Multi-omics tools reveal new clues to cardiometabolic diseases
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Circulating branched-chain amino acids and branched-chain keto acids are strong predictors of the development of obesity and type 2 diabetes, and targeting them could contribute to improved cardiometabolic health, according to a speaker.
“Our group has been using multiple ‘omics’ tools — metabolomics, proteomics, genomics —to develop molecular profiles of samples from human cardiometabolic disease cohorts, resulting in identification of perturbed branched-chain amino acid (BCAA) metabolism as a feature of obesity, insulin resistance and type 2 diabetes,” Christopher B. Newgard, PhD, director of the Sarah W. Stedman Nutrition and Metabolism Center, founding director of the Duke Molecular Physiology Institute and the W. David and Sarah W. Stedman Distinguished Professor at Duke University School of Medicine in Durham, North Carolina, told Healio. “We have investigated this further and uncovered mechanisms contributing to dysregulated BCAA metabolism and how this contributes to disease pathogenesis.”
Translating metabolite data
It was 2009 when Newgard and colleagues first reported that BCAA and related metabolites are associated with insulin resistance in type 2 diabetes, building on earlier findings that date to the late 1960s. The new observation — gained through the use of metabolomics — showed that BCAA and related metabolites were more associated with insulin resistance and type 2 diabetes than multiple panels of fatty acid-related metabolites, a surprising finding at the time, Newgard said.
“The other novel thing was it was not just the BCAA [associated with type 2 diabetes], but it was also byproducts of their catabolism,” Newgard said during a virtual plenary session on the microbiome presented at the ENDO annual meeting. “Later, we found that branched-chain keto acids — the byproduct of BCAA transamination — are also strongly associated with these disease states.”
The findings come with important prognostic implications outside of a lab, Newgard said. Researchers have since demonstrated that BCAA clusters predicted which study participants would experience improvements in insulin sensitivity in response to diet interventions; other researchers have found that BCAA and related metabolites can predict the development of type 2 diabetes.
Data also show that BCAA and related metabolites are highly responsive to the most efficacious interventions for obesity and type 2 diabetes. In a study comparing adults who underwent bariatric surgery vs. a diet intervention, participants in the bariatric surgery group experienced a sharper drop in BCAA and related metabolites than those who received diet intervention, even though the groups were matched for weight loss, Newgard said.
“That is consistent with bariatric surgery having a stronger impact on glucose homeostasis than does the behavioral intervention,” Newgard said. “One way to get at this is to add branched-chain amino acids to diets or restrict the amount of branched-chain amino acids added to diets ... the more therapeutic line of investigation.”
From rats, to humans
Newgard and colleagues have investigated the mechanistic significance of BCAA in metabolic disease by either supplementing high fat diets fed to normal rats with extra BCAA, resulting in exacerbation of insulin resistance and glucose intolerance, or by restricting the BCAA content of diets fed to genetically obese Zucker rats, which enhances insulin sensitivity and glucose disposal while also having healthful effects on cardiac metabolism. “Like humans with obesity and insulin resistance, the Zucker obese rat has about a 30% to 40% increase in circulating branched-chain amino acids relative to the lean strain,” Newgard said. “When we feed the Zucker obese rat with the restricted [BCAA] diet, we lower the circulating branched-chain amino acid to the levels found in the Zucker lean controls, resulting in clear improvements in an array of cardiometabolic disease phenotypes.”
The Newgard group and others have found that overnutrition, especially when there is high sucrose intake in the diet, induces the kinase BDK and suppresses the phosphatase PPM1K that regulate a rate-limiting BCAA metabolic enzyme, BCKDH. The result is elevated circulating BCAA and branched-chain keto acids levels. They also discovered that the increase in BDK:PPM1K ratio activates a lipogenic enzyme to enhance de novo lipogenesis.
Newgard and colleagues continue their work to answer two key questions: What are the cellular and molecular mechanisms that drive the association of BCAA with metabolic diseases, and is manipulation of BCAA metabolism a viable target for the treatment of metabolic disease in humans?
Research with small molecules that promote the dephosphorylation of BCKDH and its activation have been shown to lower levels of BCAA and levels of all three branched-chain keto acids in animal models, in conjunction with improvements in insulin sensitivity and lipid profiles.
“Perturbation of amino acid metabolism may be among the strongest diagnostic signatures of imminent cardiometabolic disease,” Newgard said. “Perturbed BCAA metabolism reflects and contributes to perturbations in glucose and lipid metabolism, all of which contribute to cardiometabolic diseases.”
Perspective
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Through metabolomic screening, we have learned that branched-chain amino acids are elevated in humans and animal models with insulin resistance. Dr. Newgard went on to show that this correlates very closely with insulin resistance and may even predict the onset of insulin resistance. Lately the field has been wondering, what mechanism links the two? The evidence suggests that accumulation of branched-chain amino acids might be a manifestation of mitochondrial stress. Inability to metabolize or catabolize these branched-chain amino acids leads to their accumulation in the circulation.
Dr. Newgard then pivoted and discussed the relationship between the heart and branched-chain amino acids. Diabetes and insulin resistance increase the likelihood for heart failure by several mechanisms. Importantly when branched-chain amino acids accumulate in the heart, they activate the mTOR signaling pathway. This promotes protein synthesis and cardiac growth, likely driving cardiac hypertrophy. Research suggests that when branched-chain amino acids are restricted in the diet, it reduced the drive to hypertrophy in the heart, particularly in the context of obesity. This shows that branched-chain amino acids are a marker of insulin resistance and could also be a potential marker of increased risk for heart failure.
This research clearly shows us that insulin resistance is not only about sugar, fat or lipids. It is also about other circulating metabolites that may play a pathogenic role in these disorders.
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Newgard CB. Multi-omics approaches define new regulatory nodes in cardiometabolic disease pathogenesis. Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting).
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