Expanding neurotransmitters in the hypothalamic neurocircuitry for energy balance regulation

Yuanzhong Xu1, Qingchun Tong1,2()

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Protein Cell ›› 2011, Vol. 2 ›› Issue (10) : 800-813. DOI: 10.1007/s13238-011-1112-4
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Expanding neurotransmitters in the hypothalamic neurocircuitry for energy balance regulation

  • Yuanzhong Xu1, Qingchun Tong1,2()
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Abstract

The current epidemic of obesity and its associated metabolic syndromes impose unprecedented challenges to our society. Despite intensive research on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of the leptin neural pathway in the hypothalamus in the regulation of body weight homeostasis. Important hypothalamic neuropeptides have been identified as critical neurotransmitters from leptin-sensitive neurons to mediate leptin action. Recent research advance has significantly expanded the list of neurotransmitters involved in body weight-regulating neural pathways, including fast-acting neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate. Given the limited knowledge on the leptin neural pathway for body weight homeostasis, understanding the function of neurotransmitters released from key neurons for energy balance regulation is essential for delineating leptin neural pathway and eventually for designing effective therapeutic drugs against the obesity epidemic.

Keywords

obesity / leptin / neurotransmitter / hypothalamus

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Yuanzhong Xu, Qingchun Tong. Expanding neurotransmitters in the hypothalamic neurocircuitry for energy balance regulation. Prot Cell, 2011, 2(10): 800‒813 https://doi.org/10.1007/s13238-011-1112-4

References

[1] Adamantidis, A., Carter, M.C., and de Lecea, L. (2010). Optogenetic deconstruction of sleep-wake circuitry in the brain. Front Mol Neurosci 2, 31.20126433
[2] Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., and Flier, J.S. (1996). Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252. PMID:8717038.
[3] Alexander, G.M., Rogan, S.C., Abbas, A.I., Armbruster, B.N., Pei, Y., Allen, J.A., Nonneman, R.J., Hartmann, J., Moy, S.S., Nicolelis, M.A., (2009). Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63, 27–39. 19607790
[4] Aponte, Y., Atasoy, D., and Sternson, S.M. (2011). AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 14, 351–355. 21209617
[5] Balthasar, N., Coppari, R., McMinn, J., Liu, S.M., Lee, C.E., Tang, V., Kenny, C.D., McGovern, R.A., Chua, S.C. Jr, Elmquist, J.K., (2004). Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983–991. 15207242
[6] Bates, S.H., and Myers, M.G. Jr. (2003). The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrinol Metab 14, 447–452. 14643059
[7] Berthoud, H.R., and Morrison, C. (2008). The brain, appetite, and obesity. Annu Rev Psychol 59, 55–92. 18154499
[8] Bj?rbaek, C., and Kahn, B.B. (2004). Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 59, 305–331. 14749508
[9] Blevins, J.E., Schwartz, M.W., and Baskin, D.G. (2004). 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. 15044184
[10] Blouet, C., and Schwartz, G.J. (2010). Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res 209, 1–12. 20035790
[11] Bouret, S.G. (2010). Neurodevelopmental actions of leptin. Brain Res 1350, 2–9 20399755.
