Herpes virus entry mediator signaling in the brain is imperative in acute inflammation-induced anorexia and body weight loss

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.

Keywords: Anorexia; Brain; Inflammation; Receptors, tumor necrosis factor.

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.