Hypothalamic-autonomic control of energy homeostasis

Endocrine

Volumn 50, Issue 2, 2015, Pages 276-291

  Seoane Collazo, Patricia ^a,b   Fernø, Johan ^a,c   Gonzalez, Francisco ^a,d   Diéguez, Carlos ^a,b   Leis, Rosaura ^e   Nogueiras, Rubén ^a,b   López, Miguel ^a,b  

^a UNIVERSITY OF SANTIAGO DE COMPOSTELA   (Spain)

^b Instituto de Salud Carlos III   (Spain)

^c UNIVERSITY OF BERGEN   (Norway)

^d HOSPITAL CLÍNICO UNIVERSITARIO   (Spain)

^e Instituto de Investigación Sanitaria de Santiago de Compostela IDIS   (Spain)

Author keywords

Autonomic nervous system; Energy balance; Hypothalamus

Indexed keywords

ESTROGEN; GHRELIN; INSULIN; THYROID HORMONE;

ADRENERGIC SYSTEM; AUTONOMIC NERVOUS SYSTEM FUNCTION; BROWN ADIPOSE TISSUE; CENTRAL NERVOUS SYSTEM; EFFERENT NERVE; ENERGY HOMEOSTASIS; GLUCAGON RELEASE; GLUCONEOGENESIS; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; HOMEOSTASIS; HORMONE ACTION; HUMAN; HYPOTHALAMUS FUNCTION; NEUROMODULATION; NONHUMAN; PANCREAS; PRIORITY JOURNAL; REVIEW; SECRETORY PATHWAY; SENSORY FEEDBACK; SENSORY NERVE; SENSORY SYSTEM; THERMOGENESIS; THERMOREGULATION; TISSUE DIFFERENTIATION; WHITE ADIPOSE TISSUE; AUTONOMIC NERVOUS SYSTEM; HYPOTHALAMUS; METABOLISM; PHYSIOLOGY;

AUTONOMIC NERVOUS SYSTEM; HOMEOSTASIS; HUMANS; HYPOTHALAMUS;

EID: 84945459176     PISSN: 1355008X     EISSN: 15590100     Source Type: Journal    
DOI: 10.1007/s12020-015-0658-y     Document Type: Review

References (215)