[12] Bouret, S.G., Draper, S.J., and Simerly, R.B. (2004a). Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 24, 2797–2805. 15028773
[13] Bouret, S.G., Draper, S.J., and Simerly, R.B. (2004b). Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110. 15064420
[14] Breen, T.L., Conwell, I.M., and Wardlaw, S.L. (2005). Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus. Brain Res 1032, 141–148. 15680952
[15] Brobeck, J.R. (1946). Mechanism of the development of obesity in animals with hypothalamic lesions. Physiol Rev 26, 541–559. 21002972
[16] Broberger, C., Johansen, J., Johansson, C., Schalling, M., and H?kfelt, T. (1998). The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci U S A 95, 15043–15048. 9844012
[17] Buettner, C., Patel, R., Muse, E.D., Bhanot, S., Monia, B.P., McKay, R., Obici, S., and Rossetti, L. (2005). Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice. J Clin Invest 115, 1306–1313. 15864350
[18] Chao, P.T., Yang, L., Aja, S., Moran, T.H., and Bi, S. (2011). Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell Metab 13, 573–583. 21531339
[19] Chemelli, R.M., Willie, J.T., Sinton, C.M., Elmquist, J.K., Scammell, T., Lee, C., Richardson, J.A., Williams, S.C., Xiong, Y., Kisanuki, Y., (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451. 10481909
[20] Chen, H., Charlat, O., Tartaglia, L.A., Woolf, E.A., Weng, X., Ellis, S.J., Lakey, N.D., Culpepper, J., Moore, K.J., Breitbart, R.E., (1996). 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. 8608603
[21] Chen, H.Y., Trumbauer, M.E., Chen, A.S., Weingarth, D.T., Adams, J.R., Frazier, E.G., Shen, Z., Marsh, D.J., Feighner, S.D., Guan, X.M., (2004). Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 145, 2607–2612. 14962995
[22] Cheng, H., Isoda, F., Belsham, D.D., and Mobbs, C.V. (2008). Inhibition of agouti-related peptide expression by glucose in a clonal hypothalamic neuronal cell line is mediated by glycolysis, not oxidative phosphorylation. Endocrinology 149, 703–710. 17974626
[23] Choudhury, A.I., Heffron, H., Smith, M.A., Al-Qassab, H., Xu, A.W., Selman, C., Simmgen, M., Clements, M., Claret, M., Maccoll, G., (2005). The role of insulin receptor substrate 2 in hypothalamic and beta cell function. J Clin Invest 115, 940–950. 15841180
[24] Clément, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J., Lacorte, J.M., (1998). A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401. 9537324
[25] Cohen, P., Zhao, C., Cai, X., Montez, J.M., Rohani, S.C., Feinstein, P., Mombaerts, P., and Friedman, J.M. (2001). Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 108, 1113–1121 11602618.
[26] Coleman, D.L. (1973). Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294–298. 4767369
[27] Coleman, D.L., and Hummel, K.P. (1969). Effects of parabiosis of normal with genetically diabetic mice. Am J Physiol 217, 1298–1304. 5346292
[28] Coppari, R., Ichinose, M., Lee, C.E., Pullen, A.E., Kenny, C.D., McGovern, R.A., Tang, V., Liu, S.M., Ludwig, T., Chua, S.C. Jr, (2005). The hypothalamic arcuate nucleus: a key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell Metab 1, 63–72. 16054045
[29] Covey, S.D., Wideman, R.D., McDonald, C., Unniappan, S., Huynh, F., Asadi, A., Speck, M., Webber, T., Chua, S.C., and Kieffer, T.J. (2006). The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis. Cell Metab 4, 291–302. 17011502
[30] Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdán, M.G., Diano, S., Horvath, T.L., Cone, R.D., and Low, M.J. (2001). Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484. 11373681
[31] Cravo, R.M., Margatho, L.O., Osborne-Lawrence, S., Donato, J. Jr, Atkin, S., Bookout, A.L., Rovinsky, S., Fraz?o, R., Lee, C.E., Gautron, L., (2011). Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 173, 37–56. 21093546
[32] d’Anglemont de Tassigny, X., Fagg, L.A., Dixon, J.P., Day, K., Leitch, H.G., Hendrick, A.G., Zahn, D., Franceschini, I., Caraty, A., Carlton, M.B., (2007). Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci U S A 104, 10714–10719. 17563351
[33] de Luca, C., Kowalski, T.J., Zhang, Y., Elmquist, J.K., Lee, C., Kilimann, M.W., Ludwig, T., Liu, S.M., and Chua, S.C. Jr. (2005). Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest 115, 3484–3493. 16284652
[34] Deisseroth, K. (2011). Optogenetics. Nat Methods 8, 26–29 21191368.
