A systems biology analysis of lipolysis and fatty acid release from adipocytes in vitro and from adipose tissue in vivo

Abstract

Lipolysis and the release of fatty acids to supply energy fuel to other organs, such as between meals, during exercise, and starvation, are fundamental functions of the adipose tissue. The intracellular lipolytic pathway in adipocytes is activated by adrenaline and noradrenaline, and inhibited by insulin. Circulating fatty acids are elevated in type 2 diabetic individuals. The mechanisms behind this elevation are not fully known, and to increase the knowledge a link between the systemic circulation and intracellular lipolysis is key. However, data on lipolysis and knowledge from in vitro systems have not been linked to corresponding in vivo data and knowledge in vivo. Here, we use mathematical modelling to provide such a link. We examine mechanisms of insulin action by combining in vivo and in vitro data into an integrated mathematical model that can explain all data. Furthermore, the model can describe independent data not used for training the model. We show the usefulness of the model by simulating new and more challenging experimental setups in silico, e.g. the extracellular concentration of fatty acids during an insulin clamp, and the difference in such simulations between individuals with and without type 2 diabetes. Our work provides a new platform for model-based analysis of adipose tissue lipolysis, under both non-diabetic and type 2 diabetic conditions.

A comprehensive mechanistic model of adipocyte signaling with layers of confidence

“…We first established a core model of adipocyte signaling (Fig. 2), based on our earlier work [11,14,15]. The included earlier works are the following: 1) a lipolysis model [15] that describes the release of fatty acids and glycerol in response to α-and β-adrenergic receptor agonists and inhibitors, as well as the anti-lipolytic effect of insulin.…”

“…2), based on our earlier work [11,14,15]. The included earlier works are the following: 1) a lipolysis model [15] that describes the release of fatty acids and glycerol in response to α-and β-adrenergic receptor agonists and inhibitors, as well as the anti-lipolytic effect of insulin. The lipolysis model includes intracellular signaling intermediaries and data from both non-diabetic and diabetic patients.…”

“…Within adipocyte signaling, there are several different models for different aspects of the adipocyte, such as glucose uptake, lipolysis, and adiponectin secretion [10][11][12][13][14][15]. The adipocytes of an expanding adipose tissue are central to understand the mechanisms behind type 2 diabetes, and several of the mentioned models are developed using not only data from adipocytes from non-diabetics, but also from type 2 diabetic patients [10][11][12]15]. However, there exist no core model including all these different aspects of adipocyte signaling.…”

“…For methods that divide the problem into sub-problems and adding a single interaction or molecule at a time, the establishment of a core model is key. Within adipocyte signaling, there are several different models for different aspects of the adipocyte, such as glucose uptake, lipolysis, and adiponectin secretion [10][11][12][13][14][15]. The adipocytes of an expanding adipose tissue are central to understand the mechanisms behind type 2 diabetes, and several of the mentioned models are developed using not only data from adipocytes from non-diabetics, but also from type 2 diabetic patients [10][11][12]15].…”

“…Within adipocyte signaling, we have developed several partially overlapping models for different aspects of the adipocyte, such as glucose uptake, lipolysis, and adiponectin secretion [11][12][13][14][15][16]. These models have not been combined into a single high confidence core model.…”