What is BAIBA?

BAIBA structure

β-aminoisobutyric acid, also known as BAIBA, was first identified in 1951, as “a new amino-acid” detected in human urine. [1]

Later it was discovered that BAIBA originates both as a catabolite of the amino acid valine, and of the nucleobase thymine. Thymine degradation gives rise to the R-enantiomer, [2] and the S-enantiomer is a degradation product of valine. [3]

BAIBA can also occur as a metabolic byproduct of some thymine-based drugs. Zidovudine (azidothymidine or AZT) can produce thymine and subsequently BAIBA as catabolites. In obese mice, both AZT and BAIBA enhanced hepatic fat oxidation and decreased body fat mass without causing insulin resistance. [4]
These results were repeated in 2010, [5] when its effects were attributed to the satiety hormone leptin, at the time the centre of anti-obesity attention.

Scientists studying the signalling mechanisms behind the beneficial effects of exercise have identified a number of proteins and small molecules that they believe are responsible for facilitating communication between muscles and lipid stores (fat tissue).

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a transcriptional coactivator that binds to and activates transcription factors that regulate the genes involved in energy metabolism, and is strongly induced by exercise. Indirectly, through a number of downstream effectors, PGC-1α is responsible for many of the metabolic benefits of exercise.

Some of those recently-identified circulating PGC-1α-induced agents include irisin (FNDC5), [6] meteorin-like (metrnl), [7] and BAIBA. [8] While proteins like irisin and metrnl are interesting targets, research around them is conflicted and controversial. [9,10] BAIBA on the other hand, as a more readily-synthesized small-molecule amino acid, may offer more direct potential.

BAIBA’s potential role in metabolic health was illustrated recently in findings from The Framingham Heart Study. The Framingham Heart Study is an ongoing study into cardiovascular disease involving thousands of people from one town (Framingham) that started in 1948, and has contributed much of modern understanding of heart disease and its causes. For example, the fact that diet, exercise, smoking, and cholesterol levels influence risk of atherosclerosis and cardiovascular disease is now widely known, but those findings were based on this study of the residents of Framingham, Massachusetts. In fact the term “risk factor” itself was invented by a Framingham doctor to describe the discovery that lifestyle and environmental factors are variables that influence the probability of an individual developing cardiovascular disease. According to data from participants in the Framingham Heart Study, naturally-occurring BAIBA levels in participants blood were inversely correlated with fasting glucose, insulin, triglycerides, and total cholesterol. [8] Dr Gerszten, director of clinical and translational research at the Massachusetts General Hospital Institute for Heart, Vascular and Stroke Care, summarized the correlation as “The more BAIBA, the lower your insulin, the better your glucose, the less you weigh.” [11]

Lipolysis and beta-oxidation are the processes by which energy reserves, stored as fat, are released and burned for fuel. According to current research, BAIBA acts as a kind of messenger signalling molecule, triggered by the breakdown of amino acids during exercise, that helps the body respond to demands for more energy by increasing this beta-oxidation of fatty acids. [8]

Brown fat is a thermogenic tissue found in hibernating animals in large amounts, and in humans in small amounts. It keeps hibernators warm in winter, which is why it was originally (though inaccurately) described as the “hibernating gland”. [12] In fact the evolutionary success of mammals as a whole group may be attributed, at least in part, to brown fat, due to the advantages it confers to survival in cold conditions, particularly to infant survival rates. [13]

Whereas white fat stores energy (as triglycerides), releasing it as required to be burned elsewhere to generate ATP, brown fat cells burn triglycerides to produce heat (through mitochondrial uncoupling) facilitated by uncoupling protein 1 (or UCP-1), also known as “thermogenin”.

Until recently white fat and brown fat were believed to be the only two types of adipose tissue, though a third type, known variously as “beige fat” or “brite fat” has since been discovered. This “beige” fat has some of the characteristics of brown fat (like containing thermogenin, and burning energy to produce heat), but exists within white fat deposits. [14] Somewhat remarkably, it has been found that a number of nutraceutical agents are capable of inducing white fat cells, and white fat cell precursors, to develop into this thermogenic beige/brite fat tissue, sparking hopes that developments in this field will yield effective treatments for obesity and metabolic disorders.

