Abstract
Leptin is an adipocyte-derived hormone that relays a satiety signal to the brain. The effect of leptin on the sympathetic nervous system is an important aspect in the regulation of energy homeostasis as well as several other physiological functions. The arcuate nucleus of the hypothalamus is considered a major site for the regulation of physiological processes by leptin. However, there is growing recognition that other hypothalamic and extra-hypothalamic brain nuclei are important for leptin regulation of physiological processes including sympathetic nerve traffic. The current review discusses the various hypothalamic and extra-hypothalamic nuclei that have been implicated in leptin-induced increase in regional sympathetic nerve activity. The continuous rise in the prevalence of obesity underscores the importance of understanding the underlying neural mechanisms regulating sympathetic traffic to different tissues to design effective strategies to reverse obesity and associated diseases.
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References
Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443(7109):289–295
Elmquist JK, Elias CF, Saper CB (1999) From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22(2):221–232
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432
Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415(6869):339–343
Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, Pfluger PT, Castaneda TR, Neschen S, Hofmann SM, Howles PN, Morgan DA, Benoit SC, Szanto I, Schrott B, Schurmann A, Joost HG, Hammond C, Hui DY, Woods SC, Rahmouni K, Butler AA, Farooqi IS, O’Rahilly S, Rohner-Jeanrenaud F, Tschop MH (2007) The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 117(11):3475–3488
Warne JP, Alemi F, Reed AS, Varonin JM, Chan H, Piper ML, Mullin ME, Myers MG Jr, Corvera CU, Xu AW (2011) Impairment of central leptin-mediated PI3 K signaling manifested as hepatic steatosis independent of hyperphagia and obesity. Cell Metab 14(6):791–803
Plum L, Rother E, Munzberg H, Wunderlich FT, Morgan DA, Hampel B, Shanabrough M, Janoschek R, Konner AC, Alber J, Suzuki A, Krone W, Horvath TL, Rahmouni K, Bruning JC (2007) Enhanced leptin-stimulated Pi3 k activation in the CNS promotes white adipose tissue transdifferentiation. Cell Metab 6(6):431–445
Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA, Mostoslavsky R, Stuart RC, Perello M, Vianna CR, Nillni EA, Rahmouni K, Coppari R (2010) SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 12(1):78–87
Rahmouni K, Haynes WG, Mark AL (2002) Cardiovascular and sympathetic effects of leptin. Curr Hypertens Rep 4(2):119–125
Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G (2005) Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434(7032):514–520
Rahmouni K, Fath MA, Seo S, Thedens DR, Berry CJ, Weiss R, Nishimura DY, Sheffield VC (2008) Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest 118(4):1458–1467
Correia ML, Haynes WG, Rahmouni K, Morgan DA, Sivitz WI, Mark AL (2002) The concept of selective leptin resistance: evidence from agouti yellow obese mice. Diabetes 51(2):439–442
Prior LJ, Eikelis N, Armitage JA, Davern PJ, Burke SL, Montani JP, Barzel B, Head GA (2010) Exposure to a high-fat diet alters leptin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits. Hypertension 55(4):862–868
Rahmouni K, Morgan DA, Morgan GM, Mark AL, Haynes WG (2005) Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes 54(7):2012–2018
Harlan SM, Morgan DA, Dellsperger DJ, Myers MG Jr, Mark AL, Rahmouni K (2011) Cardiovascular and sympathetic effects of disrupting tyrosine 985 of the leptin receptor. Hypertension 57(3):627–632
Vaz M, Jennings G, Turner A, Cox H, Lambert G, Esler M (1997) Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects. Circulation 96(10):3423–3429
Eikelis N, Schlaich M, Aggarwal A, Kaye D, Esler M (2003) Interactions between leptin and the human sympathetic nervous system. Hypertension 41(5):1072–1079
