endocrinology 153: 2208‐2222, 2012. Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG. The hypocretins: Hypothalamus‐specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95: 322‐327, 1998.
 35.Ding WG, Kitasato H, Kimura H. Development of neuropeptide Y innervation in the liver. Microsc Res Tech 39: 365‐371, 1997.
 36.Ding WG, Tooyama I, Kitasato H, Fujimura M, Kimura H. Phylogenetic and ontogenetic study of neuropeptide Y‐containing nerves in the liver. Histochem J 26: 453‐459, 1994.
 37.Domeij S, Dahlqvist A, Forsgren S. Enkephalin‐like immunoreactivity in ganglionic cells in the larynx and superior cervical ganglion of the rat. Regul Pept 32: 95‐107, 1991.
 38.Dunning BE, Moltz JH, Fawcett CP. Modulation of insulin and glucagon secretion from the perfused rat pancreas by the neurohypophysial hormones and by desamino‐D‐arginine vasopressin (DDAVP). Peptides 5: 871‐875, 1984.
 39.Egawa M, Yoshimatsu H, Bray GA. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats. Am J Physiol 260: R328‐R334, 1991.
 40.el‐Salhy M, Stenling R, Grimelius L. Peptidergic innervation and endocrine cells in the human liver. Scand J Gastroenterol 28: 809‐815, 1993.
 41.Fadel J, Bubser M, Deutch AY. Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 22: 6742‐6746, 2002.
 42.Farooqi IS. Monogenic human obesity. Front Horm Res 36: 1‐11, 2008.
 43.Farooqi S. Obesity genes‐it's all about the parents! Cell Metab 9: 487‐488, 2009.
 44.Finan B, Yang B, Ottaway N, Stemmer K, Muller TD, Yi CX, Habegger K, Schriever SC, Garcia‐Caceres C, Kabra DG, Hembree J, Holland J, Raver C, Seeley RJ, Hans W, Irmler M, Beckers J, de Angelis MH, Tiano JP, Mauvais‐Jarvis F, Perez‐Tilve D, Pfluger P, Zhang L, Gelfanov V, DiMarchi RD, Tschop MH. Targeted estrogen delivery reverses the metabolic syndrome. Nat Med 18: 1847‐1856, 2012.
 45.Fioramonti X, Lorsignol A, Taupignon A, Penicaud L. A new ATP‐sensitive K+ channel‐independent mechanism is involved in glucose‐excited neurons of mouse arcuate nucleus. Diabetes 53: 2767‐2775, 2004.
 46.Fujiwara Y, Hiroyama M, Sanbe A, Aoyagi T, Birumachi J, Yamauchi J, Tsujimoto G, Tanoue A. Insulin hypersensitivity in mice lacking the V1b vasopressin receptor. J Physiol 584: 235‐244, 2007.
 47.Fukuda Y, Imoto M, Koyama Y, Miyazawa Y, Hayakawa T. Demonstration of noradrenaline‐immunoreactive nerve fibres in the liver. J Int Med Res 24: 466‐472, 1996.
 48.Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, Yanagisawa M. Enhanced orexin receptor‐2 signaling prevents diet‐induced obesity and improves leptin sensitivity. Cell Metab 9: 64‐76, 2009.
 49.Gamse R, Lembeck F, Cuello AC. Substance P in the vagus nerve. Immunochemical and immunohistochemical evidence for axoplasmic transport. Naunyn Schmiedebergs Arch Pharmacol 306: 37‐44, 1979.
 50.German J, Kim F, Schwartz GJ, Havel PJ, Rhodes CJ, Schwartz MW, Morton GJ. Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology 150: 4502‐4511, 2009.
 51.Geumei A, Mahfouz M. The presence of beta‐adrenergic receptors in the hepatic vasculature. Br J Pharmacol Chemother 32: 466‐472, 1968.
 52.Gilbey MP, Coote JH, Fleetwood‐Walker S, Peterson DF. The influence of the paraventriculo‐spinal pathway, and oxytocin and vasopressin on sympathetic preganglionic neurones. Brain Res 251: 283‐290, 1982.
 53.Gimpl G, Fahrenholz F. The oxytocin receptor system: Structure, function, and regulation. Physiol Rev 81: 629‐683, 2001.
 54.Girault EM, Foppen E, Ackermans MT, Fliers E, Kalsbeek A. Central administration of an orexin receptor 1 antagonist prevents the stimulatory effect of Olanzapine on endogenous glucose production. Brain Res 1527: 238‐245, 2013.
 55.Goehler LE, Sternini C. Neuropeptide Y immunoreactivity in the mammalian liver: Pattern of innervation and coexistence with tyrosine hydroxylase immunoreactivity. Cell Tissue Res 265: 287‐295, 1991.
 56.Gomori A, Ishihara A, Ito M, Matsushita H, Mashiko S, Iwaasa H, Matsuda M, Bednarek MA, Qian S, MacNeil DJ, Kanatani A. Blockade of MCH1 receptor signalling ameliorates obesity and related hepatic steatosis in ovariectomized mice. Br J Pharmacol 151: 900‐908, 2007.
 57.Gray SL, Cummings KJ, Jirik FR, Sherwood NM. Targeted disruption of the pituitary adenylate cyclase‐activating polypeptide gene results in early postnatal death associated with dysfunction of lipid and carbohydrate metabolism. Mol Endocrinol 15: 1739‐1747, 2001.
 58.Green HD, Hall LS, Sexton J, Deal CP. Autonomic vasomotor responses in the canine hepatic arterial and venous beds. Am J Physiol 196: 196‐202, 1959.
 59.Green T, Dockray GJ. Calcitonin gene‐related peptide and substance P in afferents to the upper gastrointestinal tract in the rat. Neurosci Lett 76: 151‐156, 1987.
