Sedentary behaviour is a key determinant of metabolic inflexibility

Abstract

Metabolic flexibility is defined as the ability to adapt substrate oxidation rates in response to changes in fuel availability. The inability to switch between the oxidation of lipid and carbohydrate appears to be an important feature of chronic disorders such as obesity and type 2 diabetes. Laboratory assessment of metabolic flexibility has traditionally involved measurement of the respiratory quotient (RQ) by indirect calorimetry during the fasted to fed transition (e.g. mixed meal challenge) or during a hyperinsulinaemic-euglycaemic clamp. Under these controlled experimental conditions, 'metabolic inflexibility' is characterized by lower fasting fat oxidation (higher fasting RQ) and/or an impaired ability to oxidize carbohydrate during feeding or insulin-stimulated conditions (lower postprandial or clamp RQ). This experimental paradigm has provided fundamental information regarding the role of substrate oxidation in the development of obesity and insulin resistance. However, the key determinants of metabolic flexibility among relevant clinical populations remain unclear. Herein, we propose that habitual physical activity levels are a primary determinant of metabolic flexibility. We present evidence demonstrating that high levels of physical activity predict metabolic flexibility, while physical inactivity and sedentary behaviours trigger a state of metabolic 'inflexibility', even among individuals who meet physical activity recommendations. Furthermore, we describe alternative experimental approaches to studying the concept of metabolic flexibility across a range of activity and inactivity. Finally, we address the promising use of strategies that aim to reduce sedentary behaviours as therapy to improve metabolic flexibility and reduce weight gain risk.

Keywords: Physical activity; glucose metabolism; insulin sensitivity; lipid metabolism; obesity; physical inactivity; weight regulation.

© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Figures

Figure 1. The variance‐based concept of metabolic flexibility

Physical activity and inactivity levels modulate the response to challenges (stressors) to the system. The variation in 24 h insulin and respiratory quotient (RQ) represent the regulator and effector components of the system, respectively. It is the allostatic relationship between the regulator and effector responses that are measured experimentally and inform on the degree of metabolic flexibility. A physically active metabolically flexible individual is characterized by a high variance in RQ and low variance in plasma insulin concentration (A). To the contrary, a physically inactive, metabolically inflexible individual has a low amplitude RQ response to marked changes in insulin levels (B), resulting in a low variance in RQ for a high variance in insulin. By plotting the variances of 24 h RQ and insulin, we obtain a clear graphic representation of the effects of physical activity status on metabolic flexibility status (C). Another way of graphically representing the data is a log transformation plot of the RQ and insulin percentiles (D; see text for details).

Figure 2. Metabolic flexibility represented by variances and percentile–percentile plots of RQ and insulin

Data shown were collected on 8 women and 8 men who performed a 5 h oral glucose tolerance test before and after a 7 day bed rest study (Blanc et al. 2000b). In A, the decrease in metabolic flexibility after bed rest is indicated by a shift in the relationship between the insulin and RQ variance. Values plotted in B and C represent the 1st, 5th, 10th, the lower quartile, the median, the upper quartile, 90th, 95th and 99th percentiles of RQ and insulin. The significantly steeper slope in the percentile–percentile plots indicate a decrease in metabolic flexibility following bed rest.

Figure 3. Physical activity and exercise exert influences on metabolic flexibility through regulation of energy balance and fuel homeostasis

Based on J. P. Flatt's theory (Flatt, 1995, 2004), the main regulator of lipid oxidation, and hence balance, is carbohydrate availability and oxidation. While an increase in carbohydrate intake leads to an increase in carbohydrate oxidation, an increase in fat intake does not trigger fat oxidation and results in fat storage. By utilizing glycogen stores, exercise increases fat oxidation. By being one of the main components of total energy expenditure, physical acivity and exercise further contribute to the regulation of energy balance. Energy balance is the result of energy intake composed of lipids, carbohydrates and proteins on one side and energy expenditure composed of physical activity energy expenditure, thermic effect of food (TEF) and resting metabolic rate (RMR). Both energy and oxidative balance are key factors involved in the regulation of body weight.

Figure 4. Contrasting levels of habitual physical activity predict adaptations to high fat feeding, dietary lipid oxidation and energy balance

In reponse to high fat intake, physical activity helps to adjust fat oxidation to fat availability (A; Smith et al. 2000). There is a positive association between changes in dietary fat oxidation and activity energy expenditure along this same physical activity continuum (B; based on Bergouignan et al. 2013b). Because of the effects on glycogen storage, there exists a tight negative relationship between fat and carbohydrate balance along the physical activity continuum (C; based on Smith et al. 2000). Together these relationships provide a higher fat tolerance to active individuals than inactive individuals, i.e. active individuals are able to achieve a stable energy balance at a higher fat intake compared to inactive individuals (D; based on Stubbs et al. 2004).