1. M.W. Schwartz, S.C. Woods, D. Porte Jr, R.J. Seeley, D.G. Baskin, Central nervous system control of food intake. Nature 404, 661–671 (2000)
2. G.J. Morton, D.E. Cummings, D.G. Baskin, G.S. Barsh, M.W. Schwartz, Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006)
3. M. Lopez, C.J. Lelliott, A. Vidal-Puig, Hypothalamic fatty acid metabolism: a housekeeping pathway that regulates food intake. BioEssays 29, 248–261 (2007)
4. K. Rahmouni, Obesity, sympathetic overdrive, and hypertension: the leptin connection. Hypertension 55, 844–845 (2010)
5. K. Rahmouni, Obesity-associated hypertension: recent progress in deciphering the pathogenesis. Hypertension 64, 215–221 (2014)
6. M.P.B. de Martinez, M. Lopez, “Mens sana in corpore sano”: exercise and hypothalamic ER stress. PLoS Biol. 8(8), e1000464 (2010)
7. D.B. Savage, K.F. Petersen, G.I. Shulman, Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol. Rev. 87, 507–520 (2007)
8. J. Park, T.S. Morley, M. Kim, D.J. Clegg, P.E. Scherer, Obesity and cancer—mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014)
9. R. Roubenoff, R.A. Roubenoff, J.G. Cannon, J.J. Kehayias, H. Zhuang, B. Dawson-Hughes, C.A. Dinarello, I.H. Rosenberg, Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest. 93, 2379–2386 (1994)
10. J.E. Morley, D.R. Thomas, M.M. Wilson, Cachexia: pathophysiology and clinical relevance. Am. J. Clin. Nutr. 83, 735–743 (2006)
11. S. Kir, J.P. White, S. Kleiner, L. Kazak, P. Cohen, V.E. Baracos, B.M. Spiegelman, Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513, 100–104 (2014)
12. M. Petruzzelli, M. Schweiger, R. Schreiber, R. Campos-Olivas, M. Tsoli, J. Allen, M. Swarbrick, S. Rose-John, M. Rincon, G. Robertson, R. Zechner, E.F. Wagner, A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 20, 433–447 (2014)
13. T.J. Bartness, Y.B. Shrestha, C.H. Vaughan, G.J. Schwartz, C.K. Song, Sensory and sympathetic nervous system control of white adipose tissue lipolysis. Mol. Cell. Endocrinol. 318, 34–43 (2010)
14. E. Fliers, L.P. Klieverik, A. Kalsbeek, Novel neural pathways for metabolic effects of thyroid hormone. Trends Endocrinol. Metab. 21, 230–236 (2010)
15. S.M. Harlan, K. Rahmouni, PI3K signaling: a key pathway in the control of sympathetic traffic and arterial pressure by leptin. Mol Metab. 2, 69–73 (2013)
16. R.M. Buijs, The autonomic nervous system: a balancing act. Handb Clin Neurol. 117, 1–11 (2013)
17. T.J. Bartness, C.H. Vaughan, C.K. Song, Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 34(Suppl 1), S36–S42 (2010)
18. K. Nonogaki, New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43, 533–549 (2000)
19. A. Giordano, C.K. Song, R.R. Bowers, J.C. Ehlen, A. Frontini, S. Cinti, T.J. Bartness, White adipose tissue lacks significant vagal innervation and immunohistochemical evidence of parasympathetic innervation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1243–R1255 (2006)
20. F. Kreier, R.M. Buijs, Evidence for parasympathetic innervation of white adipose tissue, clearing up some vagaries. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R548–R549 (2007)
21. L.P. Klieverik, S.F. Janssen, A. van Rial, E. Foppen, P.H. Bisschop, M.J. Serlie, A. Boelen, M.T. Ackermans, H.P. Sauerwein, E. Fliers, A. Kalsbeek, Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver. Proc. Natl. Acad. Sci. U.S.A. 106, 5966–5971 (2009)
22. C.X. Yi, S.E. la Fleur, E. Fliers, A. Kalsbeek, The role of the autonomic nervous liver innervation in the control of energy metabolism. Biochim. Biophys. Acta 1802, 416–431 (2010)
23. R. Rodriguez-Diaz, A. Caicedo, Neural control of the endocrine pancreas. Best Pract Res Clin Endocrinol Metab. 28, 745–756 (2014)
24. Y. Zhang, R. Proenca, M. Maffei, M. Barone, L. Leopold, J.M. Friedman, Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994)
25. R.S. Ahima, J.S. Flier, Adipose tissue as an endocrine organ. Trends Endocrinol. Metab. 11, 327–332 (2000)
26. B. Cannon, J. Nedergaard, Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004)
27. A.J. Whittle, M. Lopez, A. Vidal-Puig, Using brown adipose tissue to treat obesity—the central issue. Trends Mol Med. 17, 405–411 (2011)
28. C. Contreras, F. Gonzalez, J. Ferno, C. Dieguez, K. Rahmouni, R. Nogueiras, M. Lopez, The brain and brown fat. Ann. Med. 0, 1–19 (2014)
29. S.F. Morrison, C.J. Madden, D. Tupone, Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab. 19, 741–756 (2014)
30. J. Nedergaard, T. Bengtsson, B. Cannon, Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 293, E444–E452 (2007)
31. A.M. Cypess, S. Lehman, G. Williams, I. Tal, D. Rodman, A.B. Goldfine, F.C. Kuo, E.L. Palmer, Y.H. Tseng, A. Doria, G.M. Kolodny, C.R. Kahn, Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009)
32. K.A. Virtanen, M.E. Lidell, J. Orava, M. Heglind, R. Westergren, T. Niemi, M. Taittonen, J. Laine, N.J. Savisto, S. Enerback, P. Nuutila, Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009)
33. W.D. van Marken Lichtenbelt, J.W. Vanhommerig, N.M. Smulders, J.M. Drossaerts, G.J. Kemerink, N.D. Bouvy, P. Schrauwen, G.J. Teule, Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009)
34. F. Villarroya, A. Vidal-Puig, Beyond the sympathetic tone: the new brown fat activators. Cell Metab. 17, 638–643 (2013)
35. A. Frontini, S. Cinti, Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 11, 253–256 (2010)
36. A. Giordano, A. Frontini, M. Castellucci, S. Cinti, Presence and distribution of cholinergic nerves in rat mediastinal brown adipose tissue. J. Histochem. Cytochem. 52, 923–930 (2004)