[35] Denroche, H.C., Levi, J., Wideman, R.D., Sequeira, R.M., Huynh, F.K., Covey, S.D., and Kieffer, T.J. (2011). Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 60, 1414–1423. 21464443
[36] Dhillon, H., Zigman, J.M., Ye, C., Lee, C.E., McGovern, R.A., Tang, V., Kenny, C.D., Christiansen, L.M., White, R.D., Edelstein, E.A., (2006). Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203. 16423694
[37] Diester, I., Kaufman, M.T., Mogri, M., Pashaie, R., Goo, W., Yizhar, O., Ramakrishnan, C., Deisseroth, K., and Shenoy, K.V. (2011). An optogenetic toolbox designed for primates. Nat Neurosci 14, 387–397 21278729.
[38] Dungan Lemko, H.M., Clifton, D.K., Steiner, R.A., and Fraley, G.S. (2008). Altered response to metabolic challenges in mice with genetically targeted deletions of galanin-like peptide. Am J Physiol Endocrinol Metab 295, E605–E612. 18775887
[39] Ebihara, S., Obata, K., and Yanagawa, Y. (2003). Mouse vesicular GABA transporter gene: genomic organization, transcriptional regulation and chromosomal localization. Brain Res Mol Brain Res 110, 126–139. 12573541
[40] Elias, C.F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R.S., Bjorbaek, C., Flier, J.S., Saper, C.B., and Elmquist, J.K. (1999). Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786. 10482243
[41] Elmquist, J.K., Coppari, R., Balthasar, N., Ichinose, M., and Lowell, B.B. (2005). Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 493, 63–71. 16254991
[42] Enriori, P.J., Sinnayah, P., Simonds, S.E., Garcia Rudaz, C., and Cowley, M.A. (2011). Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J Neurosci 31, 12189–12197. 21865462
[43] Erdmann, G., Schütz, G., and Berger, S. (2007). Inducible gene inactivation in neurons of the adult mouse forebrain. BMC Neurosci 8, 63.17683525
[44] Faouzi, M., Leshan, R., Bj?rnholm, M., Hennessey, T., Jones, J., and M?nzberg, H. (2007). Differential accessibility of circulating leptin to individual hypothalamic sites. Endocrinology 148, 5414–5423. 17690165
[45] Fenno, L., Yizhar, O., and Deisseroth, K. (2011). The development and application of optogenetics. Annu Rev Neurosci 34, 389–412. 21692661
[46] Ferguson, S.M., Eskenazi, D., Ishikawa, M., Wanat, M.J., Phillips, P.E., Dong, Y., Roth, B.L., and Neumaier, J.F. (2011). Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci 14, 22–24. 21131952
[47] Flier, J.S. (2004). Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350. 14744442
[48] Flier, J.S. (2006). AgRP in energy balance: Will the real AgRP please stand up? Cell Metab 3, 83–85. 16459309
[49] Flier, J.S., and Maratos-Flier, E. (2010). Lasker lauds leptin. Cell 143, 9–12. 20887884
[50] Fraley, G.S., Scarlett, J.M., Shimada, I., Teklemichael, D.N., Acohido, B.V., Clifton, D.K., and Steiner, R.A. (2004). Effects of diabetes and insulin on the expression of galanin-like peptide in the hypothalamus of the rat. Diabetes 53, 1237–1242. 15111492
[51] Fremeau, R.T. Jr, Kam, K., Qureshi, T., Johnson, J., Copenhagen, D.R., Storm-Mathisen, J., Chaudhry, F.A., Nicoll, R.A., and Edwards, R.H. (2004). Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science 304, 1815–1819. 15118123
[52] Fujikawa, T., Chuang, J.C., Sakata, I., Ramadori, G., and Coppari, R. (2010). Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107, 17391–17396. 20855609
[53] Garcia, E.L., and Mills, A.A. (2002). Getting around lethality with inducible Cre-mediated excision. Semin Cell Dev Biol 13, 151–158. 12127267
[54] Gasnier, B. (2004). The SLC32 transporter, a key protein for the synaptic release of inhibitory amino acids. Pflugers Arch 447, 756–759. 12750892
[55] Gavériaux-Ruff, C., and Kieffer, B.L. (2007). Conditional gene targeting in the mouse nervous system: Insights into brain function and diseases. Pharmacol Ther 113, 619–634. 17289150
[56] German, J.P., Thaler, J.P., Wisse, B.E., Oh-I, S., Sarruf, D.A., Matsen, M.E., Fischer, J.D., Taborsky, G.J. Jr, Schwartz, M.W., and Morton, G.J. (2011). Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology 152, 394–404. 21159853
