Systemic and vascular inflammation in an in-vitro model of central obesity

Abstract

Metabolic disorders due to over-nutrition are a major global health problem, often associated with obesity and related morbidities. Obesity is peculiar to humans, as it is associated with lifestyle and diet, and so difficult to reproduce in animal models.Here we describe a model of human central adiposity based on a 3-tissue system consisting of a series of interconnected fluidic modules. Given the causal link between obesity and systemic inflammation, we focused primarily on pro-inflammatory markers, examining the similarities and differences between the 3-tissue model and evidence from human studies in the literature. When challenged with high levels of adiposity, the in-vitro system manifests cardiovascular stress through expression of E-selectin and von Willebrand factor as well as systemic inflammation (expressing IL-6 and MCP-1) as observed in humans. Interestingly, most of the responses are dependent on the synergic interaction between adiposity and the presence of multiple tissue types. The set-up has the potential to reduce animal experiments in obesity research and may help unravel specific cellular mechanisms which underlie tissue response to nutritional overload. Keywords: Obesity, multi-organ model, endogenous metabolism, inflammation IntroductionOverweight and obesity are major risk factors for a number of chronic diseases, including diabetes [1], cardiovascular diseases and cancer [2]. Since the turn of the century, the number of obese adults has increased to over 300 million. Obese individuals often have excess central visceral adiposity, a condition that contributes to a chronic increase in circulating free fatty acids and metabolites, such as glycerol and triglycerides. These metabolites in turn activate various signaling cascades that interfere with insulin signaling and β-cell function, further contributing to gluco/lipotoxicity [3]. A great deal of research has been dedicated to delineate the etiopathogenic mechanisms of obesity and diabetes using animal models. The most widely employed models of obesity are rodents, either mutant or genetically engineered mice or rats in which adiposity is induced by prolonged feeding on high fat diets [4,5]. As succinctly put by Wang et al, "despite the extensive use of these rodent models, many mechanistic details of human metabolism remain poorly understood and treatment options for humans are limited and largely unsatisfactory" [6]. Indeed, we now know much about the details of rodent metabolism, but still lack a detailed understanding of the mechanisms underlying human glucose homeostasis and response to chronic over-nutrition as well as human obesity related comorbidities and responses to interventions [7]. Besides the evident differences between human and rodent lifespan, diet, and basic biology, animal models are not amenable to dissociation of metabolite dynamics in different tissues and

Neutrophil‐to‐lymphocyte ratio and its relation with pro‐inflammatory mediators, visceral adiposity and carotid intima‐media thickness in population with obesity

“…Neutrophil-to-lymphocyte ratio represents a rapidly accessible and inexpensive marker derived from values of a routine hemogram, which has shown to correlate with systemic inflammation in critical ill patients, chronic low-grade inflammation, accumulation of lipids in the vascular wall and atherogenic mechanisms. 24,31,32 Our results provide new insights on the NLR, potential interacting factors and sources, which may drive to atherogenesis. We found that NLR positively correlated with hsCPR, TNF-α, IL1β, adiposity indicators, leptin, and negatively correlated with adiponectin.…”

“…Neutrophil‐to‐lymphocyte ratio represents a rapidly accessible and inexpensive marker derived from values of a routine hemogram, which has shown to correlate with systemic inflammation in critical ill patients, chronic low‐grade inflammation, accumulation of lipids in the vascular wall and atherogenic mechanisms …”

Use of dual-flow bioreactor to develop a simplified model of nervous-cardiovascular systems crosstalk: A preliminary assessment

“…In particular, two different environmental conditions were used: the apical side of the LiveBox2 chamber was filled with the SH-SY5Y medium, whereas the basal compartment was filled with the HCASMC medium. This is an innovative feature since, in general, a multi-organ approach needs to previously characterize the potential common medium, which has to be compatible with all the tissues within the pathway [ 16 ]. This process forces the cells to adapt to a novel environmental condition that is not the best option for them; therefore, this could cause a change in their behaviour.…”

Scleroderma-specific autoantibodies embedded in immune complexes mediate endothelial damage: an early event in the pathogenesis of systemic sclerosis

“…Such partial insight into disease aetiopathogenesis provides one of the limitations that aw our study. To overcome this critical issue, we are implementing a dynamic in vitro model that envisages multiple bioreactors for 3D cell cultures interconnected by a dynamic ow in order to mimic the cell crosstalk that characterizes SSc pathogenesis in humans [50]. Another major limitation of this study relates to the scarce number of samples for each autoantibody speci city; unfortunately, the recruitment of a broader cohort of patients is prevented by the relative rarity of certain antibodies (e.g., ARA and anti-Th/To) in the Italian SSc population [51].…”