37. F.M. Fisher, S. Kleiner, N. Douris, E.C. Fox, R.J. Mepani, F. Verdeguer, J. Wu, A. Kharitonenkov, J.S. Flier, E. Maratos-Flier, B.M. Spiegelman, FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012)
38. J. Nedergaard, B. Cannon, The browning of white adipose tissue: some burning issues. Cell Metab. 20, 396–407 (2014)
39. T.J. Bartness, C.H. Vaughan, C.K. Song, Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 34(Suppl 1), S36–S42 (2010)
40. L.W. Enquist, Exploiting circuit-specific spread of pseudorabies virus in the central nervous system: insights to pathogenesis and circuit tracers. J. Infect. Dis. 186(Suppl 2), S209–S214 (2002)
41. M. Bamshad, C.K. Song, T.J. Bartness, CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am. J. Physiol. 276, R1569–R1578 (1999)
42. B.J. Oldfield, M.E. Giles, A. Watson, C. Anderson, L.M. Colvill, M.J. McKinley, The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience 110, 515–526 (2002)
43. M.N. Perkins, N.J. Rothwell, M.J. Stock, T.W. Stone, Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus. Nature 289, 401–402 (1981)
44. T. Yoshida, G.A. Bray, Catecholamine turnover in rats with ventromedial hypothalamic lesions. Am. J. Physiol. 246, R558–R565 (1984)
45. S.J. Holt, H.V. Wheal, D.A. York, Hypothalamic control of brown adipose tissue in Zucker lean and obese rats. Effect of electrical stimulation of the ventromedial nucleus and other hypothalamic centres. Brain Res. 405, 227–233 (1987)
46. D. Lindberg, P. Chen, C. Li, Conditional viral tracing reveals that steroidogenic factor 1-positive neurons of the dorsomedial subdivision of the ventromedial hypothalamus project to autonomic centers of the hypothalamus and hindbrain. J Comp Neurol. 521, 3167–3190 (2013)
47. K.W. Kim, L. Zhao, J. Donato Jr, D. Kohno, Y. Xu, C.F. Elias, C. Lee, K.L. Parker, J.K. Elmquist, Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc. Natl. Acad. Sci. USA 108, 10673–10678 (2011)
48. S.F. Morrison, RVLM and raphe differentially regulate sympathetic outflows to splanchnic and brown adipose tissue. Am. J. Physiol. 276, R962–R973 (1999)
49. T. Uno, M. Shibata, Role of inferior olive and thoracic IML neurons in nonshivering thermogenesis in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R536–R546 (2001)
50. T. Sakaguchi, K. Arase, G.A. Bray, Effect of intrahypothalamic hydroxybutyrate on sympathetic firing rate. Metabolism. 37, 732–735 (1988)
51. T. Sakaguchi, G.A. Bray, Effect of norepinephrine, serotonin and tryptophan on the firing rate of sympathetic nerves. Brain Res. 492, 271–280 (1989)
52. S. Amir, Intra-ventromedial hypothalamic injection of glutamate stimulates brown adipose tissue thermogenesis in the rat. Brain Res. 511, 341–344 (1990)
53. M. Lopez, L. Varela, M.J. Vazquez, S. Rodriguez-Cuenca, C.R. Gonzalez, V.R. Velagapudi, D.A. Morgan, E. Schoenmakers, K. Agassandian, R. Lage, M.P.B. Martinez de, S. Tovar, R. Nogueiras, D. Carling, C. Lelliott, R. Gallego, M. Oresic, K. Chatterjee, A.K. Saha, K. Rahmouni, C. Dieguez, A. Vidal-Puig, Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat. Med. 16, 1001–1008 (2010)
54. A.J. Whittle, S. Carobbio, L. Martins, M. Slawik, E. Hondares, M.J. Vazquez, D. Morgan, R.I. Csikasz, R. Gallego, S. Rodriguez-Cuenca, M. Dale, S. Virtue, F. Villarroya, B. Cannon, K. Rahmouni, M. Lopez, A. Vidal-Puig, BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149, 871–885 (2012)
55. M. Tanida, N. Yamamoto, T. Shibamoto, K. Rahmouni, Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation. PLoS One 8, e56660 (2013)
56. P. Seoane-Collazo, M.P.B. Martinez de, J. Ferno, C. Dieguez, R. Nogueiras, M. Lopez, Nicotine improves obesity and hepatic steatosis and ER stress in diet-induced obese male rats. Endocrinology 155, 1679–1689 (2014)
57. M.P.B. Martinez de, I. Gonzalez-Garcia, L. Martins, R. Lage, D. Fernandez-Mallo, N. Martinez-Sanchez, F. Ruiz-Pino, J. Liu, D.A. Morgan, L. Pinilla, R. Gallego, A.K. Saha, A. Kalsbeek, E. Fliers, P.H. Bisschop, C. Dieguez, R. Nogueiras, K. Rahmouni, M. Tena-Sempere, M. Lopez, Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 20, 41–53 (2014)
58. D. Beiroa, M. Imbernon, R. Gallego, A. Senra, D. Herranz, F. Villaroya, M. Serrano, J. Ferno, J. Salvador, J. Escalada, C. Dieguez, M. Lopez, G. Fruhbeck, R. Nogueiras, GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63, 3346–3358 (2014)
59. B.M. Owen, X. Ding, D.A. Morgan, K.C. Coate, A.L. Bookout, K. Rahmouni, S.A. Kliewer, D.J. Mangelsdorf, FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab. 20, 670–677 (2014)
60. C. Fernandes-Santos, Z. Zhang, D.A. Morgan, D.F. Guo, A.F. Russo, K. Rahmouni, Amylin acts in the central nervous system to increase sympathetic nerve activity. Endocrinology 154, 2481–2488 (2013)
61. M. Lopez, R. Nogueiras, Firing up brown fat with brain amylin. Endocrinology 154, 2263–2265 (2013)
62. C. Contreras, I. Gonzalez-Garcia, N. Martinez-Sanchez, P. Seoane-Collazo, J. Jacas, D.A. Morgan, D. Serra, R. Gallego, F. Gonzalez, N. Casals, R. Nogueiras, K. Rahmouni, C. Dieguez, M. Lopez, Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep. 9, 366–377 (2014)
63. L.L. Bernardis, L.L. Bellinger, The dorsomedial hypothalamic nucleus revisited: 1998 update. Proc. Soc. Exp. Biol. Med. 218, 284–306 (1998)
64. J.A. Dimicco, D.V. Zaretsky, The dorsomedial hypothalamus: a new player in thermoregulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R47–R63 (2007)
65. W.H. Cao, S.F. Morrison, Glutamate receptors in the raphe pallidus mediate brown adipose tissue thermogenesis evoked by activation of dorsomedial hypothalamic neurons. Neuropharmacology 51, 426–437 (2006)