[57] Ghamari-Langroudi, M., Srisai, D., and Cone, R.D. (2011). Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin. Proc Natl Acad Sci U S A 108, 355–360. 21169216
[58] Hawke, Z., Ivanov, T.R., Bechtold, D.A., Dhillon, H., Lowell, B.B., and Luckman, S.M. (2009). PACAP neurons in the hypothalamic ventromedial nucleus are targets of central leptin signaling. J Neurosci 29, 14828–14835. 19940178
[59] Hill, J.W., Elmquist, J.K., and Elias, C.F. (2008). Hypothalamic pathways linking energy balance and reproduction. Am J Physiol Endocrinol Metab 294, E827–E832. 18285524
[60] Hunter, R.G., Philpot, K., Vicentic, A., Dominguez, G., Hubert, G.W., and Kuhar, M.J. (2004). CART in feeding and obesity. Trends Endocrinol Metab 15, 454–459. 15519893
[61] Huo, L., Gamber, K., Greeley, S., Silva, J., Huntoon, N., Leng, X.H., and Bj?rbaek, C. (2009). Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab 9, 537–547. 19490908
[62] Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., (1997). Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141. 9019399
[63] Juréus, A., Cunningham, M.J., McClain, M.E., Clifton, D.K., and Steiner, R.A. (2000). Galanin-like peptide (GALP) is a target for regulation by leptin in the hypothalamus of the rat. Endocrinology 141, 2703–2706. 10875277
[64] Kalra, S.P., Dube, M.G., Pu, S., Xu, B., Horvath, T.L., and Kalra, P.S. (1999). Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 20, 68–100. 10047974
[65] Kalra, S.P., and Kalra, P.S. (2004). NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy. Neuropeptides 38, 201–211. 15337372
[66] Kalra, S.P., and Kalra, P.S. (2010). Neuroendocrine control of energy homeostasis: update on new insights. Prog Brain Res 181, 17–33. 20478430.
[67] Kirchgessner, A.L., and Sclafani, A. (1988). PVN-hindbrain pathway involved in the hypothalamic hyperphagia-obesity syndrome. Physiol Behav 42, 517–528. 3166142
[68] Kong, D., Vong, L., Parton, L.E., Ye, C., Tong, Q., Hu, X., Choi, B., Brüning, J.C., and Lowell, B.B. (2010). Glucose stimulation of hypothalamic MCH neurons involves K(ATP) channels, is modulated by UCP2, and regulates peripheral glucose homeostasis. Cell Metab 12, 545–552. 21035764
[69] K?nner, A.C., Janoschek, R., Plum, L., Jordan, S.D., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G.S., (2007). Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5, 438–449. 17550779
[70] Krashes, M.J., Koda, S., Ye, C., Rogan, S.C., Adams, A.C., Cusher, D.S., Maratos-Flier, E., Roth, B.L., and Lowell, B.B. (2011). Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121, 1424–1428. 21364278
[71] Kristensen, P., Judge, M.E., Thim, L., Ribel, U., Christjansen, K.N., Wulff, B.S., Clausen, J.T., Jensen, P.B., Madsen, O.D., Vrang, N., (1998). Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72–76. 9590691
[72] Kruger, A.J., Yang, C., Lipson, K.L., Pino, S.C., Leif, J.H., Hogan, C.M., Whalen, B.J., Guberski, D.L., Lee, Y., Unger, R.H., (2011). Leptin treatment confers clinical benefit at multiple stages of virally induced type 1 diabetes in BB rats. Autoimmunity 44, 137–148. 20695765
[73] Kublaoui, B.M., Gemelli, T., Tolson, K.P., Wang, Y., and Zinn, A.R. (2008). Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. Mol Endocrinol 22, 1723–1734. 18451093
[74] Kubota, N., Terauchi, Y., Tobe, K., Yano, W., Suzuki, R., Ueki, K., Takamoto, I., Satoh, H., Maki, T., Kubota, T., (2004). Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. J Clin Invest 114, 917–927. 15467830
[75] Lam, T.K., Gutierrez-Juarez, R., Pocai, A., and Rossetti, L. (2005a). Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943–947. 16081739
[76] Lam, T.K., Schwartz, G.J., and Rossetti, L. (2005b). Hypothalamic sensing of fatty acids. Nat Neurosci 8, 579–584. 15856066
[77] Lee, G.H., Proenca, R., Montez, J.M., Carroll, K.M., Darvishzadeh, J.G., Lee, J.I., and Friedman, J.M. (1996). Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 8628397.
