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Unmasking insulin resistance triggering mechanisms using microphysiological two-organ systems as in vitro disease models of metabolic syndrome and non-alcoholic fatty liver disease

Project description

Organ-on-a-chip technology for studying metabolic diseases

Non-alcoholic fatty liver disease (NAFLD) is associated with the deregulation of adipose tissue lipolysis. Although hepatic cell insulin resistance may be the underlying culprit, there is a need to understand how hepatic and adipocyte insulin resistance develop and influence each other. To address this limitation and study liver–adipose tissue crosstalk, the EU-funded LIV-AD-ON-CHIP project will develop a two-organ-on-a-chip model. Researchers will culture hepatocytes and adipocytes in connected systems and undertake transcriptomic and metabolomic analyses after inducing insulin resistance. This in vitro model can be used with patient-specific cells to identify potential biomarkers and new biomarkers of NAFLD or other metabolic diseases.

Objective

Insulin resistance is one of the key factors for non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome development and progression. Both diseases have an immense societal and economic impact. However, the biological mechanisms triggering the onset of the diseases are still poorly understood. NAFLD is assumed to be triggered by hepatic insulin resistance, possibly resulting from adipose tissue lipolysis dysregulation. The study of the crosstalk between liver and adipose tissue is thus essential for the understanding of insulin resistance triggering events but is limited by the availability of suitable models. Hence, the aim of this proposal is to establish a two-organ-on-a-chip-model and to utilize it to study liver-adipose tissue crosstalk and understand how hepatic and adipocyte insulin resistance develop and influence each other. In order to study the molecular mechanisms of inter-tissue communication and overcome the complexity and non-human nature of animal models, an innovative organ-on-a-chip system using a flexible connection technology will be utilized to culture hepatocytes and adipocytes in connected systems. Human stem cell derived adipocyte- and hepatocytes-like cells with the same genetic background will be cultured in this system and characterized regarding their metabolic competence. The cell’s functional characterization, transcriptomic and metabolomic analysis, upon pharmacological induction of insulin resistance, will allow to unravel its molecular triggering mechanisms in vitro. The same approach will be applied to patient-specific cells creating a patient-specific physiopatological in vitro model under distinct nutrient mixtures. This project is a highly innovative multidisciplinary approach that uses organ-on-a-chip technology for in vitro disease modeling to study the triggering molecular mechanisms and possibly identify potential biomarkers and/or pharmacological and non-pharmacological targets of high impact diseases.

Coordinator

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Net EU contribution
€ 145 621,50
Address
GESCHWISTER-SCHOLL-PLATZ
72074 Tuebingen
Germany

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Region
Baden-Württemberg Tübingen Tübingen, Landkreis
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 145 621,51

Participants (1)