A variety of circulating signals provide essential information to the central nervous system (CNS) regarding nutritional status. The gastrointestinal system produces many such molecules that are now known to have profound effects on feeding behavior and the control of metabolism as a consequence of their ability to regulate the neural circuitry involved in metabolic homeostasis. Although many of these substances have been suggested to directly access such brain centers, their lipophobic characteristics suggest that alternative mechanisms should be considered. In this paper, we consider one such alternative, namely, that a specialized group of CNS structures collectively known as the sensory circumventricular organs (CVOs), which are not protected by the normal blood–brain barrier, may play important roles in such blood to brain communications. Specifically, we review a developing literature that shows receptors for, and functional actions of, gastrointestinal hormones such as amylin, cholecystokinin, ghrelin and peptide YY in the area postrema and subfornical organ. Collectively, these observations suggest potentially significant roles for the sensory CVOs in the regulation of energy balance.
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Badman MK, Flier JS . The gut and energy balance: visceral allies in the obesity wars. Science 2005; 307: 1909–1914.
Murphy KG, Bloom SR . Gut hormones and the regulation of energy homeostasis. Nature 2006; 444: 854–859.
Kastin AJ, Pan W, Maness LM, Banks WA . Peptides crossing the blood–brain barrier: some unusual observations. Brain Res 1999; 848: 96–100.
Janigro D, West GA, Nguyen TS, Winn HR . Regulation of blood–brain barrier endothelial cells by nitric oxide. Circ Res 1994; 75: 528–538.
Paton JF, Deuchars J, Ahmad Z, Wong LF, Murphy D, Kasparov S . Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat. J Physiol 2001; 531: 445–458.
Banks WA, Kastin AJ . Bidirectional passage of peptides across the blood–brain barrier. Prog Brain Res 1992; 91: 139–148.
Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM . Leptin enters the brain by a saturable system independent of insulin. Peptides 1996; 17: 305–311.
Shaver SW, Pang JJ, Wainman DS, Wall KM, Gross PM . Morphology and function of capillary networks in subregions of the rat tuber cinereum. Cell Tissue Res 1992; 267: 437–448.
Krisch B, Leonhardt H, Buchheim W . The functional and structural border between the CSF- and blood-milieu in the circumventricular organs (organum vasculosum laminae terminalis, subfornical organ, area postrema) of the rat. Cell Tissue Res 1978; 195: 485–497.
Petrov T, Howarth AG, Krukoff TL, Stevenson BR . Distribution of the tight junction-associated protein ZO-1 in circumventricular organs of the CNS. Brain Res Mol Brain Res 1994; 21: 235–246.
Rodriguez EM . The cerebrospinal fluid as a pathway in neuroendocrine integration. J Endocrinol 1976; 71: 407–443.
Broadwell RD, Brightman MW . Entry of peroxidase into neurons of the central and periferal nervous systems from extracerebral and cerebral blood. J Comp Neurol 1976; 166: 257–283.
Cheunsuang O, Morris R . Astrocytes in the arcuate nucleus and median eminence that take up a fluorescent dye from the circulation express leptin receptors and neuropeptide Y Y1 receptors. Glia 2005; 52: 228–233.
Cheunsuang O, Stewart AL, Morris R . Differential uptake of molecules from the circulation and CSF reveals regional and cellular specialisation in CNS detection of homeostatic signals. Cell Tissue Res 2006; 325: 397–402.
Gross PM . Circumventricular organ capillaries. Prog Brain Res 1992; 91: 219–233.
McKinley MJ, McAllen RM, Davern P, Giles ME, Penschow J, Sunn N et al. The sensory circumventricular organs of the mammalian brain. Adv Anat Embryol Cell Biol 2003; 172: 1–122.
Carlberg M, Gundlach AL, Mercer LD, Beart PM . Autoradiographic localization of cholecystokinin A and B receptors in rat brain using d-Tyr25 (Nle28,31)-CCK 25–33S. Eur J Neurosci 1992; 4: 563–573.
Christopoulos G, Paxinos G, Huang XF, Beaumont K, Toga AW, Sexton PM . Comparative distribution of receptors for amylin and the related peptides calcitonin gene related peptide and calcitonin in rat and monkey brain. Can J Physiol Pharmacol 1995; 73: 1037–1041.
Göke R, Larsen PJ, Mikkelsen JD, Sheikh SP . Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci 1995; 7: 2294–2300.
Hyde TM, Peroutka SJ . Distribution of cholecystokinin receptors in the dorsal vagal complex and other selected nuclei in the human medulla. Brain Res 1989; 495: 198–202.
Pulman KJ, Fry WM, Cottrell GT, Ferguson AV . The subfornical organ: a central target for circulating feeding signals. J Neurosci 2006; 26: 2022–2030.
Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK . Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 2006; 494: 528–548.