66. P.J. Enriori, P. Sinnayah, S.E. Simonds, R.C. Garcia, M.A. Cowley, Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J. Neurosci. 31, 12189–12197 (2011)
67. Y. Zhang, I.A. Kerman, A. Laque, P. Nguyen, M. Faouzi, G.W. Louis, J.C. Jones, C. Rhodes, H. Munzberg, Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J. Neurosci. 31, 1873–1884 (2011)
68. P.T. Chao, L. Yang, S. Aja, T.H. Moran, S. Bi, Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell Metab. 13, 573–583 (2011)
69. K. Rezai-Zadeh, S. Yu, Y. Jiang, A. Laque, C. Schwartzenburg, C.D. Morrison, A.V. Derbenev, A. Zsombok, H. Munzberg, Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol Metab. 3, 681–693 (2014)
70. S.J. Lee, S. Verma, S.E. Simonds, M.A. Kirigiti, P. Kievit, S.R. Lindsley, A. Loche, M.S. Smith, M.A. Cowley, K.L. Grove, Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice. J. Neurosci. 33, 15306–15317 (2013)
71. S.M. Harlan, D.A. Morgan, K. Agassandian, D.F. Guo, M.D. Cassell, C.D. Sigmund, A.L. Mark, K. Rahmouni, Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ. Res. 108, 808–812 (2011)
72. G.A. Bewick, J.V. Gardiner, W.S. Dhillo, A.S. Kent, N.E. White, Z. Webster, M.A. Ghatei, S.R. Bloom, Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 19, 1680–1682 (2005)
73. Y.C. Shi, J. Lau, Z. Lin, H. Zhang, L. Zhai, G. Sperk, R. Heilbronn, M. Mietzsch, S. Weger, X.F. Huang, R.F. Enriquez, P.A. Baldock, L. Zhang, A. Sainsbury, H. Herzog, S. Lin, Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab. 17, 236–248 (2013)
74. R.D. Cone, Anatomy and regulation of the central melanocortin system. Nat. Neurosci. 8, 571–578 (2005)
75. R.D. Cone, Studies on the physiological functions of the melanocortin system. Endocr. Rev. 27, 736–749 (2006)
76. H. Krude, H. Biebermann, W. Luck, R. Horn, G. Brabant, A. Gruters, Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155–157 (1998)
77. C. Vaisse, K. Clement, E. Durand, S. Hercberg, B. Guy-Grand, P. Froguel, Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest. 106, 253–262 (2000)
78. A.A. Butler, R.D. Cone, The melanocortin receptors: lessons from knockout models. Neuropeptides 36, 77–84 (2002)
79. I.S. Farooqi, S. Drop, A. Clements, J.M. Keogh, J. Biernacka, S. Lowenbein, B.G. Challis, S. O’Rahilly, Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55, 2549–2553 (2006)
80. E.D. Berglund, T. Liu, X. Kong, J.W. Sohn, L. Vong, Z. Deng, C.E. Lee, S. Lee, K.W. Williams, D.P. Olson, P.E. Scherer, B.B. Lowell, J.K. Elmquist, Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Nat. Neurosci. 17, 911–913 (2014)
81. Y. Zhang, G.E. Kilroy, T.M. Henagan, V. Prpic-Uhing, W.G. Richards, A.W. Bannon, R.L. Mynatt, T.W. Gettys, Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin. FASEB J. 19, 1482–1491 (2005)
82. M. Schneeberger, M.O. Dietrich, D. Sebastian, M. Imbernon, C. Castano, A. Garcia, Y. Esteban, A. Gonzalez-Franquesa, I.C. Rodriguez, A. Bortolozzi, P.M. Garcia-Roves, R. Gomis, R. Nogueiras, T.L. Horvath, A. Zorzano, M. Claret, Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155, 172–187 (2013)
83. G. Ramadori, T. Fujikawa, M. Fukuda, J. Anderson, D.A. Morgan, R. Mostoslavsky, R.C. Stuart, M. Perello, C.R. Vianna, E.A. Nillni, K. Rahmouni, R. Coppari, SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab. 12, 78–87 (2010)
84. H.B. Ruan, M.O. Dietrich, Z.W. Liu, M.R. Zimmer, M.D. Li, J.P. Singh, K. Zhang, R. Yin, J. Wu, T.L. Horvath, X. Yang, O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 159, 306–317 (2014)
85. J.K. Elmquist, R. Coppari, N. Balthasar, M. Ichinose, B.B. Lowell, Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol. 493, 63–71 (2005)
86. G.S. Yeo, L.K. Heisler, Unraveling the brain regulation of appetite: lessons from genetics. Nat. Neurosci. 15, 1343–1349 (2012)
87. C.J. Madden, S.F. Morrison, Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R831–R843 (2009)
88. D. Kong, Q. Tong, C. Ye, S. Koda, P.M. Fuller, M.J. Krashes, L. Vong, R.S. Ray, D.P. Olson, B.B. Lowell, GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151, 645–657 (2012)
89. M. Lopez, C.V. Alvarez, R. Nogueiras, C. Dieguez, Energy balance regulation by thyroid hormones at central level. Trends Mol Med. 19, 418–427 (2013)
90. E. Satinoff, D. Valentino, P. Teitelbaum, Thermoregulatory cold-defense deficits in rats with preoptic/anterior hypothalamic lesions. Brain Res. Bull. 1, 553–565 (1976)
91. J.D. Guieu, J.D. Hardy, Effects of heating and cooling of the spinal cord on preoptic unit activity. J. Appl. Physiol. 29, 675–683 (1970)
92. J.A. Boulant, J.D. Hardy, The effect of spinal and skin temperatures on the firing rate and thermosensitivity of preoptic neurones. J. Physiol. 240, 639–660 (1974)
93. H.T. Hammel, J.D. Hardy, M.M. Fusco, Thermoregulatory responses to hypothalamic cooling in unanesthetized dogs. Am. J. Physiol. 198, 481–486 (1960)
94. K. Imai-Matsumura, K. Matsumura, T. Nakayama, Involvement of ventromedial hypothalamus in brown adipose tissue thermogenesis induced by preoptic cooling in rats. Jpn. J. Physiol. 34, 939–943 (1984)
95. S. Amir, A. Schiavetto, Injection of prostaglandin E2 into the anterior hypothalamic preoptic area activates brown adipose tissue thermogenesis in the rat. Brain Res. 528, 138–142 (1990)
96. C.H. Vaughan, T.J. Bartness, Anterograde transneuronal viral tract tracing reveals central sensory circuits from brown fat and sensory denervation alters its thermogenic responses. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R1049–R1058 (2012)
97. V. Ryu, J.T. Garretson, Y. Liu, C.H. Vaughan, T.J. Bartness, Brown adipose tissue has sympathetic-sensory feedback circuits. J. Neurosci. 35, 2181–2190 (2015)