Baskin DG, Seeley RJ, Kuijper JL, Lok S, Weigle DS, Erickson JC, Palmiter RD, Schwartz MW (1998) Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting. Diabetes 47(4):538–543
Myers MG Jr (2010) Outstanding Scientific Achievement Award Lecture 2010: deconstructing leptin: from signals to circuits. Diabetes 59(11):2708–2714
Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern RA, Tang V, Liu SM, Ludwig T, Chua SC Jr, Lowell BB, Elmquist JK (2005) The hypothalamic arcuate nucleus: a key site for mediating leptin’s effects on glucose homeostasis and locomotor activity. Cell Metab 1(1):63–72
Satoh N, Ogawa Y, Katsuura G, Hayase M, Tsuji T, Imagawa K, Yoshimasa Y, Nishi S, Hosoda K, Nakao K (1997) The arcuate nucleus as a primary site of satiety effect of leptin in rats. Neurosci Lett 224(3):149–152
Morton GJ, Niswender KD, Rhodes CJ, Myers MG Jr, Blevins JE, Baskin DG, Schwartz MW (2003) Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats. E. Endocrinology 144(5):2016–2024
Dawson R, Pelleymounter MA, Millard WJ, Liu S, Eppler B (1997) Attenuation of leptin-mediated effects by monosodium glutamate-induced arcuate nucleus damage. Am J Physiol 273(1Pt1):E202–6
Berglund ED, Vianna CR, Donato J Jr, Kim MH, Chuang JC, Lee CE, Lauzon DA, Lin P, Brule LJ, Scott MM, Coppari R, Elmquist JK (2012) Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest 122(3):1000–1009
Huo L, Gamber K, Greeley S, Silva J, Huntoon N, Leng XH, Bjorbaek C (2009) Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab 9(6):537–547
Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2(6):411–420
Rahmouni K, Morgan DA (2007) Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension 49(3):647–652
Montanaro MS, Allen AM, Oldfield BJ (2005) Structural and functional evidence supporting a role for leptin in central neural pathways influencing blood pressure in rats. Exp Physiol 90(5):689–696
Haynes W, Morgan D, Walsh S (1998) Sympathetic activation to leptin is mediated by the hypothalamus. J Hypertens 16:S11
Harlan SM, Morgan DA, Agassandian K, Guo DF, Cassell MD, Sigmund CD, Mark AL, Rahmouni K (2011) Ablation of the Leptin Receptor in the Hypothalamic Arcuate Nucleus Abrogates Leptin-Induced Sympathetic Activation. Circ Res 108(7):808–812
Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD (1999) Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24(1):155–163
Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, Entwistle ML, Simerly RB, Cone RD (1993) Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci U S A 90(19):8856–8860
Tallam LS, Stec DE, Willis MA, da Silva AA, Hall JE (2005) Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia. Hypertension 46(2):326–332
Rahmouni K, Haynes WG, Morgan DA, Mark AL (2003) Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin. J Neurosci 23(14):5998–6004
Kuo JJ, da Silva AA, Tallam LS, Hall JE (2004) Role of adrenergic activity in pressor responses to chronic melanocortin receptor activation. Hypertension 43(2):370–375
Kuo JJ, Silva AA, Hall JE (2003) Hypothalamic melanocortin receptors and chronic regulation of arterial pressure and renal function. Hypertension 41(3Pt2):768–774
Sayk F, Heutling D, Dodt C, Iwen KA, Wellhoner JP, Scherag S, Hinney A, Hebebrand J, Lehnert H (2010) Sympathetic function in human carriers of melanocortin-4 receptor gene mutations. J Clin Endocrinol Metab 95(4):1998–2002
Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, Astruc B, Mayer JP, Brage S, See TC, Lomas DJ, O’Rahilly S, Farooqi IS (2009) Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med 360(1):44–52
do Carmo JM, da Silva AA, Cai Z, Lin S, Dubinion JH, Hall JE (2011) Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 57(5):918–926
Morgan DA, Thedens DR, Weiss R, Rahmouni K (2008) Mechanisms mediating renal sympathetic activation to leptin in obesity. Am J Physiol Regul Integr Comp Physiol 295(6):R1730–R1736
Zhang ZH, Felder RB (2004) Melanocortin receptors mediate the excitatory effects of blood-borne murine leptin on hypothalamic paraventricular neurons in rat. Am J Physiol Regul Integr Comp Physiol 286(2):R303–R310