BAIBA is one of the agents that induces white adipose tissue (ordinary fat cells) to differentiate into UCP1-positive thermogenic adipocytes (beige fat cells that express brown fat-specific genes) [8]

Summary

  • Endurance exercise upregulates PGC-1a
  • PGC-1a increases the breakdown of amino acids, raising serum levels of beta-aminoisobutyric acid (BAIBA)
  • BAIBA increases lipolysis and hepatic beta-oxidation of fatty acids
  • BAIBA reduces weight and fat gain in mice
  • BAIBA induces the “browning” of white fat
  • Circulating BAIBA levels are inversely correlated with cardiovascular and metabolic risk factors in humans.

References:
[1] Crumpler, H.R., Dent, C.E., Harris, H., and Westall, R.G. (1951). beta-Aminoisobutyric acid (alpha-methyl-beta-alanine); a new amino-acid obtained from human urine. Nature 167, 307–308.
[2] Solem, E. (1974). The absolute configuration of β-aminoisobutyric acid formed by degradation of thymine in man. Clinica Chimica Acta 53, 183–190.
[3] Van Kuilenburg, A.B.P., Stroomer, A.E.M., Van Lenthe, H., Abeling, N.G.G.M., and Van Gennip, A.H. (2004). New insights in dihydropyrimidine dehydrogenase deficiency: a pivotal role for beta-aminoisobutyric acid? Biochem J 379, 119–124.
[4] Maisonneuve, C., Igoudjil, A., Begriche, K., Lettéron, P., Guimont, M.-C., Bastin, J., Laigneau, J.-P., Pessayre, D., and Fromenty, B. (2004). Effects of zidovudine, stavudine and beta-aminoisobutyric acid on lipid homeostasis in mice: possible role in human fat wasting. Antivir. Ther. (Lond.) 9, 801–810.
[5] Begriche, K., Massart, J., and Fromenty, B. (2010). Effects of β-aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesity. Fundam Clin Pharmacol 24, 269–282.
[6] Zhang, Y., Li, R., Meng, Y., Li, S., Donelan, W., Zhao, Y., Qi, L., Zhang, M., Wang, X., Cui, T., et al. (2014). Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 63, 514–525.
[7] Rao, R.R., Long, J.Z., White, J.P., Svensson, K.J., Lou, J., Lokurkar, I., Jedrychowski, M.P., Ruas, J.L., Wrann, C.D., Lo, J.C., et al. (2014). Meteorin-like Is a Hormone that Regulates Immune-Adipose Interactions to Increase Beige Fat Thermogenesis. Cell 157, 1279–1291.
[8] Roberts, L.D., Boström, P., O’Sullivan, J.F., Schinzel, R.T., Lewis, G.D., Dejam, A., Lee, Y.-K., Palma, M.J., Calhoun, S., Georgiadi, A., et al. (2014). β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors. Cell Metabolism 19, 96–108.
[9] Raschke, S., Elsen, M., Gassenhuber, H., Sommerfeld, M., Schwahn, U., Brockmann, B., Jung, R., Wisløff, U., Tjønna, A.E., Raastad, T., et al. (2013). Evidence against a Beneficial Effect of Irisin in Humans. PLoS ONE 8, e73680.
[10] Butler, D. (2013). Mystery over obesity “fraud.” Nature 501, 470–471.
[11] Mass. General scientists discover molecule that may underlie benefits of exercise By Carolyn Y. Johnson. Boston.com
[12] Sheldon, E.F. (1924). The so-called hibernating gland in mammals: A form of adipose tissue. Anat. Rec. 28, 331–347.
[13] Cannon, B., and Nedergaard, J. (2004). Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359.
[14] Harms, M., and Seale, P. (2013). Brown and beige fat: development, function and therapeutic potential. Nat Med 19, 1252–1263.

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