98. P.E. Scherer, Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55, 1537–1545 (2006)
99. A.S. Greenberg, M.S. Obin, Obesity and the role of adipose tissue in inflammation and metabolism. Am. J. Clin. Nutr. 83, 461S–465S (2006)
100. A.P. Coll, I.S. Farooqi, S. O’Rahilly, The hormonal control of food intake. Cell 129, 251–262 (2007)
101. F.F. Casanueva, C. Dieguez, Neuroendocrine regulation and actions of leptin. Front. Neuroendocrinol. 20, 317–363 (1999)
102. T.J. Bartness, S.C. Kay, H. Shi, R.R. Bowers, M.T. Foster, Brain-adipose tissue cross talk. Proc Nutr Soc. 64, 53–64 (2005)
103. R. Nogueiras, M. Lopez, C. Dieguez, Regulation of lipid metabolism by energy availability: a role for the central nervous system. Obes. Rev. 11, 185–201 (2010)
104. M. Bamshad, V.T. Aoki, M.G. Adkison, W.S. Warren, T.J. Bartness, Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue. Am. J. Physiol. 275, R291–R299 (1998)
105. H. Shi, T.J. Bartness, Neurochemical phenotype of sympathetic nervous system outflow from brain to white fat. Brain Res. Bull. 54, 375–385 (2001)
106. M.A. van Baak, The peripheral sympathetic nervous system in human obesity. Obes. Rev. 2, 3–14 (2001)
107. G. Fruhbeck, L. Mendez-Gimenez, J.A. Fernandez-Formoso, S. Fernandez, A. Rodriguez, Regulation of adipocyte lipolysis. Nutr. Res. Rev. 27, 63–93 (2014)
108. J. Shen, M. Tanida, J.F. Yao, A. Niijima, K. Nagai, Biphasic effects of orexin-A on autonomic nerve activity and lipolysis. Neurosci. Lett. 444, 166–171 (2008)
109. M. Imbernon, D. Beiroa, M.J. Vazquez, D.A. Morgan, C. Veyrat-Durebex, B. Porteiro, A. Diaz-Arteaga, A. Senra, S. Busquets, D.A. Velasquez, O. Al-Massadi, L. Varela, M. Gandara, F.J. Lopez-Soriano, R. Gallego, L.M. Seoane, J.M. Argiles, M. Lopez, R.J. Davis, G. Sabio, F. Rohner-Jeanrenaud, K. Rahmouni, C. Dieguez, R. Nogueiras, Central melanin-concentrating hormone influences liver and adipose metabolism via specific hypothalamic nuclei and efferent autonomic/JNK1 pathways. Gastroenterology 144, 636–649 (2013)
110. J.J. Hwa, L. Ghibaudi, J. Gao, E.M. Parker, Central melanocortin system modulates energy intake and expenditure of obese and lean Zucker rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R444–R451 (2001)
111. P.D. Raposinho, R.B. White, M.L. Aubert, The melanocortin agonist Melanotan-II reduces the orexigenic and adipogenic effects of neuropeptide Y (NPY) but does not affect the NPY-driven suppressive effects on the gonadotropic and somatotropic axes in the male rat. J. Neuroendocrinol. 15, 173–181 (2003)
112. C.K. Song, R.M. Jackson, R.B. Harris, D. Richard, T.J. Bartness, Melanocortin-4 receptor mRNA is expressed in sympathetic nervous system outflow neurons to white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R1467–R1476 (2005)
113. C.K. Song, C.H. Vaughan, E. Keen-Rhinehart, R.B. Harris, D. Richard, T.J. Bartness, Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R417–R428 (2008)
114. M.N. Brito, N.A. Brito, D.J. Baro, C.K. Song, T.J. Bartness, Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation. Endocrinology 148, 5339–5347 (2007)
115. R. Nogueiras, P. Wiedmer, D. Perez-Tilve, C. Veyrat-Durebex, J.M. Keogh, G.M. Sutton, P.T. Pfluger, T.R. Castaneda, S. Neschen, S.M. Hofmann, P.N. Howles, D.A. Morgan, S.C. Benoit, I. Szanto, B. Schrott, A. Schurmann, H.G. Joost, C. Hammond, D.Y. Hui, S.C. Woods, K. Rahmouni, A.A. Butler, I.S. Farooqi, S. O’Rahilly, F. Rohner-Jeanrenaud, M.H. Tschop, The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest. 117, 3475–3488 (2007)
116. S. Kaushik, E. Arias, H. Kwon, N.M. Lopez, D. Athonvarangkul, S. Sahu, G.J. Schwartz, J.E. Pessin, R. Singh, Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep. 13, 258–265 (2012)
117. M. Ruffin, S. Nicolaidis, Electrical stimulation of the ventromedial hypothalamus enhances both fat utilization and metabolic rate that precede and parallel the inhibition of feeding behavior. Brain Res. 846, 23–29 (1999)
118. A. Takahashi, T. Shimazu, Hypothalamic regulation of lipid metabolism in the rat: effect of hypothalamic stimulation on lipolysis. J. Auton. Nerv. Syst. 4, 195–205 (1981)
119. P. Cardinal, C. Andre, C. Quarta, L. Bellocchio, S. Clark, M. Elie, T. Leste-Lasserre, M. Maitre, D. Gonzales, A. Cannich, U. Pagotto, G. Marsicano, D. Cota, CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin. Mol Metab. 3, 705–716 (2014)
120. V. Ryu, T.J. Bartness, Short and long sympathetic-sensory feedback loops in white fat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306, R886–R900 (2014)
121. C.K. Song, G.J. Schwartz, T.J. Bartness, Anterograde transneuronal viral tract tracing reveals central sensory circuits from white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R501–R511 (2009)
122. B. Ahren, Autonomic regulation of islet hormone secretion–implications for health and disease. Diabetologia 43, 393–410 (2000)
123. B. Thorens, Brain glucose sensing and neural regulation of insulin and glucagon secretion. Diabetes Obes. Metab. 13(Suppl 1), 82–88 (2011)
124. T. Li, J.Y. Chiang, Nuclear receptors in bile acid metabolism. Drug Metab. Rev. 45, 145–155 (2013)
125. R.J. Perry, V.T. Samuel, K.F. Petersen, G.I. Shulman, The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510, 84–91 (2014)
126. C.J. Ramnanan, D.S. Edgerton, G. Kraft, A.D. Cherrington, Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes. Metab. 13(Suppl 1), 118–125 (2011)
127. S.E. la Fleur, A. Kalsbeek, J. Wortel, R.M. Buijs, Polysynaptic neural pathways between the hypothalamus, including the suprachiasmatic nucleus, and the liver. Brain Res. 871, 50–56 (2000)