 60.Grinevich V, Fournier A, Pelletier G. Effects of pituitary adenylate cyclase‐activating polypeptide (PACAP) on corticotropin‐releasing hormone (CRH) gene expression in the rat hypothalamic paraventricular nucleus. Brain Res 773: 190‐196, 1997.
 61.Gutierrez‐Juarez R, Obici S, Rossetti L. Melanocortin‐independent effects of leptin on hepatic glucose fluxes. J Biol Chem 279: 49704‐49715, 2004.
 62.Hammack SE, Roman CW, Lezak KR, Kocho‐Shellenberg M, Grimmig B, Falls WA, Braas K, May V. Roles for pituitary adenylate cyclase‐activating peptide (PACAP) expression and signaling in the bed nucleus of the stria terminalis (BNST) in mediating the behavioral consequences of chronic stress. J Mol Neurosci 42: 327‐340, 2010.
 63.Hannibal J. Pituitary adenylate cyclase‐activating peptide in the rat central nervous system: An immunohistochemical and in situ hybridization study. J Comp Neurol 453: 389‐417, 2002.
 64.Haussinger D, Stehle T, Tran‐Thi TA, Decker K, Gerok W. Prostaglandin responses in isolated perfused rat liver: Ca2+ and K+ fluxes, hemodynamic and metabolic effects. Biol Chem Hoppe Seyler 368: 1509‐1513, 1987.
 65.Hems DA, Rodrigues LM, Whitton PD. Rapid stimulation by vasopressin, oxytocin and angiotensin II of glycogen degradation in hepatocyte suspensions. Biochem J 172: 311‐317, 1978.
 66.Hertzberg EL, Gilula NB. Isolation and characterization of gap junctions from rat liver. J Biol Chem 254: 2138‐2147, 1979.
 67.Heuer H, Schafer MK, O'Donnell D, Walker P, Bauer K. Expression of thyrotropin‐releasing hormone receptor 2 (TRH‐R2) in the central nervous system of rats. J Comp Neurol 428: 319‐336, 2000.
 68.Hiroyama M, Aoyagi T, Fujiwara Y, Birumachi J, Shigematsu Y, Kiwaki K, Tasaki R, Endo F, Tanoue A. Hypermetabolism of fat in V1a vasopressin receptor knockout mice. Mol Endocrinol 21: 247‐258, 2007.
 69.Hiroyama M, Fujiwara Y, Nakamura K, Aoyagi T, Mizutani R, Sanbe A, Tasaki R, Tanoue A. Altered lipid metabolism in vasopressin V1B receptor‐deficient mice. Eur J Pharmacol 602: 455‐461, 2009.
 70.Hirsch MD, Helke CJ. Bulbospinal thyrotropin‐releasing hormone projections to the intermediolateral cell column: A double fluorescence immunohistochemical‐retrograde tracing study in the rat. Neuroscience 25: 625‐637, 1988.
 71.Hokfelt T, Fuxe K, Johansson O, Jeffcoate S, White N. Distribution of thyrotropin‐releasing hormone (TRH) in the central nervous system as revealed with immunohistochemistry. Eur J Pharmacol 34: 389‐392, 1975.
 72.Hokfelt T, Kellerth JO, Nilsson G, Pernow B. Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons. Brain Res 100: 235‐252, 1975.
 73.Hoover DB, Barron SE. Localization and acetylcholinesterase content of vagal efferent neurons. Brain Res Bull 8: 279‐284, 1982.
 74.Hu Y, Dunbar JC. Intracerebroventricular administration of NPY increases sympathetic tone selectively in vascular beds. Brain Res Bull 44: 97‐103, 1997.
 75.Inglott MA, Farnham MM, Pilowsky PM. Intrathecal PACAP‐38 causes prolonged widespread sympathoexcitation via a spinally mediated mechanism and increases in basal metabolic rate in anesthetized rat. Am J Physiol Heart Circ Physiol 300: H2300‐H2307, 2011.
 76.Ishiguro T, Iguchi A, Kunoh Y, Goto M, Uemura K, Miura H, Nonogaki K, Sakamoto N. Relative contribution of nervous system and hormones to hyperglycemia induced by thyrotropin‐releasing hormone in fed rats. Neuroendocrinology 54: 1‐6, 1991.
 77.Ito M, Gomori A, Ishihara A, Oda Z, Mashiko S, Matsushita H, Yumoto M, Sano H, Tokita S, Moriya M, Iwaasa H, Kanatani A. Characterization of MCH‐mediated obesity in mice. Am J Physiol Endocrinol Metab 284: E940‐E945, 2003.
 78.Ito M, Gomori A, Suzuki J, Tsujioka S, Sasaki M, Matsuda M, Bednarek MA, Ishihara A, Iwaasa H, MacNeil DJ, Kanatani A. Antagonism of central melanin‐concentrating hormone 1 receptor alleviates steatohepatitis in mice. J Endocrinol 198: 309‐315, 2008.
 79.Iwai M, Miyashita T, Shimazu T. Inhibition of glucose production during hepatic nerve stimulation in regenerating rat liver perfused in situ. Possible involvement of gap junctions in the action of sympathetic nerves. Eur J Biochem 200: 69‐74, 1991.
 80.Jamen F, Persson K, Bertrand G, Rodriguez‐Henche N, Puech R, Bockaert J, Ahren B, Brabet P. PAC1 receptor‐deficient mice display impaired insulinotropic response to glucose and reduced glucose tolerance. J Clin Invest 105: 1307‐1315, 2000.
 81.Jansen AS, Wessendorf MW, Loewy AD. Transneuronal labeling of CNS neuropeptide and monoamine neurons after pseudorabies virus injections into the stellate ganglion. Brain Res 683: 1‐24, 1995.
