Understanding the dynamic nature of metabolic interactions between different mammalian cell types is vital if we are to characterize and identify novel therapeutic targets for metabolic disorders such as obesity and diabetes. Towards this end, we have engineered a co-culture system between adipocytes (fat cells) and hepatocytes (liver cells) that can be used as a platform for investigating metabolic interactions, e.g. cross-feeding of small molecules and other nutrients. The metabolic interactions between these specific cell types are of particular interest since impaired interactions between liver and fat cells have been directly linked to a cluster of disorders including diabetes and obesity. The co-culture system that we have developed thus far provides a convenient platform for investigating how system perturbations affect adipocyte-hepatocyte metabolic interactions, as well as for fine-tuning experimental techniques so that they can be translated to future in vivo studies. In this contribution, we describe the specific adipocyte-hepatocyte co-culture system that we have engineered using a trans-well cultivation experimental setup, and we highlight how we have applied this setup and recently developed approaches for co-culture 13C-metabolic flux analysis (co-MFA) to analyze in detail how global regulators of mammalian metabolism (e.g. insulin and isoproterenol) impact adipocyte-hepatocyte metabolic interactions (e.g. metabolite cross-feeding) and individual cell population physiology. Towards this end, we have performed a series of co-culture experiments with global regulators of cellular metabolism added to the medium. As an example, the addition of insulin induced both cell types to transition into a “fed state metabolism”, the state in which hepatocytes and adipocytes consumed glucose and utilized it for glycogenesis (in liver cells) and lipogenesis (in fat cells). In contrast, the addition of isoproterenol promoted “fasted state metabolism”, the state in which adipocytes released metabolic precursors such as glycerol, lactate, and fatty acids that were then used by hepatocytes for energy generation and gluconeogenesis. To gain further insights into the metabolic phenotypes, we also applied advanced co-MFA methods based on 13C-tracer experiments to quantify precisely the intricate cross-cell metabolite communications that occurred in these two metabolic states.

Metabolic cross-feeding interactions between adipocytes and hepatocytes in an engineered mammalian co-culture system

2019 Spring National Meeting

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