Weight Loss-Induced Changes in Adipose Tissue Proteins Associated With Fatty Acid and Glucose Metabolism Correlate With Adaptations in Energy Expenditure

Stefan G. J. A. Camps; Sanne P. M. Verhoef; Nadia Roumans; Freek G. Bouwman; Edwin C. M. Mariman; Klaas R. Westerterp

Disclosures

Nutr Metab. 2015;12(37) 

In This Article

Discussion

Measuring proteins involved in glucose and fatty acid metabolism before and after an 8-wk VLED reflects the metabolic adaptations occurring in adipose tissue linked to energy expenditure. More specifically, the decrease of AldoC, an enzyme of glycolysis, is correlated with the decrease in AEE, and the non-significant change HADHsc, a crucial enzyme for mitochondrial beta-oxidation, is negatively correlated with the adaptation in REE. Furthermore, there is a correlation between the increase in FABP4, the intracellular fatty acid transporter, and the decrease in fat mass, and a correlation between the decrease in AldoC and the decrease in fat free mass. FABP4, AldoC and HADHsc are all positively correlated.

The increased FABP4 after the VLED weight loss is in accordance with previous results in obese subjects.[11,12,44] It is in line with an elevation in intracellular trafficking of fatty acids, which is expected during a negative energy balance when lipolysis is stimulated, with the release of fatty acids from stored triglycerides that can then be used for the mitochondrial beta-oxidation within the fat cell or be secreted from the cell to serve as energy source for other tissues. During conditions of energy restriction, an increase of the lipolysis, and intracellular trafficking of fatty acids, results in a decrease in fat mass. This would be in line with the observed correlation between increase of FABP4 and loss of fat mass.

The decreased AldoC during energy restriction is in accordance with previous results in obese subjects on an energy-restricted diet.[11,12] Concurrently, blood glucose is not changed after energy restriction. The consistently observed decrease in AldoC during energy restriction,[13] suggests that it may be a marker for the glycolytic flux in fat tissue. In addition, a parallel between a decrease of glycolytic flux in fat tissue on one hand and a decrease in activity and muscle use on the other hand, may underlie the observed correlation between the decrease in AldoC and the decrease in AEE. The decrease in AEE is in line with previous studies that show a reduction in physical activity following energy restriction.[23–28] Hypothetically, our results could indicate that during reduced glucose availability as a substrate, there is decreased glycolytic flux in fat tissue and decreased activity in order to preserve blood glucose as a supply for glucose-dependent tissues, such as the brain or red blood cells.[45] Additionally, reduced substrate availability may increase the demand for amino acids as an energy source for other tissues.[46] This would be in keeping with the observed correlation between the decrease in AldoC and the decrease in fat free mass.

HADHsc is not significantly increased at the end of the 8-wk VLED, which has been described before.[11,12] Previously, Bouwman et al. showed a positive correlation between three enzymes of the beta-oxidation (HADHsc, Acetyl-CoA acetyltransferase and Acyl-CoA dehydrogenase) and plasma free fatty acids (FFA) during weight loss maintenance.[13] Apparently, the adipose tissue level of HADHsc parallels the level of plasma FFA. An increased level of FFA during energy restriction would support the energy flux to other peripheral tissues, which could allow lower adaptative thermogenesis in REE. This seems to be in line with the observed correlation between the change in HADHsc and adaptive thermogenesis after the 8-wk VLED. HADHsc is crucial for beta-oxidation.[29,30] Therefore, it is possible that changes in HADHsc reflect changes in the flux of fatty acids through the mitochondrial beta-oxidation pathway. Hypothetically, up-regulation of the mitochondrial beta-oxidation flux might be the consequence of an activated lipolysis, leading to increased plasma FFA and smaller adaptive thermogenesis in REE.

The correlation between FABP4 and HADHsc would also be in line with the HADHsc level reflecting the lipolytic activity, because this would parallel the requirement for intracellular trafficking of fatty acids. Additionally, an increased trafficking and beta-oxidation of fatty acids in the adipose tissue might coincide with a reduced flux through the glycolytic pathway. In this respect, a positive correlation between AldoC and FABP4 and HADHsc would imply that higher fatty acid flux is better for maintenance of glycolytic flux.

A limitation of this study is the use of total adipose tissue biopsy material for Western blotting, because this could have contained other cell types in the stromal vascular fraction. However, the findings of our previous studies indicate that the majority of the isolated protein is derived from adipocytes.[13] Furthermore, beta-actin showed no significant changes and was chosen as a housekeeping control to be able to compare the present results with those of other studies. Although the selected proteins are involved in the major steps of the glucose and fatty acid metabolism and may reflect the capacity of metabolic pathways, it should be noted that protein levels do not represent the actual flux through the pathways. Furthermore, the observed correlations of the adipose tissues cannot be translated into regulatory mechanisms and are not suited to prove causation. Though, the observed outcomes are consistent with intuitive expectations and the hypothesized mechanisms could be subject of future research.

In conclusion, during energy restriction, the molecular metabolism in adipose tissue is linked to energy expenditure. More specifically, the decrease in AldoC is correlated to the decrease in AEE, which could be explained by the preservation of glucose, and the change in HADHsc is correlated to adaptive thermogensis in REE, which could be explained by changes in the beta-oxidation and lipolysis. Overall, our findings reveal a link between changes on a physiological level and changes of the molecular metabolism in fat cells. This shows the important role of adipose tissue in obese people. The molecular changes in adipose tissue as a result of a negative energy balance might even be the underlying driver of adaptations in body composition and energy expenditure (Fig. 2).

Figure 2.

Overview of the network of changes inside the adipose tissue as a result of a negative energy balance and the hypothetical connections with adaptations in body composition and energy expenditure. FABP4, Fatty acid binding protein 4, HADHsc, Short chain 3-hydroxyacyl-CoA dehydrogenase, AldoC, Fructose-bisphosphate aldolase C, FM, fat mass, FFM, fat free mass, FFA, free fatty acids, REE, resting energy expenditure, AEE, activity induced energy expenditure, TEE, total energy expenditure

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