Ferguson AV, Day TA, Renaud LP . Subfornical organ stimulation excites paraventricular neurons projecting to dorsal medulla. Am J Physiol 1984; 247: R1088–R1092.
Ferguson AV, Kasting NW . Electrical stimulation in the subfornical organ increases plasma vasopressin concentrations in the conscious rat. Am J Physiol 1986; 251: R422–R428.
Ferguson AV, Plotsky PM . A role for the subfornical organ in the control of ACTH secretion. Fed Proc 1987; 30: 127.
Mangiapane ML, Simpson JB . Subfornical organ: forebrain site of pressor and dipsogenic action of angiotensin II. Am J Physiol 1980; 239: R382–R389.
Plotsky PM, Sutton SW, Bruhn TO, Ferguson AV . Analysis of the role of angiotensin II in the mediation of adrenocorticotropin secretion. Endocrinology 1988; 122: 538–545.
Lind RW, Van Hoesen GW, Johnson AK . An HRP study of the connections of the subfornical organ of the rat. J Comp Neurol 1982; 210: 265–277.
Miselis RR . The efferent projections of the subfornical organ of the rat: a circumventricular organ within a neural network subserving water balance. Brain Res 1981; 230: 1–23.
Lindstrom PA, Brizzee KR . Relief of intractable vomiting from surgical lesions in the area postrema. J Neurosurg 1962; 19: 228–236.
Cowley Jr AW, Monos E, Guyton AC . Interaction of vasopressin and the baroreceptor reflex system in the regulation of arterial blood pressure in the dog. Circ Res 1974; 34: 505–514.
Undesser KP, Hasser EM, Haywood JR, Johnson AK, Bishop VS . Interactions of vasopressin with the area postrema in arterial baroreflex function in conscious rabbits. Circ Res 1985; 56: 410–417.
Bickerton RK, Buckley JP . Evidence for a central mechanism in angiotensin induced hypertension. Proc Soc Exp Biol Med 1961; 106: 834.
Joy MD, Lowe RD . The site of cardiovascular action of angiotensin II in the brain. Clin Sci 1970; 39: 327–336.
Shapiro RE, Miselis RR . The central neural connections of the area postrema of the rat. J Comp Neurol 1985; 234: 344–364.
van der Kooy D, Koda LY . Organization of the projections of a circumventricular organ: the area postrema in the rat. J Comp Neurol 1983; 219: 328–338.
Hyde TM, Miselis RR . Effects of area postrema/caudal medial nucleus of solitary tract lesions on food intake and body weight. Am J Physiol 1983; 244: R577–R587.
Kenney NJ, Kott JN, Tomoyasu N, Bhatia AJ, Ruiz AS, McDowell MM . Body weight of rats following area postrema ablation: effect of early force-feeding. Am J Physiol 1989; 256: R939–R945.
Wang T, Edwards GL . Differential effects of dorsomedial medulla lesion size on ingestive behavior in rats. Am J Physiol 1997; 273: R1299–R1308.
Sun K, Ferguson AV . Cholecystokinin activates area postrema neurons in rat brain slices. Am J Physiol 1997; 272: R1625–R1630.
Yamamoto H, Kishi T, Lee CE, Choi BJ, Fang H, Hollenberg AN et al. Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites. J Neurosci 2003; 23: 2939–2946.
Rowland NE, Crews EC, Gentry RM . Comparison of Fos induced in rat brain by GLP-1 and amylin. Regul Pept 1997; 71: 171–174.
Riediger T, Rauch M, Schmid HA . Actions of amylin on subfornical organ neurons and on drinking behavior in rats. Am J Physiol 1999; 276: R514–R521.
Riediger T, Schmid HA, Lutz TA, Simon E . Amylin and glucose co-activate area postrema neurons of the rat. Neurosci Lett 2002; 328: 121–124.
Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS . A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001; 50: 1714–1719.
Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37: 649–661.
Batterham RL, ffytche DH, Rosenthal JM, Zelaya FO, Barker GJ, Withers DJ et al. PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature 2007; 450: 106–109.
Trinh T, van Dumont Y, Quirion R . High levels of specific neuropeptide Y/pancreatic polypeptide receptors in the rat hypothalamus and brainstem. Eur J Pharmacol 1996; 318: R1–R3.
Iqbal J, Pompolo S, Murakami T, Grouzmann E, Sakurai T, Meister B et al. Immunohistochemical characterization of localization of long-form leptin receptor (OB-Rb) in neurochemically defined cells in the ovine hypothalamus. Brain Res 2001; 920: 55–64.
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Hoyda, T., Smith, P. & Ferguson, A. Gastrointestinal hormone actions in the central regulation of energy metabolism: potential sensory roles for the circumventricular organs. Int J Obes 33 (Suppl 1), S16–S21 (2009). https://doi.org/10.1038/ijo.2009.11
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