 82.Jensen KJ, Alpini G, Glaser S. Hepatic nervous system and neurobiology of the liver. Nat Rev Neurosci 14: 851‐858, 2013.
 83.Jordan SD, Konner AC, Bruning JC. Sensing the fuels: Glucose and lipid signaling in the CNS controlling energy homeostasis. Cell Mol Life Sci 67: 3255‐3273, 2010.
 84.Kabayama Y, Kato Y, Tojo K, Shimatsu A, Ohta H, Imura H. Central effects of DN1417, a novel TRH analog, on plasma glucose and catecholamines in conscious rats. Life Sci 36: 1287‐1294, 1985.
 85.Kalsbeek A, Bruinstroop E, Yi CX, Klieverik LP, La Fleur SE, Fliers E. Hypothalamic control of energy metabolism via the autonomic nervous system. Ann N Y Acad Sci 1212: 114‐129, 2010.
 86.Kalsbeek A, Fliers E, Franke AN, Wortel J, Buijs RM. Functional connections between the suprachiasmatic nucleus and the thyroid gland as revealed by lesioning and viral tracing techniques in the rat. Endocrinology 141: 3832‐3841, 2000.
 87.Kalsbeek A, Foppen E, Schalij I, Van HC, Van der Vies J, Fliers E, Buijs RM. Circadian control of the daily plasma glucose rhythm: An interplay of GABA and glutamate. PLoS ONE 3: e3194, 2008.
 88.Kalsbeek A, La Fleur SE, Van Heijningen C, Buijs RM. Suprachiasmatic GABAergic inputs to the paraventricular nucleus control plasma glucose concentrations in the rat via sympathetic innervation of the liver. J Neurosci 2413262: 7604‐7613, 2004.
 89.Kalsbeek A, Yi CX, La Fleur SE, Fliers E. The hypothalamic clock and its control of glucose homeostasis. Trends Endocrinol Metab 21: 402‐410, 2010.
 90.Kilduff TS, Lein ES, de la Iglesia H, Sakurai T, Fu YH, Shaw P. New developments in sleep research: Molecular genetics, gene expression, and systems neurobiology. J Neurosci 28: 11814‐11818, 2008.
 91.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.
 92.Kishore P, Boucai L, Zhang K, Li W, Koppaka S, Kehlenbrink S, Schiwek A, Esterson YB, Mehta D, Bursheh S, Su Y, Gutierrez‐Juarez R, Muzumdar R, Schwartz GJ, Hawkins M. Activation of KATP channels suppresses glucose production in humans. J Clin Invest 121: 4916‐4920, 2011.
 93.Klieverik LP, Coomans CP, Endert E, Sauerwein HP, Havekes LM, Voshol PJ, Rensen PC, Romijn JA, Kalsbeek A, Fliers E. Thyroid hormone effects on whole‐body energy homeostasis and tissue‐specific fatty acid uptake in vivo. Endocrinology 150: 5639‐5648, 2009.
 94.Kokorovic A, Cheung GW, Rossetti L, Lam TK. Hypothalamic sensing of circulating lactate regulates glucose production. J Cell Mol Med 13: 4403‐4408, 2009.
 95.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.
 96.Koster JC, Permutt MA, Nichols CG. Diabetes and insulin secretion: The ATP‐sensitive K+ channel (KATP) connection. Diabetes 54: 3065‐3072, 2005.
 97.Kow LM, Pfaff DW. Vasopressin excites ventromedial hypothalamic glucose‐responsive neurons in vitro. Physiol Behav 37: 153‐158, 1986.
 98.Kowalski TJ, Spar BD, Weig B, Farley C, Cook J, Ghibaudi L, Fried S, O'Neill K, Del Vecchio RA, McBriar M, Guzik H, Clader J, Hawes BE, Hwa J. Effects of a selective melanin‐concentrating hormone 1 receptor antagonist on food intake and energy homeostasis in diet‐induced obese mice. Eur J Pharmacol 535: 182‐191, 2006.
 99.Kublaoui BM, Gemelli T, Tolson KP, Wang Y, Zinn AR. Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. Mol Endocrinol 22: 1723‐1734, 2008.
 100.Kumar NM, Gilula NB. Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein. J Cell Biol 103: 767‐776, 1986.
 101.Lam TK, Gutierrez‐Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L. Brain glucose metabolism controls the hepatic secretion of triglyceride‐rich lipoproteins. Nat Med 13: 171‐180, 2007.
 102.Lam TK, Gutierrez‐Juarez R, Pocai A, Rossetti L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309: 943‐947, 2005.
 103.Lechan RM, Snapper SB, Jackson IM. Evidence that spinal cord thyrotropin‐releasing hormone is independent of the paraventricular nucleus. Neurosci Lett 43: 61‐65, 1983.
 104.Liu J, Bisschop PH, Eggels L, Foppen E, Ackermans MT, Zhou JN, Fliers E, Kalsbeek A. Intrahypothalamic estradiol regulates glucose metabolism via the sympathetic nervous system in female rats. Diabetes 62: 435‐443, 2013.
 105.Lu M, Wan M, Leavens KF, Chu Q, Monks BR, Fernandez S, Ahima RS, Ueki K, Kahn CR, Birnbaum MJ. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med 18: 388‐395, 2012.
 106.Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J, Lowell B, Flier JS, Maratos‐Flier E. Melanin‐concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J Clin Invest 107: 379‐386, 2001.
 107.Lynn RB, Kreider MS, Miselis RR. Thyrotropin‐releasing hormone‐immunoreactive projections to the dorsal motor nucleus and the nucleus of the solitary tract of the rat. J Comp Neurol 311: 271‐288, 1991.