Hubschle T, Thom E, Watson A, Roth J, Klaus S, Meyerhof W (2001) Leptin-induced nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei involved in body weight regulation. J Neurosci 21(7):2413–2424
Elmquist JK, Ahima RS, Maratos-Flier E, Flier JS, Saper CB (1997) Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138(2):839–842
Bingham NC, Anderson KK, Reuter AL, Stallings NR, Parker KL (2008) Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 149(5):2138–2148
Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V, Kenny CD, Christiansen LM, White RD, Edelstein EA, Coppari R, Balthasar N, Cowley MA, Chua S Jr, Elmquist JK, Lowell BB (2006) Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49(2):191–203
Satoh N, Ogawa Y, Katsuura G, Numata Y, Tsuji T, Hayase M, Ebihara K, Masuzaki H, Hosoda K, Yoshimasa Y, Nakao K (1999) Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. Diabetes 48(9):1787–1793
Marsh AJ, Fontes MA, Killinger S, Pawlak DB, Polson JW, Dampney RA (2003) Cardiovascular responses evoked by leptin acting on neurons in the ventromedial and dorsomedial hypothalamus. Hypertension 42(4):488–493
Tanida M, Nagai K, Kaneko H (2003) Activation of the renal sympathetic nerve by leptin microinjection into the ventromedial hypothalamus in rats. In Vivo 17(3):213–217
Fontes MA, Tagawa T, Polson JW, Cavanagh SJ, Dampney RA (2001) Descending pathways mediating cardiovascular response from dorsomedial hypothalamic nucleus. Am J Physiol Heart Circ Physiol 280(6):H2891–H2901
Zhang Y, Kerman IA, Laque A, Nguyen P, Faouzi M, Louis GW, Jones JC, Rhodes C, Munzberg H (2011) Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J Neurosci 31(5):1873–1884
Enriori PJ, Sinnayah P, Simonds SE, Garcia RC, Cowley MA (2011) Leptin action in the dorsomedial hypothalamus increases sympathetic tone to brown adipose tissue in spite of systemic leptin resistance. J Neurosci 31(34):12189–12197
Leinninger GM (2011) Lateral thinking about leptin: a review of leptin action via the lateral hypothalamus. Physiol Behav 104(4):572–581
Leinninger GM, Opland DM, Jo YH, Faouzi M, Christensen L, Cappellucci LA, Rhodes CJ, Gnegy ME, Becker JB, Pothos EN, Seasholtz AF, Thompson RC, Myers MG Jr (2011) Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab 14(3):313–323
Shih CD, Au LC, Chan JY (2003) Differential role of leptin receptors at the hypothalamic paraventricular nucleus in tonic regulation of food intake and cardiovascular functions. J Biomed Sci 10(4):367–378
Mark AL, Agassandian K, Morgan DA, Liu X, Cassell MD, Rahmouni K (2009) Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney. Hypertension 53(2):375–380
Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J, Baskin DG (2002) Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 143(1):239–246
Ellacott KL, Halatchev IG, Cone RD (2006) Characterization of leptin-responsive neurons in the caudal brainstem. Endocrinology 147(7):3190–3195
Huo L, Grill HJ, Bjorbaek C (2006) Divergent regulation of proopiomelanocortin neurons by leptin in the nucleus of the solitary tract and in the arcuate hypothalamic nucleus. Diabetes 55(3):567–573
Smith PM, Ferguson AV (2011) Cardiovascular actions of leptin in the subfornical organ are abolished by diet induced obesity. J Neuroendocrinol 24(3):504–510
Dulloo AG (2002) Biomedicine. A sympathetic defense against obesity. Science 297(5582):780–781
Acknowledgments
The authors’ work is supported by grants from NIH (HL084207 and HL014388) and American Diabetes Association (1-11-BS-127). SMH is supported by Postdoctoral Fellowship Award from The American Heart Association (12POST9410009).
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Harlan, S.M., Rahmouni, K. Neuroanatomical determinants of the sympathetic nerve responses evoked by leptin. Clin Auton Res 23, 1–7 (2013). https://doi.org/10.1007/s10286-012-0168-4
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DOI: https://doi.org/10.1007/s10286-012-0168-4