Endocrinol Metab.  2013 Sep;28(3):214-220. 10.3803/EnM.2013.28.3.214.

Herpes Virus Entry Mediator Signaling in the Brain Is Imperative in Acute Inflammation-Induced Anorexia and Body Weight Loss

• Kim KK
• Jin SH
• Lee BJ

• KMID: 1973826
• DOI: http://doi.org/10.3803/EnM.2013.28.3.214

Abstract

BACKGROUND
Reduced appetite and body weight loss are typical symptoms of inflammatory diseases. A number of inflammatory stimuli are responsible for the imbalance in energy homeostasis, leading to metabolic disorders. The herpes virus entry mediator (HVEM) protein plays an important role in the development of various inflammatory diseases, such as intestinal inflammation and diet-induced obesity. However, the role of HVEM in the brain is largely unknown. This study aims to investigate whether HVEM signaling in the brain is involved in inflammation-induced anorexia and body weight loss.
METHODS
Food intake and body weight were measured at 24 hours after intraperitoneal injection of lipopolysaccharide (LPS) or intracerebroventricular injection of recombinant mouse LIGHT (also called tumor necrosis factor receptor superfamily 14, TNFSF14), an HVEM ligand, into 8- to 10-week-old male C57BL/6 mice and mice lacking HVEM expression (HVEM-/-). We also assessed LPS-induced change in hypothalamic expression of HVEM using immunohistochemistry.
RESULTS
Administration of LPS significantly reduced food intake and body weight, and moreover, increased expression of HVEM in the hypothalamic arcuate nucleus. However, LPS induced only minor decreases in food intake and body weight in HVEM-/- mice. Administration of LIGHT into the brain was very effective at decreasing food intake and body weight in wild-type mice, but was less effective in HVEM-/- mice.
CONCLUSION
Activation of brain HVEM signaling is responsible for inflammation-induced anorexia and body weight loss.

Keyword

Brain; Inflammation; Receptors, tumor necrosis factor; Anorexia

MeSH Terms

Animals
Anorexia
Appetite
Arcuate Nucleus
Body Weight
Brain
Eating
Homeostasis
Humans
Inflammation
Injections, Intraperitoneal
Light
Male
Mice
Obesity
Receptors, Tumor Necrosis Factor
Virus Internalization
Viruses
Receptors, Tumor Necrosis Factor

Figure

• 

  Fig. 1 Effect of lipopolysaccharide (LPS) on food intake and body weight. Food intake and body weight were measured in mice that had received an intraperitoneal administration of LPS. (A) Food intake was measured for 24 hours after administration of LPS (100 µg/kg). Control mice (CTL) received 0.9% saline solution. (B) Effect of LPS on body weight changes 24 hours after administration of LPS. Data are represented as mean±standard error of measure (n=4). aP<0.001 vs. control mice.

• 

  Fig. 2 Effect of lipopolysaccharide (LPS) on herpes virus entry mediator (HVEM) expression in the hypothalamic arcuate nucleus. LPS (100 µg/kg) was intraperitoneally-injected into the mice. Three hours after the injection, the mice were sacrificed and their brains were fixed via transcardiac perfusion. HVEM expression was determined using immunohistochemistry. (A, B) The panels show representative results from two repeated experiments using mice injected with (A) control or (B) LPS. (C) An amplification image (×200) of the inset of panel (B, ×100). Scale bar=100 µm. 3V, third ventricle; CTL, control mice injected with 0.9% saline solution.

• 

  Fig. 3 Herpes virus entry mediator (HVEM) signaling is required for lipopolysaccharide (LPS)-induced anorexia. Food intake and body weight were measured in mice that received an intraperitoneal-injection of LPS (100 µg/kg). (A) Effect of LPS on the change in food intake in the HVEM-/- mice. Food intake was measured for 24 hours after administration of LPS. Control mice (CTL) received 0.9% saline solution. (B) Effect of LPS on body weight changes for 24 hours. Data are represented as mean±standard error of measure (n=4). aP<0.001 vs. control mice; bP<0.01 vs. LPS-injected wild-type mice.

• 

  Fig. 4 Effect of LIGHT on the food intake and body weight of herpes virus entry mediator (HVEM)-/- mice. Food intake and body weight were measured in mice which received an intracerebroventricular (ICV) administration of LIGHT (300 ng). (A) Effect of ICV-injected LIGHT on the change in food intake in HVEM-/- mice. Food intake was measured for 24 hours after administration of LIGHT. Control mice (CTL) received 0.9% saline solution. (B) Effect of LIGHT on body weight change for 24 hours after the ICV-injection of LIGHT. Data are represented as mean±standard error of measure (n=4). aP<0.001 vs. control mice; bP<0.05 vs. LIGHT-injected wild-type mice.

Reference

1. Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev. 1988; 12:123–137. PMID: 3050629.

2. Plata-Salaman CR. Anorexia during acute and chronic disease. Nutrition. 1996; 12:69–78. PMID: 8724375.

3. Szelenyi Z, Szekely M. Sickness behavior in fever and hypothermia. Front Biosci. 2004; 9:2447–2456. PMID: 15353297.

4. Matthys P, Billiau A. Cytokines and cachexia. Nutrition. 1997; 13:763–770. PMID: 9290087.

5. Kotler DP. Cachexia. Ann Intern Med. 2000; 133:622–634. PMID: 11033592.

6. Grinspoon S, Mulligan K. Department of Health and Human Services Working Group on the Prevention and Treatment of Wasting and Weight Loss. Weight loss and wasting in patients infected with human immunodeficiency virus. Clin Infect Dis. 2003; 36(Suppl 2):S69–S78. PMID: 12652374.

