Relating tissue/organ energy expenditure to metabolic fluxes in mouse and human: experimental data integrated with mathematical modeling.

Gerald M Saidel,Nicola Lai,China M Kummitha,Satish C Kalhan

doi:10.14814/phy2.12159

Gerald M Saidel, Nicola Lai + Show 2 more

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https://doi.org/10.14814/phy2.12159

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Abstract

Mouse models of human diseases are used to study the metabolic and physiological processes leading to altered whole‐body energy expenditure (EE), which is the sum of EE of all body organs and tissues. Isotopic techniques, arterio‐venous difference of substrates, oxygen, and blood flow measurements can provide essential information to quantify tissue/organ EE and substrate oxidation. To complement and integrate experimental data, quantitative mathematical model analyses have been applied in the design of experiments and evaluation of metabolic fluxes. In this study, a method is presented to quantify the energy expenditure of the main mouse organs using metabolic flux measurements. The metabolic fluxes and substrate utilization of the main metabolic pathways of energy metabolism in the mouse tissue/organ systems and the whole body are quantified using a mathematical model based on mass and energy balances. The model is composed of six organ/tissue compartments: brain, heart, liver, gastrointestinal tract, muscle, and adipose tissue. Each tissue/organ is described with a distinct system of metabolic reactions. This model quantifies metabolic and energetic characteristics of mice under overnight fasting conditions. The steady‐state mass balances of metabolites and energy balances of carbohydrate and fat are integrated with available experimental data to calculate metabolic fluxes, substrate utilization, and oxygen consumption in each tissue/organ. The model serves as a paradigm for designing experiments with the minimal reliable measurements necessary to quantify tissue/organs fluxes and to quantify the contributions of tissue/organ EE to whole‐body EE that cannot be easily determined currently.

Highlights

Mouse-human metabolism relationMouse models are valuable tools to investigate and identify metabolic processes that regulate energy metabolism and body weight (BW) (Tam et al 2009; Guo and Hall 2011)
Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
The methodology developed in this study can be useful in the design of experimental studies to quantify the metabolic fluxes affecting energy expenditure in mouse models of disease

Summary

Introduction

Mouse-human metabolism relationMouse models are valuable tools to investigate and identify metabolic processes that regulate energy metabolism and body weight (BW) (Tam et al 2009; Guo and Hall 2011). The results obtained from the models in mice can be translated to humans to a large extent because mice and humans share similar physiological functions at cellular, tissue/organ, and whole-body levels (Rangarajan and Weinberg 2003; Shultz et al 2007). Even though mice and humans share metabolic similarities associated with energy metabolism, the magnitude of these processes in organs and tissues differ significantly between them. It is important to identify and quantify the metabolic processes that lead to those distinctions in mice and a 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society

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