128. V. Ulken, G.P. Puschel, K. Jungermann, Increase in glucose and lactate output and perfusion resistance by stimulation of hepatic nerves in isolated perfused rat liver: role of alpha 1-, alpha 2-, beta 1- and beta 2-receptors. Biol Chem Hoppe Seyler. 372, 401–409 (1991)
129. R. Burcelin, M. Uldry, M. Foretz, C. Perrin, A. Dacosta, M. Nenniger-Tosato, J. Seydoux, S. Cotecchia, B. Thorens, Impaired glucose homeostasis in mice lacking the alpha1b-adrenergic receptor subtype. J. Biol. Chem. 279, 1108–1115 (2004)
130. T.O. Mundinger, G.J. Taborsky Jr, Differential action of hepatic sympathetic neuropeptides: metabolic action of galanin, vascular action of NPY. Am J Physiol Endocrinol Metab. 278, E390–E397 (2000)
131. S.T. Ruohonen, U. Pesonen, N. Moritz, K. Kaipio, M. Roytta, M. Koulu, E. Savontaus, Transgenic mice overexpressing neuropeptide Y in noradrenergic neurons: a novel model of increased adiposity and impaired glucose tolerance. Diabetes 57, 1517–1525 (2008)
132. N. Uyama, A. Geerts, H. Reynaert, Neural connections between the hypothalamus and the liver. Anat Rec A Discov Mol Cell Evol Biol. 280, 808–820 (2004)
133. T. Shimazu, Nervous control of peripheral metabolism. Acta Physiol Pol. 30, 1–18 (1979)
134. T. Shimazu, S. Ogasawara, Effects of hypothalamic stimulation on gluconeogenesis and glycolysis in rat liver. Am. J. Physiol. 228, 1787–1793 (1975)
135. C.X. Yi, M.J. Serlie, M.T. Ackermans, E. Foppen, R.M. Buijs, H.P. Sauerwein, E. Fliers, A. Kalsbeek, A major role for perifornical orexin neurons in the control of glucose metabolism in rats. Diabetes 58, 1998–2005 (2009)
136. H. Tsuneki, E. Tokai, Y. Nakamura, K. Takahashi, M. Fujita, T. Asaoka, K. Kon, Y. Anzawa, T. Wada, I. Takasaki, K. Kimura, H. Inoue, M. Yanagisawa, T. Sakurai, T. Sasaoka, Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice. Diabetes 64, 459–470 (2015)
137. A. Takahashi, H. Ishimaru, Y. Ikarashi, E. Kishi, Y. Maruyama, Effects of ventromedial hypothalamus stimulation on glycogenolysis in rat liver using in vivo microdialysis. Metabolism. 46, 897–901 (1997)
138. R.J. McCrimmon, X. Fan, Y. Ding, W. Zhu, R.J. Jacob, R.S. Sherwin, Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes 53, 1953–1958 (2004)
139. R.J. McCrimmon, X. Fan, H. Cheng, E. McNay, O. Chan, M. Shaw, Y. Ding, W. Zhu, R.S. Sherwin, Activation of AMP-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes 55, 1755–1760 (2006)
140. R.J. McCrimmon, M. Shaw, X. Fan, H. Cheng, Y. Ding, M.C. Vella, L. Zhou, E.C. McNay, R.S. Sherwin, Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes 57, 444–450 (2008)
141. Q. Tong, C. Ye, R.J. McCrimmon, H. Dhillon, B. Choi, M.D. Kramer, J. Yu, Z. Yang, L.M. Christiansen, C.E. Lee, C.S. Choi, J.M. Zigman, G.I. Shulman, R.S. Sherwin, J.K. Elmquist, B.B. Lowell, Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab. 5, 383–393 (2007)
142. R. Zhang, H. Dhillon, H. Yin, A. Yoshimura, B.B. Lowell, E. Maratos-Flier, J.S. Flier, Selective inactivation of Socs3 in SF1 neurons improves glucose homeostasis without affecting body weight. Endocrinology 149, 5654–5661 (2008)
143. O. Chan, W. Zhu, Y. Ding, R.J. McCrimmon, R.S. Sherwin, Blockade of GABA(A) receptors in the ventromedial hypothalamus further stimulates glucagon and sympathoadrenal but not the hypothalamo-pituitary-adrenal response to hypoglycemia. Diabetes 55, 1080–1087 (2006)
144. O. Chan, S. Paranjape, D. Czyzyk, A. Horblitt, W. Zhu, Y. Ding, X. Fan, M. Seashore, R. Sherwin, Increased GABAergic output in the ventromedial hypothalamus contributes to impaired hypoglycemic counterregulation in diabetic rats. Diabetes 60, 1582–1589 (2011)
145. R. Coppari, M. Ichinose, C.E. Lee, A.E. Pullen, C.D. Kenny, R.A. McGovern, V. Tang, S.M. Liu, T. Ludwig, S.C. Chua Jr, B.B. Lowell, J.K. Elmquist, The hypothalamic arcuate nucleus: a key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell Metab. 1, 63–72 (2005)
146. L. Huo, K. Gamber, S. Greeley, J. Silva, N. Huntoon, X.H. Leng, C. Bjorbaek, Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 9, 537–547 (2009)
147. G.H. Goncalves, W. Li, A.V. Garcia, M.S. Figueiredo, C. Bjorbaek, Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin’s antidiabetic actions. Cell Rep. 7, 1093–1103 (2014)
148. A.M. van den Hoek, C. van Heijningen, J.P. Schröder-van der Elst, D.M. Ouwens, L.M. Havekes, J.A. Romijn, A. Kalsbeek, H. Pijl, Intracerebroventricular administration of neuropeptide Y induces hepatic insulin resistance via sympathetic innervation. Diabetes 57, 2304–2310 (2008)
149. C.X. Yi, E. Foppen, W. Abplanalp, Y. Gao, A. Alkemade, S.E. la Fleur, M.J. Serlie, E. Fliers, R.M. Buijs, M.H. Tschop, A. Kalsbeek, Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity. Diabetes 61, 339–345 (2012)
150. A. Kalsbeek, E. Foppen, I. Schalij, C. van Heijningen, J. van der Vliet, E. Fliers, R.M. Buijs, Circadian control of the daily plasma glucose rhythm: an interplay of GABA and glutamate. PLoS One 3, e3194 (2008)
151. A. Pick, J. Clark, C. Kubstrup, M. Levisetti, W. Pugh, S. Bonner-Weir, K.S. Polonsky, Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 47, 358–364 (1998)
152. C. Bernard, M.F. Berthault, C. Saulnier, A. Ktorza, Neogenesis vs. apoptosis As main components of pancreatic beta cell ass changes in glucose-infused normal and mildly diabetic adult rats. FASEB J. 13, 1195–1205 (1999)
153. M. Paris, C. Bernard-Kargar, M.F. Berthault, L. Bouwens, A. Ktorza, Specific and combined effects of insulin and glucose on functional pancreatic beta-cell mass in vivo in adult rats. Endocrinology 144, 2717–2727 (2003)