 108.Manaker S, Rizio G. Autoradiographic localization of thyrotropin‐releasing hormone and substance P receptors in the rat dorsal vagal complex. J Comp Neurol 290: 516‐526, 1989.
 109.Marks JL, Waite K. Some acute effects of intracerebroventricular neuropeptide Y on insulin secretion and glucose metabolism in the rat. J Neuroendocrinol 8: 507‐513, 1996.
 110.Marks JL, Waite K. Intracerebroventricular neuropeptide Y acutely influences glucose metabolism and insulin sensitivity in the rat. J Neuroendocrinol 9: 99‐103, 1997.
 111.Martin B, Shin YK, White CM, Ji S, Kim W, Carlson OD, Napora JK, Chadwick W, Chapter M, Waschek JA, Mattson MP, Maudsley S, Egan JM. Vasoactive intestinal peptide‐null mice demonstrate enhanced sweet taste preference, dysglycemia, and reduced taste bud leptin receptor expression. Diabetes 59: 1143‐1152, 2010.
 112.Martins PJ, Marques MS, Tufik S, D'Almeida V. Orexin activation precedes increased NPY expression, hyperphagia, and metabolic changes in response to sleep deprivation. Am J Physiol Endocrinol Metab 298: E726‐E734, 2010.
 113.Marubashi S, Kunii Y, Tominaga M, Sasaki H. Modulation of plasma glucose levels by thyrotropin‐releasing hormone administered intracerebroventricularly in the rat. Neuroendocrinology 48: 640‐644, 1988.
 114.Mashiko S, Ishihara A, Iwaasa H, Sano H, Oda Z, Ito J, Yumoto M, Okawa M, Suzuki J, Fukuroda T, Jitsuoka M, Morin NR, MacNeil DJ, Van der Ploeg LH, Ihara M, Fukami T, Kanatani A. Characterization of neuropeptide Y (NPY) Y5 receptor‐mediated obesity in mice: Chronic intracerebroventricular infusion of D‐Trp(34)NPY. Endocrinology 144: 1793‐1801, 2003.
 115.Meisinger C, Heier M, Loewel H. Sleep disturbance as a predictor of type 2 diabetes mellitus in men and women from the general population. Diabetologia 48: 235‐241, 2005.
 116.Mighiu PI, Yue JTY, Filippi BM, Abraham MA, Chari M, Lam CKL, Yang CS, Christian NR, Charron MJ, Lam TKT. Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat Med 19: 766‐772, 2013.
 117.Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH. Isolation of a novel 38 residue‐hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164: 567‐574, 1989.
 118.Mizuno Y, Kondo K, Terashima Y, Arima H, Murase T, Oiso Y. Anorectic effect of pituitary adenylate cyclase activating polypeptide (PACAP) in rats: Lack of evidence for involvement of hypothalamic neuropeptide gene expression. J Neuroendocrinol 10: 611‐616, 1998.
 119.Morgan K, Obici S, Rossetti L. Hypothalamic responses to long‐chain fatty acids are nutritionally regulated. J Biol Chem 279: 31139‐31148, 2004.
 120.Morimoto M, Morita N, Ozawa H, Yokoyama K, Kawata M. Distribution of glucocorticoid receptor immunoreactivity and mRNA in the rat brain: An immunohistochemical and in situ hybridization study. Neuroscience Research 26: 235‐269, 1996.
 121.Morley JE, Horowitz M, Morley PM, Flood JF. Pituitary adenylate cyclase activating polypeptide (PACAP) reduces food intake in mice. Peptides 13: 1133‐1135, 1992.
 122.Morrow NS, Novin D, Garrick T. Microinjection of thyrotropin‐releasing hormone in the paraventricular nucleus of the hypothalamus stimulates gastric contractility. Brain Res 644: 243‐250, 1994.
 123.Mounien L, Do Rego JC, Bizet P, Boutelet I, Gourcerol G, Fournier A, Brabet P, Costentin J, Vaudry H, Jegou S. Pituitary adenylate cyclase‐activating polypeptide inhibits food intake in mice through activation of the hypothalamic melanocortin system. Neuropsychopharmacology 34: 424‐435, 2008.
 124.Mul JD, Yi CX, van den Berg SA, Ruiter M, Toonen PW, van der Elst MC, Voshol PJ, Ellenbroek BA, Kalsbeek A, La Fleur SE, Cuppen E. Pmch expression during early development is critical for normal energy homeostasis. Am J Physiol Endocrinol Metab 298: E477‐E488, 2010.
 125.Musatov S, Chen W, Pfaff DW, Mobbs CV, Yang XJ, Clegg DJ, Kaplitt MG, Ogawa S. Silencing of estrogen receptor {alpha} in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. PNAS 104: 2501‐2506, 2007.
 126.Nagai K, Nagai N, Shimizu K, Chun S, Nakagawa H, Niijima A. SCN output drives the autonomic nervous system: With special reference to the autonomic function related to the regulation of glucose metabolism. Prog Brain Res 111: 253‐272, 1996.
 127.Nagai N, Kajikawa H, Sasaki T, Nagai K, Nakagawa H. Hyperglycemic response to intracranial injection of vasoactive intestinal peptide. J Clin BiochemNutr 1705135: 29‐34, 1994.
 128.Nakagawa H, Okumura N. Coordinated regulation of circadian rhythms and homeostasis by the suprachiasmatic nucleus. Proc Jpn Acad Ser B Phys Biol Sci 86: 391‐409, 2010.
 129.Nakata M, Kohno D, Shintani N, Nemoto Y, Hashimoto H, Baba A, Yada T. PACAP deficient mice display reduced carbohydrate intake and PACAP activates NPY‐containing neurons in the rat hypothalamic arcuate nucleus. Neurosci Lett 370: 252‐256, 2004.