[78] Leinninger, G.M. (2011). Lateral thinking about leptin: a review of leptin action via the lateral hypothalamus. Physiol Behav 104, 572–581. 21550356
[79] Leinninger, G.M., Jo, Y.H., Leshan, R.L., Louis, G.W., Yang, H., Barrera, J.G., Wilson, H., Opland, D.M., Faouzi, M.A., Gong, Y., (2009). Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab 10, 89–98. 19656487
[80] Lin, X., Taguchi, A., Park, S., Kushner, J.A., Li, F., Li, Y., and White, M.F. (2004). Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J Clin Invest 114, 908–916. 15467829
[81] Lin, Y., Hall, R.A., and Kuhar, M.J. (2011). CART peptide stimulation of G protein-mediated signaling in differentiated PC12 Cells: Identification of PACAP 6-38 as a CART receptor antagonist. Neuropeptides . [Epub ahead of print]. 2011Aug19.
[82] Lorden, J.F., and Caudle, A. (1986). Behavioral and endocrinological effects of single injections of monosodium glutamate in the mouse. Neurobehav Toxicol Teratol 8, 509–519. 3785512
[83] Louis, G.W., Greenwald-Yarnell, M., Phillips, R., Coolen, L.M., Lehman, M.N., and Myers, M.G. Jr. (2011). Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 152, 2302–2310. 21427219
[84] Luquet, S., Perez, F.A., Hnasko, T.S., and Palmiter, R.D. (2005). NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685. 16254186
[85] Marino, J.S., Xu, Y., and Hill, J.W. (2011). Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol Metab 22, 275–285. 21489811
[86] McIntire, S.L., Reimer, R.J., Schuske, K., Edwards, R.H., and Jorgensen, E.M. (1997). Identification and characterization of the vesicular GABA transporter. Nature 389, 870–876. 9349821
[87] Mezey, E., Kiss, J.Z., Mueller, G.P., Eskay, R., O’Donohue, T.L., and Palkovits, M. (1985). Distribution of the pro-opiomelanocortin derived peptides, adrenocorticotrope hormone, alpha-melanocyte-stimulating hormone and beta-endorphin (ACTH, alpha-MSH, beta-END) in the rat hypothalamus. Brain Res 328, 341–347. 2985184
[88] Mineur, Y.S., Abizaid, A., Rao, Y., Salas, R., DiLeone, R.J., Gündisch, D., Diano, S., De Biasi, M., Horvath, T.L., Gao, X.B., (2011). Nicotine decreases food intake through activation of POMC neurons. Science 332, 1330–1332. 21659607
[89] Montague, C.T., Farooqi, I.S., Whitehead, J.P., Soos, M.A., Rau, H., Wareham, N.J., Sewter, C.P., Digby, J.E., Mohammed, S.N., Hurst, J.A., (1997). Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908. 9202122
[90] Morris, D.L., and Rui, L. (2009). Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 297, E1247–E1259. 19724019
[91] Morrison, C.D., and Berthoud, H.R. (2007). Neurobiology of nutrition and obesity. Nutr Rev 65, 517–534. 18236691
[92] Morton, G.J. (2007). Hypothalamic leptin regulation of energy homeostasis and glucose metabolism. J Physiol 583, 437–443. 17584844
[93] Myers, M.G. Jr, Leibel, R.L., Seeley, R.J., and Schwartz, M.W. (2010). Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab 21, 643–651. 20846876
[94] Myers, M.G. Jr, Münzberg, H., Leinninger, G.M., and Leshan, R.L. (2009). The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab 9, 117–123. 19187770
[95] Obici, S., Feng, Z., Karkanias, G., Baskin, D.G., and Rossetti, L. (2002a). Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5, 566–572. 12021765
[96] Obici, S., Zhang, B.B., Karkanias, G., and Rossetti, L. (2002b). Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8, 1376–1382. 12426561
