In response to exercise, muscle cells express a protein that appears to set off a virtuous chain of metabolic events. While all the links have yet to be identified, the protein has already been implicated in the secretion of β-aminoisobutyric acid (BAIBA) from muscle cells. BAIBA levels are known to be inversely correlated with fasting blood sugar levels, insulin, triglycerides, and total cholesterol. In addition, as shown by the Framingham Heart Study, BAIBA levels tend to be inversely associated with body mass index.

The protein is called PGC-1α, or transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α. Researchers at Harvard Medical School had demonstrated that PGC-1α regulates metabolic genes in muscle and contributes to the response of muscle to exercise. They also observed that the PGC-1α-mediated response in muscle appears to convey signals capable of influencing metabolism in other tissues, such as fat and liver. The means by which this influence is conveyed, however, remained unclear.

In hopes of learning more about the connection between exercise and virtuous metabolic events, researchers based at Harvard’s Cardiology Division and Cardiovascular Research Center forced the expression of PGC-1α in muscle cells and then looked for metabolites that were secreted from the cells. Through their experiments, which were conducted in cells and mice, the scientists discovered that one such metabolite was BAIBA. Moreover, they found that BAIBA increased fat cells’ expression of genes that are involved with burning calories.

These results were presented January 7 in Cell Metabolism, in an article entitled “β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors.” In this article, the authors described how they employed a metabolomic approach to identify BAIBA as a small molecule myokine. In addition, they wrote, “BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice.”

According to senior author Robert Gerszten, M.D., these findings “bolster the underlying notion that signals generated in one organ—such as exercising muscle—are released into the circulation and influence other tissues such as fat cells and liver.” In addition, the findings suggest that BAIBA may contribute to exercise-induced protection from metabolic diseases.

In their conclusions, the authors note that BAIBA represents the first in its class of nonadrenergic activators of the thermogenic program in white adipose tissue: “The identification of BAIBA as a PGC-1α-mediated and exercise-triggered signal has significant implications not only for our understanding of exercise and its protective role against the development of metabolic diseases, but also for potential therapeutics for type 2 diabetes and the metabolic syndrome.”

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