Three Fat Mice

Obesity continues to be a rising epidemic in many countries and has been linked to various metabolic disorders and metabolic dysregulation. Although there has been much research about the effects of metabolic disorders and dysregulation of cells in relation to obesity,  little is known about the metabolic changes that occur in obese adipose tissue. Given that there is a significant mass of adipose tissue in obese people, understanding the metabolic dysregulation that occurs is important. It has been known that adipose tissues produce and secrete various biologically active molecules that are collectively called adipocytokines/adipokines. The dysregulation of adipocytokines has been shown to have a key role in the pathophysiology of metabolic disorders and atherosclerosis in obesity, one of the leading causes of death around the world.  Nagao et al. uses both static and in vivo analyses to evaluate the metabolic dynamics in obese mice; they found that glutamate and other metabolites of the tricarboxylic acid cycle (TCA) was increased only in white adipose tissue (WAT) of obese mice but not in the liver or skeletal muscles1)1. In addition, in vivo analyses show that glucose derived metabolites were dynamically and specifically produced in obese WAT when compared to lean WAT. It was also found that high levels of one of the metabolites, glutamate, could potentially be associated with adipocyte dysfunction in obesity.

Previous work has shown that hypertrophied adipocytes from obese adipose tissue have increase lipid catabolism given the large excess of free fatty acids and glycerol present. Other work by Nagao et al. reports that adipose tissue secrets uric acid and overproduction of uric acid may contribute to enhanced purine metabolism. It has also be shown that obese subjects and animal models demonstrate a change in the amino acid profiles of their plasma. This means that the metabolic dysregulation of adipose tissue extends beyond what is already known about glucose and fatty acid metabolism and can lead to problems throughout the body . In addition, most research focuses on a single aspect of metabolic dysregulation when it is known that there is an arguably significant overlap between the various metabolic pathways in adipose tissue. Nagao et al. gives a novel report of the metabolic dynamics in in vivo tissues of obese mouse models.

The purpose of this study was to determine the static and dynamic and static metabolic changes in obese adipose tissue when compared to lean adipose tissue and show the association between metabolic changes and what is already known about hypertrophied adipocytes. Nagao et al. focused on the actions of adiponectin, a molecule important in glucose regulation and fatty acid catabolic and insulin, an highly important signaling molecule.

In order to get a baseline of the effect of obesity on adipose tissue metabolic, static metabolic analysis was conducted using LC/MS-MS and GC/MS on epididymal white adipose tissue (Epi WAT). The authors were looking for the relative levels of many metabolites involved in various pathways including glycolysis, pentose phosphate pathway (PPP), TCA cycle, and amino acids. The authors used three types of mice; ob/ob mice that were genetically mutated to eat excessively and were predisposed to obesity, C57 lean control mice, and diet induced obesity (DIO) mice that were fed a high fat/high sucrose diet. When comparing the levels of metabolites in ob/ob and C57 mice the authors found that there were increased levels of glycolytic and TCA metabolites in ob/ob mice. However, there were no significant changes in liver tissues or skeletal muscles indicating that it the metabolic changes occur specifically in adipose tissue.  Amino acid quantification was done using the same methods and found that there were higher concentrations of alanine, and glutamate in ob/ob Epi WAT mice. Next, the authors looked at the DIO mice in order to determine what happens to the metabolite levels when a subject becomes obese. They found that the differences were similar to the comparison between DIO and ob/ob mice. This suggests high levels of glutamate and other TCA associated metabolites in adipose tissues.

Figure 1. ob/ob mouse on left, normal mouse on right

Nagao proposed that either the rapid turnover of the TCA cycle due to excess fatty acids and glycerol present results in high levels of glutamate or that stopping the TCA cycle causes an accumulation of glutamate. In order to investigate and analyze adipose tissues in vivo, Nagao et al. used a combination of C13 isotopic glucose injections and a high-resolution metabolome analysis on ob/ob, C57, and DIO mice. This allowed them to take timed samples to find out where the glucose was, and what it was being broken down into. They determined that the rise in glutamate levels was due to a cataplerotic TCA flux in the adipose tissues in both ob/ob and DIO mice. Figure 2 shows that there was an excess of TCA metabolites across the board in addition to a higher plasma glucose levels in adipose tissue. Figure 3 shows that metabolic turnover in liver and skeletal muscle was not markedly different.  This suggests that the adipose tissues are using the excess glucose to create excess TCA metabolites which in turn may reduce the activity of the TCA cycle. In addition, the fact that increased metabolites were only in adipose tissue, it may reflect a need for rapid turnover and the expansion of adipose cells.

Figure 2. Metabolic turnover analysis of Epi WAT in DIO mice
Figure 3. Metabolic turnover analysis of the liver and skeletal muscle in DIO mice

In vivo analysis suggests the TCA cycle metabolites that are derived from glucose may induce a rise in glutamate in obese adipose tissue to to an abundance of glycogen. These high glutamate levels have negative downstream effects that are implicated in obesity and atherosclerosis. Given our many discussions on how we shouldn’t think of metabolic pathways as isolate events, this work nicely highlights the ways in which many metabolic pathways intersect and are affected by one another.

An interesting thing to look at would be whether or not the metabolic dysregulation can be reverted back to normal activity if the subject were to lose weight and whether or not the metabolic activity is forever changed.

 

  1. Nagao et al. January 2017. Increased Dynamics of Tricarboxylic Acid Cycle and Glutamate Synthesis in Obese Adipose Tissue In Vivo Metabolic Turnover Analysis. J Bio Chm. 292:4469-4483

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