154. B. Thorens, Neural regulation of pancreatic islet cell mass and function. Diabetes Obes. Metab. 16(Suppl 1), 87–95 (2014)
155. A.S. Jansen, J.L. Hoffman, A.D. Loewy, CNS sites involved in sympathetic and parasympathetic control of the pancreas: a viral tracing study. Brain Res. 766, 29–38 (1997)
156. L. Rinaman, R.R. Miselis, The organization of vagal innervation of rat pancreas using cholera toxin-horseradish peroxidase conjugate. J. Auton. Nerv. Syst. 21, 109–125 (1987)
157. R.M. Buijs, S.J. Chun, A. Niijima, H.J. Romijn, K. Nagai, 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)
158. R. Rodriguez-Diaz, S. Speier, R.D. Molano, A. Formoso, I. Gans, M.H. Abdulreda, O. Cabrera, J. Molina, A. Fachado, C. Ricordi, I. Leibiger, A. Pileggi, P.O. Berggren, A. Caicedo, Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function. Proc Natl Acad Sci USA 109, 21456–21461 (2012)
159. W.P. Borg, R.S. Sherwin, M.J. During, M.A. Borg, G.I. Shulman, Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. Diabetes 44, 180–184 (1995)
160. M.A. Borg, R.S. Sherwin, W.P. Borg, W.V. Tamborlane, G.I. Shulman, Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats. J Clin Invest. 99, 361–365 (1997)
161. H.R. Berthoud, B. Jeanrenaud, Acute hyperinsulinemia and its reversal by vagotomy after lesions of the ventromedial hypothalamus in anesthetized rats. Endocrinology 105, 146–151 (1979)
162. S.A. Paranjape, O. Chan, W. Zhu, A.M. Horblitt, E.C. McNay, J.A. Cresswell, J.S. Bogan, R.J. McCrimmon, R.S. Sherwin, Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo. Diabetes 59, 1521–1527 (2010)
163. S.A. Paranjape, O. Chan, W. Zhu, A.M. Horblitt, C.A. Grillo, S. Wilson, L. Reagan, R.S. Sherwin, Chronic reduction of insulin receptors in the ventromedial hypothalamus produces glucose intolerance and islet dysfunction in the absence of weight gain. Am J Physiol Endocrinol Metab. 301, E978–E983 (2011)
164. J.D. Kim, C. Toda, G. D’Agostino, C.J. Zeiss, R.J. DiLeone, J.D. Elsworth, R.G. Kibbey, O. Chan, B.K. Harvey, C.T. Richie, M. Savolainen, T. Myohanen, J.K. Jeong, S. Diano, Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice. Proc Natl Acad Sci USA 111, 11876–11881 (2014)
165. A. Joly-Amado, R.G. Denis, J. Castel, A. Lacombe, C. Cansell, C. Rouch, N. Kassis, J. Dairou, P.D. Cani, R. Ventura-Clapier, A. Prola, M. Flamment, F. Foufelle, C. Magnan, S. Luquet, Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J. 31, 4276–4288 (2012)
166. H.R. Berthoud, E.A. Fox, T.L. Powley, Localization of vagal preganglionics that stimulate insulin and glucagon secretion. Am. J. Physiol. 258, R160–R168 (1990)
167. E. Ionescu, F. Rohner-Jeanrenaud, H.R. Berthoud, B. Jeanrenaud, Increases in plasma insulin levels in response to electrical stimulation of the dorsal motor nucleus of the vagus nerve. Endocrinology 112, 904–910 (1983)
168. B.M. Mussa, D.M. Sartor, C. Rantzau, A.J. Verberne, Effects of nitric oxide synthase blockade on dorsal vagal stimulation-induced pancreatic insulin secretion. Brain Res. 1394, 62–70 (2011)
169. B.M. Mussa, A.J. Verberne, The dorsal motor nucleus of the vagus and regulation of pancreatic secretory function. Exp. Physiol. 98, 25–37 (2013)
170. S. Wan, F.H. Coleman, R.A. Travagli, Glucagon-like peptide-1 excites pancreas-projecting preganglionic vagal motoneurons. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1474–G1482 (2007)
171. S. Wan, K.N. Browning, R.A. Travagli, Glucagon-like peptide-1 modulates synaptic transmission to identified pancreas-projecting vagal motoneurons. Peptides 28, 2184–2191 (2007)
172. B.B. Kahn, J.S. Flier, Obesity and insulin resistance. J Clin Invest. 106, 473–481 (2000)
173. J.S. Marino, Y. Xu, J.W. Hill, Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol. Metab. 22, 275–285 (2011)
174. I.A. Kerman, L.W. Enquist, S.J. Watson, B.J. Yates, Brainstem substrates of sympatho-motor circuitry identified using trans-synaptic tracing with pseudorabies virus recombinants. J. Neurosci. 23, 4657–4666 (2003)
175. I.A. Kerman, H. Akil, S.J. Watson, Rostral elements of sympatho-motor circuitry: a virally mediated transsynaptic tracing study. J. Neurosci. 26, 3423–3433 (2006)
176. T. Babic, M.N. Purpera, B.W. Banfield, H.R. Berthoud, C.D. Morrison, Innervation of skeletal muscle by leptin receptor-containing neurons. Brain Res. 1345, 146–155 (2010)
177. M.S. Haque, Y. Minokoshi, M. Hamai, M. Iwai, M. Horiuchi, T. Shimazu, Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats. Diabetes 48, 1706–1712 (1999)
178. T. Shimazu, M. Sudo, Y. Minokoshi, A. Takahashi, Role of the hypothalamus in insulin-independent glucose uptake in peripheral tissues. Brain Res. Bull. 27, 501–504 (1991)
179. M. Sudo, Y. Minokoshi, T. Shimazu, Ventromedial hypothalamic stimulation enhances peripheral glucose uptake in anesthetized rats. Am. J. Physiol. 261, E298–E303 (1991)
180. Y. Minokoshi, Y. Okano, T. Shimazu, Regulatory mechanism of the ventromedial hypothalamus in enhancing glucose uptake in skeletal muscles. Brain Res. 649, 343–347 (1994)
181. Y. Minokoshi, M.S. Haque, T. Shimazu, Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes 48, 287–291 (1999)
182. T. Shiuchi, M.S. Haque, S. Okamoto, T. Inoue, H. Kageyama, S. Lee, C. Toda, A. Suzuki, E.S. Bachman, Y.B. Kim, T. Sakurai, M. Yanagisawa, S. Shioda, K. Imoto, Y. Minokoshi, Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system. Cell Metab. 10, 466–480 (2009)
183. R.S. Ahima, J.S. Flier, Leptin. Annu. Rev. Physiol. 62, 413–437 (2000)
184. M.A. Cowley, J.L. Smart, M. Rubinstein, M.G. Cerdan, S. Diano, T.L. Horvath, R.D. Cone, M.J. Low, Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001)
