Dietary Folic Acid Supplementation Inhibits High-Fat Diet-Induced Body Weight Gain through Gut Microbiota-Associated Branched-Chain Amino Acids and Mitochondria in Mice

The effects of folic acid on body weight gain in obesity and gut microbiota-as-sociated branched-chain amino acids (BCAAs) and mitochondrial function were investi-gated. Three-to four-wk-old male C57BL/6J conventional (CV) and germ-free (GF) mice were fed a high-fat diet (HD), folic acid-supplemented HD (FSHD) and a normal-fat diet (ND) for 25 wk. In CV mice, the HD-induced increases in body weight and plasma BCAA concen-trations, downregulated expression of genes related to BCAA catabolism (Bcat2, Bckdha, or Ppmlk), mitochondrial biogenesis (Pgc-1 a, Coxl, Ndl or Nd6), fusion (Mfnl, Mfn2 or Opal) and mitophagy (Pinkl or Park2), and upregulated expression of the fission -associ-ated gene Drpl in epididymal fat were reversely corrected with FSHD feeding. In contrast, the expression of these genes in the liver was the opposite under HD feeding or folic acid supplementation. In GF mice, plasma BCAA concentrations were much less affected by HD feeding and were reduced by FSHD feeding, with almost no alterations in the expression of genes associated with BCAA catabolism and mitochondrial function. Further analysis indi-cated a correlation between adipose and hepatic Mt C/N and plasma BCAA concentrations, and the latter had a close association with specific gut bacteria. Therefore, dietary folic acid supplementation differentially affected body weight gain, BCAA catabolism, and mitochon-drial dynamics and metabolism under HD feeding between CV and GF mice, suggesting that gut bacteria-altered BCAAs and mitochondria might partially share the responsibility for the beneficial effects of dietary folic acid on obesity.