Journal Club Summary

Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism.

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In this article the investigators studied the involvement of insulin, specifically medial basal hypothalamic (MBH) insulin signaling, on branched-chain amino acid (BCAA) metabolism, as the title implies. Our lab has recently developed an interest in the relationship between BCAAs and insulin sensitivity given some recent data; therefore, I chose this article to learn more about the current findings in this area.

The BCAAs include leucine, isoleucine, and valine, and are among the nine essential amino acids required by the diet. Amino acids are the building blocks for proteins and are important in many biological processes, such as muscle synthesis. When protein is broken down, through a process called proteolysis, it is once again returned to its amino acid constituents. These amino acids are then further broken down into even smaller metabolites. There are multiple reasons why the body would undergo proteolysis, a few examples include to provide a fuel source and/or to maintain blood glucose during fasting and exercise, as well as general protein turnover that is a normal biological function that is required for health. Additionally, drug treatments and certain diseases can cause increases in proteolysis.

The first step of proteolysis primarily occurs in the kidney, heart and muscle tissues which express the branched-chain aminotransferase (BCAT) enzyme that converts BCAAs into their α-keto acids (α-ketoisovalerate, α-keto-β-methylvalerate and α-ketoisocaproate). These α-keto acids can then travel through the circulation to either the liver or adipose tissue (the two main sites of BCAA catabolism) to be further catabolized into Acyl-CoA derivatives, via the enzyme complex branched-chain α-keto acid dehydrogenase (BCKDH), and enter the TCA cycle or other metabolic pathways. As with most biological processes there is a counter enzyme to BCKDH, branched-chain branched-chain α-keto acid dehydrogenase kinase (BCKDK), which phosphorylates BCKDH, thereby inactivating the complex. Defects in these enzymes, either by decreased activities of BCAT or BCKDH, or increased activity of BCKDK, can result the buildup of BCAAs and lead to metabolic complications, as is the case with Maple Syrup Urine Disease.

The buildup of BCAAs in the blood has long been associated with obesity as well as decreased insulin sensitivity/Type 2 Diabetes in multiple model systems (reviewed in Lynch and Adams, 2014) and this is thought to be due to a decrease in BCAA catabolic enzyme proteins as well as increased BCKDK activity (She et al., 2007). Moreover, a decrease in BCAA levels has also seen following weight loss (Lafferrere et al., 2011). Therefore, the authors of this article sought to determine the role of insulin on the regulation of BCAA catabolism.

Most of the studies were conducted on adult male SD rats, but they also used mice, monkeys and worms to answer this research question. They first determined that insulin did in fact lower circulating BCAA levels, and did so in a dose dependent manner, by performing a basal or hyperinsulinemic euglycemic clamp, which is an experiment that is repeated multiple times throughout the publication. They also observed increases in hepatic BCKDH protein expression and activity, as well as decreased BCKDK protein expression. Following these results, they wanted to determine whether these changes were due to neuroendocrine mechanisms, as brain signaling plays a critical role in the regulation of glucose metabolism. To do this they performed another euglycemic clamp and infused MBH insulin (insulin injected into the MBH) or artificial cerebrospinal fluid as a control. Basal plasma BCAA levels were not different between the groups; however, the rats infused with MBH insulin showed a significant decrease in circulating BCAA levels as compared to controls, which was paired with increased hepatic BCKDH protein expression and activity. Furthermore, partially oxidized BCAAs were lower and fully metabolized products were enhanced.

The investigators then wanted to observe what would happen if CNS signaling were ablated. To do this they used various knockout (KO) mouse models including inducible peripheral (PER) and whole body (WB) insulin KO mice, comparing them to wild type mice. Hepatic BCKDH protein levels were higher in the PER mice and lower in the WB mice when compared to controls. This, along with the above information, led the authors to conclude that CNS signaling is an important part of insulin regulation of BCAA catabolism.

Interestingly, long-term high fat feeding and adiposity are associated with impaired BCAA catabolism. This was shown by decreased hepatic BCKDH protein expression and activity in male macaquey monkeys following 1.5 years of high fat feeding when compared to controls. Additionally, body weight and percent adiposity were inversely correlated with BCKDH levels in these monkeys.

In conclusion, the authors’ take-home points were that insulin resistance is the main cause of increased circulating BCAAs in obese and diabetic individuals and hypothalamic insulin signaling is responsible for lowering elevated BCAAs. They also suggest that plasma BCAA levels may serve as a clinical marker for hypothalamic insulin signaling.

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