[97] Ohtaki, T., Kumano, S., Ishibashi, Y., Ogi, K., Matsui, H., Harada, M., Kitada, C., Kurokawa, T., Onda, H., and Fujino, M. (1999). Isolation and cDNA cloning of a novel galanin-like peptide (GALP) from porcine hypothalamus. J Biol Chem 274, 37041–37045. 10601261
[98] Okamoto, H., Obici, S., Accili, D., and Rossetti, L. (2005). Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J Clin Invest 115, 1314–1322. 15864351
[99] Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., Gantz, I., and Barsh, G.S. (1997). Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138. 9311920
[100] Padilla, S.L., Carmody, J.S., and Zeltser, L.M. (2010). Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat Med 16, 403–405. 20348924
[101] Parton, L.E., Ye, C.P., Coppari, R., Enriori, P.J., Choi, B., Zhang, C.Y., Xu, C., Vianna, C.R., Balthasar, N., Lee, C.E., (2007). Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228–232. 17728716
[102] Patel, S.B., Reams, G.P., Spear, R.M., Freeman, R.H., and Villarreal, D. (2008). Leptin: linking obesity, the metabolic syndrome, and cardiovascular disease. Curr Hypertens Rep 10, 131–137. 18474180
[103] Patterson, C.M., Leshan, R.L., Jones, J.C., and Myers, M.G. Jr. (2011). Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells. Brain Res 1378, 18–28. 21237139
[104] Pissios, P., Frank, L., Kennedy, A.R., Porter, D.R., Marino, F.E., Liu, F.F., Pothos, E.N., and Maratos-Flier, E. (2008). Dysregulation of the mesolimbic dopamine system and reward in MCH-/- mice. Biol Psychiatry 64, 184–191. 18281019
[105] Plum, L., Lin, H.V., Dutia, R., Tanaka, J., Aizawa, K.S., Matsumoto, M., Kim, A.J., Cawley, N.X., Paik, J.H., Loh, Y.P., (2009). The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat Med 15, 1195–1201. 19767734
[106] Pocai, A., Lam, T.K., Gutierrez-Juarez, R., Obici, S., Schwartz, G.J., Bryan, J., Aguilar-Bryan, L., and Rossetti, L. (2005). Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434, 1026–1031. 15846348
[107] Qian, S., Chen, H., Weingarth, D., Trumbauer, M.E., Novi, D.E., Guan, X., Yu, H., Shen, Z., Feng, Y., Frazier, E., (2002). Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol 22, 5027–5035. 12077332
[108] Qu, D., Ludwig, D.S., Gammeltoft, S., Piper, M., Pelleymounter, M.A., Cullen, M.J., Mathes, W.F., Przypek, R., Kanarek, R., and Maratos-Flier, E. (1996). A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380, 243–247. 8637571
[109] Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., Williams, S.C., Richardson, J.A., Kozlowski, G.P., Wilson, S., (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585. 9491897
[110] Schulz, C., Paulus, K., Lobmann, R., Dallman, M., and Lehnert, H. (2010). Endogenous ACTH, not only alpha-melanocyte-stimulating hormone, reduces food intake mediated by hypothalamic mechanisms. Am J Physiol Endocrinol Metab 298, E237–E244. 19920221
[111] Schwartz, M.W., Seeley, R.J., Campfield, L.A., Burn, P., and Baskin, D.G. (1996). Identification of targets of leptin action in rat hypothalamus. J Clin Invest 98, 1101–1106. 8787671
[112] Scott, M.M., Lachey, J.L., Sternson, S.M., Lee, C.E., Elias, C.F., Friedman, J.M., and Elmquist, J.K. (2009). Leptin targets in the mouse brain. J Comp Neurol 514, 518–532. 19350671
[113] Shiba, K., Kageyama, H., Takenoya, F., and Shioda, S. (2010). Galanin-like peptide and the regulation of feeding behavior and energy metabolism. FEBS J 277, 5006–5013. 21126314
