Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues

Abstract

Summary Fatty acid synthase (FASN) predominantly generates straight-chain fatty acids using acetyl-CoA as the initiating substrate. However, monomethyl branched-chain fatty acids (mmBCFAs) are also present in mammals but thought to be primarily diet-derived. Here we demonstrate that mmBCFAs are de novo synthesized via mitochondrial BCAA catabolism, exported to the cytosol by adipose-specific expression of carnitine acetyltransferase (CrAT), and elongated by FASN. Brown fat exhibits the highest BCAA catabolic and mmBCFA synthesis fluxes, whereas these lipids are largely absent from liver and brain. mmBCFA synthesis is also sustained in the absence of microbiota. We identify hypoxia as a potent suppressor of BCAA catabolism that decreases mmBCFA synthesis in obese adipose tissue, such that mmBCFAs are significantly decreased in obese animals. These results identify adipose tissue mmBCFA synthesis as a novel link between BCAA metabolism and lipogenesis, highlighting roles for CrAT and FASN promiscuity that influence acyl-chain diversity in the lipidome.

The Effect of One Anastomosis Gastric Bypass on Branched-Chain Fatty Acid and Branched-Chain Amino Acid Metabolism in Subjects with Morbid Obesity

“…Accordingly, consumption of BCFAs and OCFAs may reduce the risk of cardiovascular disease [10,14] and metabolic disorders [15]. These fatty acids originate from ruminant fat and milk [16], but recent evidence suggests that both BCFAs and OCFAs can also be synthesized in mammalian adipocytes from branched-chain amino acids (BCAAs) [17][18][19]. Wallace et al [19] demonstrated that BCFAs were synthesized de novo in adipose tissue from BCAAs catabolized in mitochondria, and then exported by carnitine acetyltransferase to the cytosol, where they were elongated by fatty acid synthase.…”

“…These fatty acids originate from ruminant fat and milk [16], but recent evidence suggests that both BCFAs and OCFAs can also be synthesized in mammalian adipocytes from branched-chain amino acids (BCAAs) [17][18][19]. Wallace et al [19] demonstrated that BCFAs were synthesized de novo in adipose tissue from BCAAs catabolized in mitochondria, and then exported by carnitine acetyltransferase to the cytosol, where they were elongated by fatty acid synthase. In a previous study, we identified several BCFAs and OCFAs in human serum, and demonstrated that patients with morbid obesity without any dietary or surgical treatment had significantly lower levels of iso-BCFAs than lean controls, but similar OCFA levels [16].…”

Brown and beige adipose tissue regulate systemic metabolism to resist diet-induced obesity through metabolite signals in an inter-organ signaling axis

“…However, adipose tissue is capable of substantial BCAA catabolism and can modulate circulating BCAA concentrations 36 . The rate of BCAA catabolism is particularly high in BAT and can regulate whole-body energy homeostasis [37][38][39] . BCAA catabolic enzymes are downregulated in adipose tissue both in obesity and in insulin resistence 38,40 .…”

Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue

“…Obesity is a strong predisposing factor for many diseases, including hypertension, high cholesterol, diabetes, and cardiovascular diseases. The thermogenic brown adipose tissue (BAT) not only dissipates chemical energy as heat to maintain body temperature and energy balance (Cannon and Nedergaard, 2004;Rosen and Spiegelman, 2014;Yang and Ruan, 2015), but also serves as a metabolic sink for glucose, fatty acids, and branched-chain amino acids to improve metabolic health Wallace et al, 2018;Maurer et al, 2019;Yoneshiro et al, 2019). Therefore, BAT has been increasingly acknowledged as a potential therapeutic target for obesity and related disorders.…”