 130.Nilsson PM, Roost M, Engstrom G, Hedblad B, Berglund G. Incidence of diabetes in middle‐aged men is related to sleep disturbances. Diabetes Care 27: 2464‐2469, 2004.
 131.Norgren R, Smith GP. Central distribution of subdiaphragmatic vagal branches in the rat. J Comp Neurol 273: 207‐223, 1988.
 132.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.
 133.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.
 134.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.
 135.Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8: 1376‐1382, 2002.
 136.Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM, McKinley MJ. The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience 110: 515‐526, 2002.
 137.Olson BR, Drutarosky MD, Chow MS, Hruby VJ, Stricker EM, Verbalis JG. Oxytocin and an oxytocin agonist administered centrally decrease food intake in rats. Peptides 12: 113‐118, 1991.
 138.Oomura Y, Nakamura T, Sugimori M, Yamada Y. Effect of free fatty acid on the rat lateral hypothalamic neurons. Physiol Behav 14: 483‐486, 1975.
 139.Oomura Y, Ono T, Ooyama H, Wayner MJ. Glucose and osmosensitive neurones of the rat hypothalamus. Nature 222: 282‐284, 1969.
 140.Oomura Y, Yoshimatsu H. Neural network of glucose monitoring system. J Auton Nerv Syst 10: 359‐372, 1984.
 141.Oppenheimer JH, Schwartz HL, Lane JT, Thompson MP. Functional relationship of thyroid hormone‐induced lipogenesis, lipolysis, and thermogenesis in the rat. J Clin Invest 87: 125‐132, 1991.
 142.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.
 143.Pedrazzoli M, D'Almeida V, Martins PJ, Machado RB, Ling L, Nishino S, Tufik S, Mignot E. Increased hypocretin‐1 levels in cerebrospinal fluid after REM sleep deprivation. Brain Res 995: 1‐6, 2004.
 144.Perez‐Tilve D, Hofmann SM, Basford J, Nogueiras R, Pfluger PT, Patterson JT, Grant E, Wilson‐Perez HE, Granholm NA, Arnold M, Trevaskis JL, Butler AA, Davidson WS, Woods SC, Benoit SC, Sleeman MW, DiMarchi RD, Hui DY, Tschop MH. Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nat Neurosci 13: 877‐882, 2010.
 145.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.
 146.Poli F, Plazzi G, Di Dalmazi G, Ribichini D, Vicennati V, Pizza F, Mignot E, Montagna P, Pasquali R, Pagotto U. Body mass index‐independent metabolic alterations in narcolepsy with cataplexy. Sleep 32: 1491‐1497, 2009.
 147.Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, Maratos‐Flier E. A role for melanin‐concentrating hormone in the central regulation of feeding behaviour. Nature 380: 243‐247, 1996.
 148.Rabeler R, Mittag J, Geffers L, Ruther U, Leitges M, Parlow AF, Visser TJ, Bauer K. Generation of thyrotropin‐releasing hormone receptor 1‐deficient mice as an animal model of central hypothyroidism. Mol Endocrinol 18: 1450‐1460, 2004.
 149.Ramnanan CJ, Saraswathi V, Smith MS, Donahue EP, Farmer B, Farmer TD, Neal D, Williams PE, Lautz M, Mari A, Cherrington AD, Edgerton DS. Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. J Clin Invest 121: 3713‐3723, 2011.
 150.Ramnanan C, Edgerton D, Cherrington A. Evidence against a physiologic role for acute changes in CNS insulin action in the rapid regulation of hepatic glucose production. Cell Metabolism 15: 656‐664,
 151.Raybould HE, Jakobsen LJ, Novin D, Tache Y. TRH stimulation and L‐glutamic acid inhibition of proximal gastric motor activity in the rat dorsal vagal complex. Brain Res 495: 319‐328, 1989.
 152.Richards P, Parker HE, Adriaenssens AE, Hodgson JM, Cork SC, Trapp S, Gribble FM, Reimann F. Identification and characterisation of glucagon‐like peptide‐1 receptor expressing cells using a new transgenic mouse model. Diabetes 63: 1224‐1233, 2014.
 153.Riedel W, Burke SL. Selective autonomic nervous control of thyroid hormone and calcitonin secretion during metabolic and cardiorespiratory activation by intracisternal thyrotropin‐releasing hormone (TRH). J Auton Nerv Syst 24: 157‐173, 1988.
 154.Rojas JM, Stafford JM, Saadat S, Printz RL, Beck‐Sickinger AG, Niswender KD. Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats. Am J Physiol Endocrinol Metab 303: E1479‐E1488, 2012.
 155.Ross R, Wang PY, Chari M, Lam CK, Caspi L, Ono H, Muse ED, Li X, Gutierrez‐Juarez R, Light PE, Schwartz GJ, Rossetti L, Lam TK. Hypothalamic protein kinase C regulates glucose production. Diabetes 57: 2061‐2065, 2008.
 156.Rossi J, Balthasar N, Olson D, Scott M, Berglund E, Lee CE, Choi MJ, Lauzon D, Lowell BB, Elmquist JK. Melanocortin‐4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab 13: 195‐204, 2011.
 157.Rudnicki M, Rigel DF, McFadden DW. Vagal cooling blocks circulating neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) release. J Surg Res 51: 40‐45, 1991.
 158.Sainsbury A, Cusin I, Rohner‐Jeanrenaud F, Jeanrenaud B. Adrenalectomy prevents the obesity syndrome produced by chronic central neuropeptide Y infusion in normal rats. Diabetes 46: 209‐214, 1997.
 159.Sandoval DA, Bagnol D, Woods SC, D'Alessio DA, Seeley RJ. Arcuate glucagon‐like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57: 2046‐2054, 2008.