185. G. Fruhbeck, M. Aguado, J. Gomez-Ambrosi, J.A. Martinez, Lipolytic effect of in vivo leptin administration on adipocytes of lean and ob/ob mice, but not db/db mice. Biochem Biophys Res Commun. 250, 99–102 (1998)
186. S. Kamohara, R. Burcelin, J.L. Halaas, J.M. Friedman, M.J. Charron, Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389, 374–377 (1997)
187. C. Buettner, E.D. Muse, A. Cheng, L. Chen, T. Scherer, A. Pocai, K. Su, B. Cheng, X. Li, J. Harvey-White, G.J. Schwartz, G. Kunos, L. Rossetti, C. Buettner, Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat. Med. 14, 667–675 (2008)
188. W.G. Haynes, D.A. Morgan, S.A. Walsh, A.L. Mark, W.I. Sivitz, Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 100, 270–278 (1997)
189. S. Park, I.S. Ahn, D.S. Kim, Central infusion of leptin improves insulin resistance and suppresses beta-cell function, but not beta-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model. Life Sci. 86, 854–862 (2010)
190. J. German, F. Kim, G.J. Schwartz, P.J. Havel, C.J. Rhodes, M.W. Schwartz, G.J. Morton, Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve. Endocrinology 150, 4502–4511 (2009)
191. A. Warner, J. Mittag, Thyroid hormone and the central control of homeostasis. J. Mol. Endocrinol. 49, R29–R35 (2012)
192. N. Martinez-Sanchez, C.V. Alvarez, J. Ferno, R. Nogueiras, C. Dieguez, M. Lopez, Hypothalamic effects of thyroid hormones on metabolism. Best Pract Res Clin Endocrinol Metab. 28, 703–712 (2014)
193. M. Sjogren, A. Alkemade, J. Mittag, K. Nordstrom, A. Katz, B. Rozell, H. Westerblad, A. Arner, B. Vennstrom, Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1. EMBO J. 26, 4535–4545 (2007)
194. L.P. Klieverik, H.P. Sauerwein, M.T. Ackermans, A. Boelen, A. Kalsbeek, E. Fliers, Effects of thyrotoxicosis and selective hepatic autonomic denervation on hepatic glucose metabolism in rats. Am J Physiol Endocrinol Metab. 294, E513–E520 (2008)
195. C.B. Cook, I. Kakucska, R.M. Lechan, R.J. Koenig, Expression of thyroid hormone receptor beta 2 in rat hypothalamus. Endocrinology 130, 1077–1079 (1992)
196. L. Varela, N. Martinez-Sanchez, R. Gallego, M.J. Vazquez, J. Roa, M. Gandara, E. Schoenmakers, R. Nogueiras, K. Chatterjee, M. Tena-Sempere, C. Dieguez, M. Lopez, Hypothalamic mTOR pathway mediates thyroid hormone-induced hyperphagia in hyperthyroidism. J Pathol. 227, 209–222 (2012)
197. A.C. Konner, R. Janoschek, L. Plum, S.D. Jordan, E. Rother, X. Ma, C. Xu, P. Enriori, B. Hampel, G.S. Barsh, C.R. Kahn, M.A. Cowley, F.M. Ashcroft, J.C. Bruning, Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438–449 (2007)
198. A.C. Konner, T. Klockener, J.C. Bruning, Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond. Physiol. Behav. 97, 632–638 (2009)
199. D.M. Smith, S.R. Bloom, M.C. Sugden, M.J. Holness, Glucose transporter expression and glucose utilization in skeletal muscle and brown adipose tissue during starvation and re-feeding. Biochem. J. 282(Pt 1), 231–235 (1992)
200. M.C. Sugden, M.J. Holness, Physiological modulation of the uptake and fate of glucose in brown adipose tissue. Biochem. J. 295(Pt 1), 171–176 (1993)
201. K. Rahmouni, D.A. Morgan, G.M. Morgan, X. Liu, C.D. Sigmund, A.L. Mark, W.G. Haynes, Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest. 114, 652–658 (2004)
202. E. Fliers, F. Kreier, P.J. Voshol, L.M. Havekes, H.P. Sauerwein, A. Kalsbeek, R.M. Buijs, J.A. Romijn, White adipose tissue: getting nervous. J. Neuroendocrinol. 15, 1005–1010 (2003)
203. L. Koch, F.T. Wunderlich, J. Seibler, A.C. Konner, B. Hampel, S. Irlenbusch, G. Brabant, C.R. Kahn, F. Schwenk, J.C. Bruning, Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest. 118, 2132–2147 (2008)
204. T. Scherer, J. O’Hare, K. Diggs-Andrews, M. Schweiger, B. Cheng, C. Lindtner, E. Zielinski, P. Vempati, K. Su, S. Dighe, T. Milsom, M. Puchowicz, L. Scheja, R. Zechner, S.J. Fisher, S.F. Previs, C. Buettner, Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab. 13, 183–194 (2011)
205. C. Buettner, R.C. Camacho, Hypothalamic control of hepatic glucose production and its potential role in insulin resistance. Endocrinol. Metab. Clin. North Am. 37, 825–840 (2008)
206. S. Obici, B.B. Zhang, G. Karkanias, L. Rossetti, Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376–1382 (2002)
207. S.J. Fisher, C.R. Kahn, Insulin signaling is required for insulin’s direct and indirect action on hepatic glucose production. J Clin Invest. 111, 463–468 (2003)
208. A. Kleinridders, H.A. Ferris, W. Cai, C.R. Kahn, Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63, 2232–2243 (2014)
209. J. Havrankova, J. Roth, M. Brownstein, Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272, 827–829 (1978)
210. K. Rahmouni, D.A. Morgan, G.M. Morgan, X. Liu, C.D. Sigmund, A.L. Mark, W.G. Haynes, Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin. J Clin Invest. 114, 652–658 (2004)
211. N.L. Nguyen, J. Randall, B.W. Banfield, T.J. Bartness, Central sympathetic innervations to visceral and subcutaneous white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306, R375–R386 (2014)
212. M. Ahmadian, R.E. Duncan, H.S. Sul, The skinny on fat: lipolysis and fatty acid utilization in adipocytes. Trends Endocrinol. Metab. 20, 424–428 (2009)
213. K. Rahmouni, C.D. Sigmund, W.G. Haynes, A.L. Mark, Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes 58, 536–542 (2009)
214. S.M. Harlan, D.F. Guo, D.A. Morgan, C. Fernandes-Santos, K. Rahmouni, Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab. 17, 599–606 (2013)
215. A.L. Mark, A.W. Norris, K. Rahmouni, Sympathetic inhibition after bariatric surgery. Hypertension 64, 235–236 (2014)