Abstract
Metabolic disorders, such as obesity and type 2 diabetes have a large impact on global health, especially in industrialized countries. Tissue-specific chronic low-grade inflammation is a key contributor to complications in metabolic disorders. To support therapeutic approaches to these complications, it is crucial to gain a deeper understanding of the inflammatory dynamics and to monitor them on the individual level. To this end, blood-based biomarkers reflecting the tissue-specific inflammatory dynamics would be of great value. Here, we describe an in silico approach to select candidate biomarkers for tissue-specific inflammation by using a priori mechanistic knowledge from pathways and tissue-derived molecules. The workflow resulted in a list of candidate markers, in part consisting of literature confirmed biomarkers as well as a set of novel, more innovative biomarkers that reflect inflammation in the liver and adipose tissue. The first step of biomarker verification was on murine tissue gene-level by inducing hepatic inflammation and adipose tissue inflammation through a high-fat diet. Our data showed that in silico predicted hepatic markers had a strong correlation to hepatic inflammation in the absence of a relation to adipose tissue inflammation, while others had a strong correlation to adipose tissue inflammation in the absence of a relation to liver inflammation. Secondly, we evaluated the human translational value by performing a curation step in the literature using studies that describe the regulation of the markers in human, which identified 9 hepatic (such as Serum Amyloid A, Haptoglobin, and Interleukin 18 Binding Protein) and 2 adipose (Resistin and MMP-9) inflammatory biomarkers at the highest level of confirmation. Here, we identified and pre-clinically verified a set of in silico predicted biomarkers for liver and adipose tissue inflammation which can be of great value to study future development of therapeutic/lifestyle interventions to combat metabolic inflammatory complications.
Highlights
Inflammation is an important component of normal responses to infection and injury, whether locally confined or systemic
Since immune responses are linked to energy metabolism, it can be argued that the integration of these systems and their cooperation in responding to fluctuations in the energy and nutritional environment would be beneficial
In order to select those tissuespecific pathways potentially associated with inflammation, only those adipose and liver gene ontology (GO) terms were taken that contained genes present in immune-related GO terms (Meijerink et al, 2019)
Summary
Inflammation is an important component of normal responses to infection and injury, whether locally confined or systemic. An healthy immune response follows a characteristic pathway, where the first response is strong but short, resulting in the exclusion of the pathogen/damage followed by a recovery to homeostasis. Since immune responses are linked to energy metabolism, it can be argued that the integration of these systems and their cooperation in responding to fluctuations in the energy and nutritional environment would be beneficial. These responses, need to be temporally and locally regulated to maintain an healthy homeostasis
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