Obesity Impacts Fever and Sickness Behavior During Acute Systemic Inflammation.

Obesity is reaching dramatic proportions in humans and is associated with a higher risk for cardiovascular disease, diabetes, and cognitive alterations, and a higher mortality during infection and inflammation. The focus of the present review is on the influence of obesity on the presentation of fever, sickness behavior, and inflammatory responses during acute systemic inflammation.

Expression of adipokines and adipocytokines by epidural adipose tissue in cauda equina syndrome in dogs.

BACKGROUND: Compression of epidural adipose tissue (EAT) within the scope of cauda equina syndrome (CES) could lead to an enhanced expression of inflammatory mediators, possibly contributing to pain amplification in dogs. OBJECTIVES: To analyze expression of inflammatory adipo(-cyto)kines within the EAT of dogs with CES. ANIMALS: Client-owned dogs: 15 dogs with CES and 9 dogs euthanized for unrelated medical reasons (controls). METHODS: Prospective, experimental study. Epidural adipose tissue and subcutaneous adipose tissue were collected during dorsal laminectomy and used for real-time quantitative polymerase chain reaction. Tissue explants were cultured for measurements of inflammation-induced release of cytokines. RESULTS: Results show a CES-associated upregulation of the cytokines tumor necrosis factor alpha (TNFα: mean ± SD: 18.88 ± 11.87, 95% CI: 10.90-26.86 vs 9.66 ± 5.22, 95% CI: 5.29-14.02, *: P = .04) and interleukin- (IL-) 10 (20.1 ± 9.15, 95% CI: 14.82-25.39 vs 11.52 ± 6.82, 95% CI: 5.82-17.22, *: P = .03), whereas the expression of the adipokine leptin was attenuated in EAT of dogs with CES (3.07 ± 2.29, 95% CI: 1.80-3.34 vs 9.83 ± 8.42, 95% CI: 3.36-16.30, **: P = .007). Inflammatory stimulation of EAT explant cultures resulted in an enhanced release of IL-6 (LPS: 5491.55 ± 4438, 95% CI: 833.7-10 149; HMGB1: 1001.78 ± 522.2, 95% CI: 518.8-1485; PBS: 310.9 ± 98.57, 95% CI: 228.5-393.3, ***: P < .001). CONCLUSION AND CLINICAL IMPORTANCE: Expression profile of inflammatory adipo(-cyto)kines by EAT is influenced from compressive forces acting in dogs with CES and might contribute to amplification of pain.

LPS Primes Brain Responsiveness to High Mobility Group Box-1 Protein.

High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood-brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.

Age-Dependent Changes of Adipokine and Cytokine Secretion From Rat Adipose Tissue by Endogenous and Exogenous Toll-Like Receptor Agonists.

White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, ex vivo fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein (HMGB1) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. HMGB1 (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha (HMGB1) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by HMGB1 in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and HMGB1 receptors TLR4 and receptor for advanced glycation end products (RAGE) were reduced with age (TLR4/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.