[114] Shimada, M., Tritos, N.A., Lowell, B.B., Flier, J.S., and Maratos-Flier, E. (1998). Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396, 670–674. 9872314
[115] Song, J., Xu, Y., Hu, X., Choi, B., and Tong, Q. (2010). Brain expression of Cre recombinase driven by pancreas-specific promoters. Genesis 48, 628–634. 20824628
[116] Song, Z., and Routh, V.H. (2005). Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54, 15–22. 15616006
[117] Stubbusch, J., Majdazari, A., Schmidt, M., Schutz, G., Deller, T., and Rohrer, H. (2011). Generation of the tamoxifen-inducible DBH-Cre transgenic mouse line DBH-CT. Genesis . 2011Jun1. [Epub ahead of print].doi: 10.1002/dvg.20773.
[118] Sudhof, T.C. (2004). The synaptic vesicle cycle. Annu Rev Neurosci 27, 509–547. 15217342
[119] Swinburn, B.A., Sacks, G., Hall, K.D., McPherson, K., Finegood, D.T., Moodie, M.L., and Gortmaker, S.L. (2011). The global obesity pandemic: shaped by global drivers and local environments. Lancet 378, 804–814. 21872749
[120] Takahashi, K.A., and Cone, R.D. (2005). Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/Agouti-related protein neurons. Endocrinology 146, 1043–1047. 15591135
[121] Takeda, S., Elefteriou, F., and Karsenty, G. (2003). Common endocrine control of body weight, reproduction, and bone mass. Annu Rev Nutr 23, 403–411. 12730321
[122] Teitelbaum, P., and Epstein, A.N. (1962). The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychol Rev 69, 74–90. 13920110
[123] Tong, Q. (2011). Synaptotagmin 4: a new antiobesity target? Neuron 69, 401–403. 21315251
[124] Tong, Q., Ye, C., McCrimmon, R.J., Dhillon, H., Choi, B., Kramer, M.D., Yu, J., Yang, Z., Christiansen, L.M., Lee, C.E., (2007). Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab 5, 383–393. 17488640
[125] Tong, Q., Ye, C.P., Jones, J.E., Elmquist, J.K., and Lowell, B.B. (2008). Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 11, 998–1000. 19160495
[126] Touzani, K., and Velley, L. (1992). Ibotenic acid lesion of the hypothalamic paraventricular nucleus produces weight gain but modifies neither preference nor aversion for saccharin. Physiol Behav 52, 673–678. 1409938
[127] Unger, T.J., Calderon, G.A., Bradley, L.C., Sena-Esteves, M., and Rios, M. (2007). Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J Neurosci 27, 14265–14274. 18160634
[128] van de Wall, E., Leshan, R., Xu, A.W., Balthasar, N., Coppari, R., Liu, S.M., Jo, Y.H., MacKenzie, R.G., Allison, D.B., Dun, N.J., (2008). Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149, 1773–1785. 18162515
[129] van den Pol, A.N. (2003). Weighing the role of hypothalamic feeding neurotransmitters. Neuron 40, 1059–1061. 14687541
[130] Venihaki, M., and Majzoub, J.A. (1999). Animal models of CRH deficiency. Front Neuroendocrinol 20, 122–145. 10328987
[131] Vong, L., Ye, C., Yang, Z., Choi, B., Chua, S. Jr, and Lowell, B.B. (2011). Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154. 21745644
[132] Wang, M.Y., Chen, L., Clark, G.O., Lee, Y., Stevens, R.D., Ilkayeva, O.R., Wenner, B.R., Bain, J.R., Charron, M.J., Newgard, C.B., (2010). Leptin therapy in insulin-deficient type I diabetes. Proc Natl Acad Sci U S A 107, 4813–4819. 20194735
[133] Wang, Y.C., McPherson, K., Marsh, T., Gortmaker, S.L., and Brown, M. (2011). Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378, 815–825. 21872750