 160.Sawchenko PE. Toward a new neurobiology of energy balance, appetite, and obesity: The anatomists weigh in. J Comp Neurol 402: 435‐441, 1998.
 161.Schaffler A, Binart N, Scholmerich J, Buchler C. Hypothesis paper Brain talks with fat–evidence for a hypothalamic‐pituitary‐adipose axis? Neuropeptides 39: 363‐367, 2005.
 162.Scherer T, O'Hare J, Diggs‐Andrews K, Schweiger M, Cheng B, Lindtner C, Zielinski E, Vempati P, Su K, Dighe S, Milsom T, Puchowicz M, Scheja L, Zechner R, Fisher SJ, Previs SF, Buettner C. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 13: 183‐194, 2011.
 163.Schwartz MW, Marks JL, Sipols AJ, Baskin DG, Woods SC, Kahn SE, Porte D, Jr. Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food‐deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats. Endocrinology 128: 2645‐2647, 1991.
 164.Schwartz MW, Seeley RJ, Tschop MH, Woods SC, Morton GJ, Myers MG, ‘Alessio D. Cooperation between brain and islet in glucose homeostasis and diabetes. Nature 503: 59‐66, 2013.
 165.Segal JP, Stallings NR, Lee CE, Zhao L, Socci N, Viale A, Harris TM, Soares MB, Childs G, Elmquist JK, Parker KL, Friedman JM. Use of laser‐capture microdissection for the identification of marker genes for the ventromedial hypothalamic nucleus. J Neurosci 25: 4181‐4188, 2005.
 166.Segal‐Lieberman G, Bradley RL, Kokkotou E, Carlson M, Trombly DJ, Wang X, Bates S, Myers MG, Jr., Flier JS, Maratos‐Flier E. Melanin‐concentrating hormone is a critical mediator of the leptin‐deficient phenotype. Proc Natl Acad Sci U S A 100: 10085‐10090, 2003.
 167.Seseke FG, Gardemann A, Jungermann K. Signal propagation via gap junctions, a key step in the regulation of liver metabolism by the sympathetic hepatic nerves. FEBS Lett 301: 265‐270, 1992.
 168.Shen J, Tanida M, Yao JF, Niijima A, Nagai K. Biphasic effects of orexin‐A on autonomic nerve activity and lipolysis. Neurosci Lett 444: 166‐171, 2008.
 169.Shi H, Bartness TJ. Neurochemical phenotype of sympathetic nervous system outflow from brain to white fat. Brain Res Bull 54: 375‐385, 2001.
 170.Shi YC, Lau J, Lin Z, Zhang H, Zhai L, Sperk G, Heilbronn R, Mietzsch M, Weger S, Huang XF, Enriquez RF, Baldock PA, Zhang L, Sainsbury A, Herzog H, Lin S. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab 17: 236‐248, 2013.
 171.Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos‐Flier E. Mice lacking melanin‐concentrating hormone are hypophagic and lean. Nature 396: 670‐674, 1998.
 172.Shimokawa T, Kumar MV, Lane MD. Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc Natl Acad Sci U S A 99: 66‐71, 2002.
 173.Shiuchi T, Haque MS, Okamoto S, Inoue T, Kageyama H, Lee S, Toda C, Suzuki A, Bachman ES, Kim YB, Sakurai T, Yanagisawa M, Shioda S, Imoto K, Minokoshi Y. Hypothalamic orexin stimulates feeding‐associated glucose utilization in skeletal muscle via sympathetic nervous system. Cell Metab 10: 466‐480, 2009.
 174.Silver IA, Erecinska M. Glucose‐induced intracellular ion changes in sugar‐sensitive hypothalamic neurons. J Neurophysiol 79: 1733‐1745, 1998.
 175.Sorensen A, Travers MT, Vernon RG, Price NT, Barber MC. Localization of messenger RNAs encoding enzymes associated with malonyl‐CoA metabolism in mouse brain. Brain Res Gene Expr Patterns 1: 167‐173, 2002.
 176.Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E. Sleep loss: A novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol 99: 2008‐2019, 2005.
 177.Stafford JM, Yu F, Printz R, Hasty AH, Swift LL, Niswender KD. Central nervous system neuropeptide Y signaling modulates VLDL triglyceride secretion. Diabetes 57: 1482‐1490, 2008.
 178.Stanley S, Pinto S, Segal J, Perez CA, Viale A, DeFalco J, Cai X, Heisler LK, Friedman JM. Identification of neuronal subpopulations that project from hypothalamus to both liver and adipose tissue polysynaptically. Proc Natl Acad Sci U S A 107: 7024‐7029, 2010.
 179.Stefanidis A, Verty AN, Allen AM, Owens NC, Cowley MA, Oldfield BJ. The role of thermogenesis in antipsychotic drug‐induced weight gain. Obesity (Silver Spring) 17: 16‐24, 2009.
 180.Stoyanova II, Gulubova MV. Peptidergic nerve fibres in the human liver. Acta Histochem 100: 245‐256, 1998.
 181.Stumpel F, Ott T, Willecke K, Jungermann K. Connexin 32 gap junctions enhance stimulation of glucose output by glucagon and noradrenaline in mouse liver. Hepatology 28: 1616‐1620, 1998.
 182.Sun Y, Zupan B, Raaka BM, Toth M, Gershengorn MC. TRH‐receptor‐type‐2‐deficient mice are euthyroid and exhibit increased depression and reduced anxiety phenotypes. Neuropsychopharmacology 34: 1601‐1608, 2009.
 183.Sutherland SD. An evaluation of cholinesterase techniques in the study of the intrinsic innervation of the liver. J Anat 98: 321‐326, 1964.
