Arcuate Nucleus Proopiomelanocortin Neurons Mediate the Acute Anorectic Actions of Leukemia Inhibitory Factor Via Gp130

Overview

Journal Endocrinology

Publisher Oxford University Press

Specialty Endocrinology

Date 2009 Dec 18

PMID 20016025

Citations 34

Authors

Aaron J Grossberg

Jarrad M Scarlett

Xinxia Zhu

Darren D Bowe

Ayesha K Batra

Theodore P Braun

Daniel L Marks

Affiliations

Soon will be listed here.

Abstract

The proinflammatory cytokine leukemia inhibitory factor (LIF) is induced in disease states and is known to inhibit food intake when administered centrally. However, the neural pathways underlying this effect are not well understood. We demonstrate that LIF acutely inhibits food intake by directly activating pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. We show that arcuate POMC neurons express the LIF-R, and that LIF stimulates the release of the anorexigenic peptide, alpha-MSH from ex vivo hypothalami. Transgenic mice lacking gp130, the signal transducing subunit of the LIF-R complex, specifically in POMC neurons fail to respond to LIF. Furthermore, LIF does not stimulate the release of alpha-MSH from the transgenic hypothalamic explants. These findings indicate that POMC neurons mediate the acute anorectic actions of central LIF administration and provide a mechanistic link between inflammation and food intake.

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References

Mori M, Yamaguchi K, Honda S, Nagasaki K, Ueda M, Abe O . Cancer cachexia syndrome developed in nude mice bearing melanoma cells producing leukemia-inhibitory factor. Cancer Res. 1991; 51(24):6656-9. View

Wisse B, Ogimoto K, Morton G, Williams D, Schwartz M . Central interleukin-1 (IL1) signaling is required for pharmacological, but not physiological, effects of leptin on energy balance. Brain Res. 2007; 1144:101-6. PMC: 2706018. DOI: 10.1016/j.brainres.2007.01.073. View

Fan W, Boston B, Kesterson R, Hruby V, Cone R . Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. 1997; 385(6612):165-8. DOI: 10.1038/385165a0. View

Xu A, Kaelin C, Takeda K, Akira S, Schwartz M, Barsh G . PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest. 2005; 115(4):951-8. PMC: 1062894. DOI: 10.1172/JCI24301. View

Castro M, Morrison E . Post-translational processing of proopiomelanocortin in the pituitary and in the brain. Crit Rev Neurobiol. 1997; 11(1):35-57. DOI: 10.1615/critrevneurobiol.v11.i1.30. View

Benomar Y, Berthou F, Vacher C, Bailleux V, Gertler A, Djiane J . Leptin but not ciliary neurotrophic factor (CNTF) induces phosphotyrosine phosphatase-1B expression in human neuronal cells (SH-SY5Y): putative explanation of CNTF efficacy in leptin-resistant state. Endocrinology. 2008; 150(3):1182-91. DOI: 10.1210/en.2008-1097. View

Tisdale M . Biology of cachexia. J Natl Cancer Inst. 1997; 89(23):1763-73. DOI: 10.1093/jnci/89.23.1763. View

Kievit P, Howard J, Badman M, Balthasar N, Coppari R, Mori H . Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab. 2006; 4(2):123-32. DOI: 10.1016/j.cmet.2006.06.010. View

Heinrich P, Behrmann I, Haan S, Hermanns H, Muller-Newen G, Schaper F . Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003; 374(Pt 1):1-20. PMC: 1223585. DOI: 10.1042/BJ20030407. View

10.

Lorgeot V, Praloran V, Turlure P, Denizot Y . Concentrations of serum leukemia inhibitory factor (LIF) in patients with hematologic malignancies. Leukemia. 1997; 11(2):311-2. DOI: 10.1038/sj.leu.2400570. View

11.

Sonti G, Ilyin S, Plata-Salaman C . Anorexia induced by cytokine interactions at pathophysiological concentrations. Am J Physiol. 1996; 270(6 Pt 2):R1394-402. DOI: 10.1152/ajpregu.1996.270.6.R1394. View

12.

van Dam A, Bauer J, Tilders F, Berkenbosch F . Endotoxin-induced appearance of immunoreactive interleukin-1 beta in ramified microglia in rat brain: a light and electron microscopic study. Neuroscience. 1995; 65(3):815-26. DOI: 10.1016/0306-4522(94)00549-k. View

13.

Hillhouse E, MOSLEY K . Peripheral endotoxin induces hypothalamic immunoreactive interleukin-1 beta in the rat. Br J Pharmacol. 1993; 109(2):289-90. PMC: 2175692. DOI: 10.1111/j.1476-5381.1993.tb13567.x. View

14.

Larkin M . Thwarting the dwindling progression of cachexia. Lancet. 1998; 351(9112):1336. DOI: 10.1016/S0140-6736(05)79068-1. View

15.

Plata-Salaman C . Anorexia induced by activators of the signal transducer gp 130. Neuroreport. 1996; 7(3):841-4. DOI: 10.1097/00001756-199602290-00038. View

16.

Beretta E, Dhillon H, Kalra P, Kalra S . Central LIF gene therapy suppresses food intake, body weight, serum leptin and insulin for extended periods. Peptides. 2002; 23(5):975-84. DOI: 10.1016/s0196-9781(02)00021-9. View

17.

Murray M, Murray A . Anorexia of infection as a mechanism of host defense. Am J Clin Nutr. 1979; 32(3):593-6. DOI: 10.1093/ajcn/32.3.593. View

18.

Elmquist J, Elias C, Saper C . From lesions to leptin: hypothalamic control of food intake and body weight. Neuron. 1999; 22(2):221-32. DOI: 10.1016/s0896-6273(00)81084-3. View

19.

Abbud R, Kelleher R, Melmed S . Cell-specific pituitary gene expression profiles after treatment with leukemia inhibitory factor reveal novel modulators for proopiomelanocortin expression. Endocrinology. 2003; 145(2):867-80. DOI: 10.1210/en.2003-0897. View

20.

Janoschek R, Plum L, Koch L, Munzberg H, Diano S, Shanabrough M . gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor. Proc Natl Acad Sci U S A. 2006; 103(28):10707-12. PMC: 1502296. DOI: 10.1073/pnas.0600425103. View