[134] Wierup, N., Richards, W.G., Bannon, A.W., Kuhar, M.J., Ahrén, B., and Sundler, F. (2005). CART knock out mice have impaired insulin secretion and glucose intolerance, altered beta cell morphology and increased body weight. Regul Pept 129, 203–211. 15927717
[135] Williams, K.W., Margatho, L.O., Lee, C.E., Choi, M., Lee, S., Scott, M.M., Elias, C.F., and Elmquist, J.K. (2010). Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci 30, 2472–2479. 20164331
[136] Wojcik, S.M., Rhee, J.S., Herzog, E., Sigler, A., Jahn, R., Takamori, S., Brose, N., and Rosenmund, C. (2004). An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size. Proc Natl Acad Sci U S A 101, 7158–7163. 15103023
[137] Wolfe, A., Divall, S., Singh, S.P., Nikrodhanond, A.A., Baria, A.T., Le, W.W., Hoffman, G.E., and Radovick, S. (2008). Temporal and spatial regulation of CRE recombinase expression in gonadotrophin-releasing hormone neurones in the mouse. J Neuroendocrinol 20, 909–916. 18445125
[138] Wu, Q., Boyle, M.P., and Palmiter, R.D. (2009). Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137, 1225–1234. 19563755
[139] Wu, Q., Howell, M.P., Cowley, M.A., and Palmiter, R.D. (2008). Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc Natl Acad Sci U S A 105, 2687–2692. 18272480
[140] Xu, A.W., Kaelin, C.B., Takeda, K., Akira, S., Schwartz, M.W., and Barsh, G.S. (2005). PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115, 951–958. 15761497
[141] Xu, B., Goulding, E.H., Zang, K., Cepoi, D., Cone, R.D., Jones, K.R., Tecott, L.H., and Reichardt, L.F. (2003). Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6, 736–742. 12796784
[142] Xu, Y., Berglund, E.D., Sohn, J.W., Holland, W.L., Chuang, J.C., Fukuda, M., Rossi, J., Williams, K.W., Jones, J.E., Zigman, J.M., (2010). 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nat Neurosci 13, 1457–1459. 21037584
[143] Yamada, M., Satoh, T., and Mori, M. (2003). Mice lacking the thyrotropin-releasing hormone gene: what do they tell us? Thyroid 13, 1111–1121. 14751031
[144] Yang, Y., Atasoy, D., Su, H.H., and Sternson, S.M. (2011). Hunger States Switch a Flip-Flop Memory Circuit via a Synaptic AMPK-Dependent Positive Feedback Loop. Cell 146, 992–1003. 21925320
[145] Yaswen, L., Diehl, N., Brennan, M.B., and Hochgeschwender, U. (1999). Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 5, 1066–1070. 10470087
[146] Yeo, G.S., Farooqi, I.S., Aminian, S., Halsall, D.J., Stanhope, R.G., and O’Rahilly, S. (1998). A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20, 111–112. 9771698
[147] Yu, X., Park, B.H., Wang, M.Y., Wang, Z.V., and Unger, R.H. (2008). Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A 105, 14070–14075. 18779578
[148] Zhang, G., Bai, H., Zhang, H., Dean, C., Wu, Q., Li, J., Guariglia, S., Meng, Q., and Cai, D. (2011a). Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance. Neuron 69, 523–535. 21315262
[149] Zhang, Y., Kerman, I.A., Laque, A., Nguyen, P., Faouzi, M., Louis, G.W., Jones, J.C., Rhodes, C., and Münzberg, H. (2011b). Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J Neurosci 31, 1873–1884. 21289197
[150] Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J.M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432. 7984236
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