7. Argiles JM, Lopez-Soriano FJ. The role of cytokines in cancer cachexia. Med Res Rev. 1999; 19:223–248. PMID: 10232651.

8. Langhans W. Anorexia of infection: current prospects. Nutrition. 2000; 16:996–1005. PMID: 11054606.

9. McNamara MJ, Alexander HR, Norton JA. Cytokines and their role in the pathophysiology of cancer cachexia. JPEN J Parenter Enteral Nutr. 1992; 16(6 Suppl):50S–55S. PMID: 1287224.

10. Harden LM, du Plessis I, Poole S, Laburn HP. Interleukin (IL)-6 and IL-1 beta act synergistically within the brain to induce sickness behavior and fever in rats. Brain Behav Immun. 2008; 22:838–849. PMID: 18255258.

11. Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW, Johnson RW. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 2005; 19:1329–1331. PMID: 15919760.

12. Kluger MJ. Fever: role of pyrogens and cryogens. Physiol Rev. 1991; 71:93–127. PMID: 1986393.

13. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008; 9:46–56. PMID: 18073775.

14. Wohleb ES, Fenn AM, Pacenta AM, Powell ND, Sheridan JF, Godbout JP. Peripheral innate immune challenge exaggerated microglia activation, increased the number of inflammatory CNS macrophages, and prolonged social withdrawal in socially defeated mice. Psychoneuroendocrinology. 2012; 37:1491–1505. PMID: 22386198.

15. Hines DJ, Choi HB, Hines RM, Phillips AG, MacVicar BA. Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides. PLoS One. 2013; 8:e60388. PMID: 23555964.

16. Gruss HJ, Dower SK. Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas. Blood. 1995; 85:3378–3404. PMID: 7780126.

17. Shui JW, Steinberg MW, Kronenberg M. Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. J Leukoc Biol. 2011; 89:517–523. PMID: 21106644.

18. Steinberg MW, Shui JW, Ware CF, Kronenberg M. Regulating the mucosal immune system: the contrasting roles of LIGHT, HVEM, and their various partners. Semin Immunopathol. 2009; 31:207–221. PMID: 19495760.

19. Cai G, Freeman GJ. The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev. 2009; 229:244–258. PMID: 19426226.

20. Marsters SA, Ayres TM, Skubatch M, Gray CL, Rothe M, Ashkenazi A. Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-kappaB and AP-1. J Biol Chem. 1997; 272:14029–14032. PMID: 9162022.

21. Schaer C, Hiltbrunner S, Ernst B, Mueller C, Kurrer M, Kopf M, Harris NL. HVEM signalling promotes colitis. PLoS One. 2011; 6:e18495. PMID: 21533159.

22. Wang J, Anders RA, Wang Y, Turner JR, Abraham C, Pfeffer K, Fu YX. The critical role of LIGHT in promoting intestinal inflammation and Crohn’s disease. J Immunol. 2005; 174:8173–8182. PMID: 15944326.

23. An MM, Fan KX, Cao YB, Shen H, Zhang JD, Lu L, Gao PH, Jiang YY. Lymphtoxin beta receptor-Ig protects from T-cell-mediated liver injury in mice through blocking LIGHT/HVEM signaling. Biol Pharm Bull. 2006; 29:2025–2030. PMID: 17015945.

24. Kim HJ, Kim HM, Kim CS, Jeong CS, Choi HS, Kawada T, Kim BS, Yu R. HVEM-deficient mice fed a high-fat diet are protected from adipose tissue inflammation and glucose intolerance. FEBS Lett. 2011; 585:2285–2290. PMID: 21679708.

25. Kim WK, Park JS, Sul OJ, Seo JH, Choi BK, Park HY, Latour AM, Koller BH, Kwon BS, Jeong CS. Role of TNFR-related 2 mediated immune responses in dextran sulfate sodium-induced inflammatory bowel disease. Mol Cells. 2011; 31:99–104. PMID: 21347711.

26. Kim HM, Jeong CS, Choi HS, Kawada T, Yu R. LIGHT/TNFSF14 enhances adipose tissue inflammatory responses through its interaction with HVEM. FEBS Lett. 2011; 585:579–584. PMID: 21236258.

27. Langhans W. Signals generating anorexia during acute illness. Proc Nutr Soc. 2007; 66:321–330. PMID: 17637084.

28. Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem. 1995; 270:16483–16486. PMID: 7622446.

29. Cunningham C. Microglia and neurodegeneration: the role of systemic inflammation. Glia. 2013; 61:71–90. PMID: 22674585.

30. Elmquist JK, Flier JS. Neuroscience. The fat-brain axis enters a new dimension. Science. 2004; 304:63–64. PMID: 15064411.

31. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006; 443:289–295. PMID: 16988703.

32. Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. 2002; 25:154–159. PMID: 11852148.

33. Jeong HK, Jou I, Joe EH. Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra. Exp Mol Med. 2010; 42:823–832. PMID: 20962566.

34. Ware CF. Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways. Immunol Rev. 2008; 223:186–201. PMID: 18613837.