A new study published in Cell Metabolism has advanced the understanding of branched-chain amino acids, BCAA, which are a known biomarker of obesity and insulin resistance in humans. The association between BCAA and insulin resistance was first published in 1969 and it is now widely accepted that they are highly predictive of future diabetes development. The underlying mechanism that explains the link between BCAA and insulin resistance, however, has not been well understood. "These metabolites travel together with poor metabolic health," said Phillip White, an assistant professor of medicine at Duke University and leader of the study. "There's a longstanding historical record of this, but we don't know what it means."
The researchers used a “retro-translational” approach where disease biomarkers are identified and then placed back into animal models to understand what the signals means. The experiments were performed using the Zucker fatty rat, which is a model of obesity and metabolic disease. They found that different organs breakdown BCAAs differently. The liver, which stores fat and produces glucose in prediabetes, breaks down BCAA using a single molecular switch. A kinase enzyme (BDK) provides an inhibitory signal and a phosphatase (PPM1K) provides a signal to activate BCAA breakdown. The researchers showed in the rat model that both inhibiting the kinase or activating the phosphatase both resulted in increased BCAA breakdown, which reduced fat accumulation in the liver and improved glucose regulation.
The team also determined that these same kinase and phosphatase enzymes that regulate BCAA metabolism in the liver also regulate an enzyme, ATP-citrate lyase, an enzyme which has an important role in fat production in the liver. Their experiments illustrated how and where these three enzymes interact in different parts of liver cells. An additional study with a colleague at Duke demonstrated that a diet including a lot of surgery drinks can lead to an imbalance kinase-phosphatase levels, where kinase is high and phosphatase is low, leading to more liver fat and poorer metabolism.
"This helps to explain how and why BCAA are associated with disordered fat metabolism that can lead to type 2 diabetes," said Newgard, one of the authors, who has worked on BCAA in metabolic disease for more than a decade.
The research team plans to conduct longer-term studies in other animal models to corroborate these initial findings. "Although much work remains to be done there's a potential for this to be a new target for treating fatty liver disease," White said.
Image: Duke researchers have identified a key fork in the road for the way the liver deals with carbohydrates, fats and protein. A mutant version of the BDK protein was tagged with green fluorescent protein for an experiment to show it wouldn't enter the mitochondria (red). Image courtesy of Duke Molecular Physiology Institute.