 184.Swaab DF, Purba JS, Hofman MA. Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader‐Willi syndrome: A study of five cases. J Clin Endocrinol Metab 80: 573‐579, 1995.
 185.Tachibana T, Oikawa D, Adachi N, Boswell T, Furuse M. Central administration of vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide differentially regulates energy metabolism in chicks. Comp Biochem Physiol A Mol Integr Physiol 147: 156‐164, 2007.
 186.Takayanagi Y, Kasahara Y, Onaka T, Takahashi N, Kawada T, Nishimori K. Oxytocin receptor‐deficient mice developed late‐onset obesity. Neuroreport 19: 951‐955, 2008.
 187.Tanida M, Shintani N, Morita Y, Tsukiyama N, Hatanaka M, Hashimoto H, Sawai H, Baba A, Nagai K. Regulation of autonomic nerve activities by central pituitary adenylate cyclase‐activating polypeptide. Regul Pept 161: 73‐80, 2010.
 188.Tanoue A. New topics in vasopressin receptors and approach to novel drugs: Effects of vasopressin receptor on regulations of hormone secretion and metabolisms of glucose, fat, and protein. J Pharmacol Sci 109: 50‐52, 2009.
 189.Tiesjema B, Adan RA, Luijendijk MC, Kalsbeek A, La Fleur SE. Differential effects of recombinant adeno‐associated virus‐mediated neuropeptide Y overexpression in the hypothalamic paraventricular nucleus and lateral hypothalamus on feeding behavior. J Neurosci 27: 14139‐14146, 2007.
 190.Toda C, Shiuchi T, Lee S, Yamato‐Esaki M, Fujino Y, Suzuki A, Okamoto S, Minokoshi Y. Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues. Diabetes 58: 2757‐2765, 2009.
 191.Tomimoto S, Ojika T, Shintani N, Hashimoto H, Hamagami K, Ikeda K, Nakata M, Yada T, Sakurai Y, Shimada T, Morita Y, Ishida C, Baba A. Markedly reduced white adipose tissue and increased insulin sensitivity in adcyap1‐deficient mice. J Pharmacol Sci 107: 41‐48, 2008.
 192.Tsuneki H, Tokai E, Sugawara C, Wada T, Sakurai T, Sasaoka T. Hypothalamic orexin prevents hepatic insulin resistance induced by social defeat stress in mice. Neuropeptides 47: 213‐219, 2013.
 193.Uchoa ET, Sabino HA, Ruginsk SG, Antunes‐Rodrigues J, Elias LL. Hypophagia induced by glucocorticoid deficiency is associated with an increased activation of satiety‐related responses. J Appl Physiol 106: 596‐604, 2009.
 194.Unanue ER. Ito cells, stellate cells, and myofibroblasts: New actors in antigen presentation. Immunity 26: 9‐10, 2007.
 195.Unger J, McNeill TH, Moxley RT III, White M, Moss A, Livingston JN. Distribution of insulin receptor‐like immunoreactivity in the rat forebrain. Neuroscience 31: 143‐157, 1989.
 196.van den Hoek AM, Van Heijningen C, Schroder‐van der Elst JP, Ouwens DM, Havekes LM, Romijn JA, Kalsbeek A, Pijl H. Intracerebroventricular administration of neuropeptide Y induces hepatic insulin resistance via sympathetic innervation. Diabetes 57: 2304‐2310, 2008.
 197.van den Hoek AM, Voshol PJ, Karnekamp BN, Buijs RM, Romijn JA, Havekes LM, Pijl H. Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. Diabetes 53: 2529‐2534, 2004.
 198.van den Top M, Nolan MF, Lee K, Richardson PJ, Buijs RM, Davies CH, Spanswick D. Orexins induce increased excitability and synchronisation of rat sympathetic preganglionic neurones. J Physiol 549: 809‐821, 2003.
 199.van DG, Bottone AE, Strubbe JH, Steffens AB. Hormonal and metabolic effects of paraventricular hypothalamic administration of neuropeptide Y during rest and feeding. Brain Res 660: 96‐103, 1994.
 200.Wallingford NM, Sinnayah P, Bymaster FP, Gadde KM, Krishnan RK, McKinney AA, Landbloom RP, Tollefson GD, Cowley MA. Zonisamide prevents olanzapine‐associated hyperphagia, weight gain, and elevated blood glucose in rats. Neuropsychopharmacology 33: 2922‐2933, 2008.
 201.Wang Y, Seburn K, Bechtel L, Lee BY, Szatkiewicz JP, Nishina PM, Naggert JK. Defective carbohydrate metabolism in mice homozygous for the tubby mutation. Physiol Genomics 27: 131‐140, 2006.
 202.Westerhaus MJ, Loewy AD. Sympathetic‐related neurons in the preoptic region of the rat identified by viral transneuronal labeling. J Comp Neurol 414: 361‐378, 1999.
 203.Whiddon BB, Palmiter RD. Ablation of neurons expressing melanin‐concentrating hormone (MCH) in adult mice improves glucose tolerance independent of MCH signaling. J Neurosci 33: 2009‐2016, 2013.
 204.Wideman CH, Murphy HM. Modulatory effects of vasopressin on glucose and protein metabolism during food‐restriction stress. Peptides 14: 259‐261, 1993.
 205.Wittmann G, Fuzesi T, Liposits Z, Lechan RM, Fekete C. Distribution and axonal projections of neurons coexpressing thyrotropin‐releasing hormone and urocortin 3 in the rat brain. J Comp Neurol 517: 825‐840, 2009.
 206.Wu Q, Whiddon BB, Palmiter RD. Ablation of neurons expressing agouti‐related protein, but not melanin concentrating hormone, in leptin‐deficient mice restores metabolic functions and fertility. Proc Natl Acad Sci U S A 109: 3155‐3160, 2012.
