Invited Speaker

Recent Discovery of the Effects of Beta-Aminoisobutyric Acid on Lipid Homeostasis: Mechanisms and Possible Relevance for the Prevention of Obesity
Bernard Fromenty
France

We recently discovered that beta-aminoisobutyric acid (BAIBA), a natural beta-amino acid derived from thymine, could enhance fatty acid oxidation (FAO) and prevent diet-induced obesity in mice. Indeed, in 2003 and 2004, we showed for the first time that the antiretroviral drugs zidovudine (AZT) and stavudine (d4T) were able to stimulate mitochondrial FAO in liver and limit the gain of fat mass in Swiss mice fed a standard chow (1,2). These effects were not observed with zalcitabine (ddC), lamivudine (3TC) and didanosine (ddI), thus suggesting that the thymine moiety of AZT and d4T could be involved. Indeed, administration to Swiss mice of the thymine catabolite BAIBA led to higher hepatic FAO and lower body fat mass (1,2). Importantly, the reduction of body fatness was not observed in C57BL/6J ob/ob mice that are unable to produce leptin (2). Thus, it appeared that some of the metabolic effects of BAIBA could require this adipokine. However, whereas BAIBA did not limit obesity and hepatic steatosis in ob/ob mice, it reduced liver cytolysis and inflammation in this model (3). In order to clarify the mechanism whereby BAIBA could act through leptin, we subsequently undertook a study in C57BL/6-ob/+ mice that are partially deficient in leptin. Importantly, these mice are prone to obesity and related metabolic disorders when they are fed a high-calorie (HC) diet (4). Our data showed that BAIBA was able to prevent, fully or partially, the occurrence of body fatness, steatohepatitis (i.e. steatosis and necroinflammation), glucose intolerance and hypertriglyceridemia in this murine model (3). All these effects were associated with higher leptin levels in plasma, and to a lesser extent in WAT. In addition, BAIBA increased the hepatic expression of the mitochondrial FAO enzyme carnitine palmitoyltransferase 1 (CPT-1) and the phosphorylated form of acetyl-CoA carboxylase (pACC, the inactivated form of the enzyme), thus suggesting decreased levels of malonyl-CoA (3). A reduction of the hepatic expression of several enzymes involved in glycolysis and de novo lipogenesis was also observed (3). Importantly, different studies showed that leptin can present such metabolic effects in liver. Interestingly, whereas BAIBA reduced body fat mass by 40% in ob/+ mice fed the HC diet, it lowered body adiposity by 27% in +/+ mice fed the same HC diet, thus suggesting that the favorable effect of BAIBA on body adiposity is optimal in the context of partial leptin deficiency (3). Finally, BAIBA significantly stimulated the secretion of leptin and adiponectin in isolated ob/+ adipose cells, whereas this effect was marginal in +/+ cells (3,5). Interestingly, our in vitro investigations also indicated that BAIBA could favour lipolysis (3). Thus, supplementation with BAIBA could help to prevent obesity and some related metabolic disorders, in particular in individuals with relatively low plasma levels of leptin and adiponectin. Importantly, a patent is pending for BAIBA (6).

References:
1- Note R et al. Antimicrob Agents Chemother 2003, 47: 3384-3392.

2- Maisonneuve C et al. Antivir Ther 2004, 9: 803-812.

3- Begriche K et al. Obesity 2008, 16: 2053-2067.

4- Begriche K et al. Am J Physiol Endocrinol Metab 2008, 294: E939-E951.

5- Begriche K et al. Fundam Clin Pharmacol 2009 (in press).

6- Fromenty B , Maisonneuve C, Igoudjil A, Lettéron P, Begriche K: Patent pending "Method for the treatment of diseases linked to the accumulation of triglycerides and cholesterol". Priority data: PCT/IB03/01463, April 18, 2003. International extension PCT/IB2004/001166 (WO2004/091599), April 15, 2004.