 207.Xu Y, Nedungadi T, Zhu L, Sobhani N, Irani B, Davis K, Zhang X, Zou F, Gent L, Hahner L, Khan S, Elias C, Elmquist J, Clegg D. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metabolism 14: 453‐465, 2011.
 208.Xue C, Aspelund G, Sritharan KC, Wang JP, Slezak LA, Andersen DK. Isolated hepatic cholinergic denervation impairs glucose and glycogen metabolism. J Surg Res 90: 19‐25, 2000.
 209.Yamada M, Saga Y, Shibusawa N, Hirato J, Murakami M, Iwasaki T, Hashimoto K, Satoh T, Wakabayashi K, Taketo MM, Mori M. Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin‐releasing hormone gene. Proc Natl Acad Sci U S A 94: 10862‐10867, 1997.
 210.Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto K. Chronic intracerebroventricular administration of orexin‐A to rats increases food intake in daytime, but has no effect on body weight. Brain Res 849: 248‐252, 1999.
 211.Yang H, Tache Y. Prepro‐TRH‐(160‐169) potentiates gastric acid secretion stimulated by TRH microinjected into the dorsal motor nucleus of the vagus. Neurosci Lett 174: 43‐46, 1994.
 212.Yarkov A, Montero S, Lemus M, Roces de Alvarez‐Buylla E, Alvarez‐Buylla R. Arginine‐vasopressin in nucleus of the tractus solitarius induces hyperglycemia and brain glucose retention. Brain Res 902: 212‐222, 2001.
 213.Yi CX, Foppen E, Abplanalp W, Gao Y, Alkemade A, La Fleur SE, Serlie MJ, Fliers E, Buijs RM, Tschop MH, Kalsbeek A. Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity. Diabetes 61: 339‐345, 2012.
 214.Yi CX, Serlie MJ, Ackermans MT, Foppen E, Buijs RM, Sauerwein HP, Fliers E, Kalsbeek A. A major role for perifornical orexin neurons in the control of glucose metabolism in rats. Diabetes 58: 1998‐2005, 2009.
 215.Yi CX, Sun N, Ackermans MT, Alkemade A, Foppen E, Shi J, Serlie MJ, Buijs RM, Fliers E, Kalsbeek A. Pituitary adenylate cyclase‐activating polypeptide stimulates glucose production via the hepatic sympathetic innervation in rats. Diabetes 59: 1591‐1600, 2010.
 216.Yi CX, la Fleur SE, Fliers E, Kalsbeek A. The role of the autonomic nervous liver innervation in the control of energy metabolism. Biochim Biophys Acta 1802: 416‐431, 2010.
 217.Yoneda M, Kono T, Watanobe H, Tamano M, Shimada T, Hiraishi H, Nakamura K. Central thyrotropin‐releasing hormone increases hepatic cyclic AMP through vagal‐cholinergic and prostaglandin‐dependent pathways in rats. Peptides 26: 1573‐1579, 2005.
 218.Yoshida Y, Fujiki N, Nakajima T, Ripley B, Matsumura H, Yoneda H, Mignot E, Nishino S. Fluctuation of extracellular hypocretin‐1 (orexin A) levels in the rat in relation to the light‐dark cycle and sleep‐wake activities. Eur J Neurosci 14: 1075‐1081, 2001.
 219.Zakrzewska KE, Cusin I, Stricker‐Krongrad A, Boss O, Ricquier D, Jeanrenaud B, Rohner‐Jeanrenaud F. Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat. Diabetes 48: 365‐370, 1999.
 220.Zakrzewska KE, Sainsbury A, Cusin I, Rouru J, Jeanrenaud B, Rohnerjeanrenaud F. Selective dependence of intracerebroventricular neuropeptide Y‐ elicited effects on central glucocorticoids. Endocrinology 14009427: 3183‐3187, 1999.
 221.Zarjevski N, Cusin I, Vettor R, Rohner‐Jeanrenaud F, Jeanrenaud B. Chronic intracerebroventricular neuropeptide‐Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology 13304124: 1753‐1758, 1993.
 222.Zeng H, Schimpf BA, Rohde AD, Pavlova MN, Gragerov A, Bergmann JE. Thyrotropin‐releasing hormone receptor 1‐deficient mice display increased depression and anxiety‐like behavior. Mol Endocrinol 21: 2795‐2804, 2007.
 223.Zhang G, Bai H, Zhang H, Dean C, Wu Q, Li J, Guariglia S, Meng Q, Cai D. Neuropeptide exocytosis involving synaptotagmin‐4 and oxytocin in hypothalamic programming of body weight and energy balance. Neuron 69: 523‐535, 2011.
 224.Zhang G, Cai D. Circadian intervention of obesity development via resting‐stage feeding manipulation or oxytocin treatment. Am J Physiol Endocrinol Metab 301: E1004‐E1012, 2011.
 225.Zhang LN, Sinclair R, Selman C, Mitchell S, Morgan D, Clapham JC, Speakman JR. Effects of a specific MCHR1 antagonist (GW803430) on energy budget and glucose metabolism in diet‐induced obese mice. Obesity (Silver Spring) 22: 681‐690, 2014.
 226.Zhang S, Zeitzer JM, Yoshida Y, Wisor JP, Nishino S, Edgar DM, Mignot E. Lesions of the suprachiasmatic nucleus eliminate the daily rhythm of hypocretin‐1 release. Sleep 27: 619‐627, 2004.

Related Articles:

Diabetes and Obesity

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Peter H. Bisschop, Eric Fliers, Andries Kalsbeek. Autonomic Regulation of Hepatic Glucose Production. Compr Physiol 2014, 5: 147-165. doi: 10.1002/cphy.c140009