Controlling elevated blood triacylglycerol translates into substantial health benefits. The present study aimed to evaluate the triacylglycerol-lowering properties of (R)-alpha-lipoic acid (LA) once circulating triacylglycerol levels have become elevated, and identify the molecular targets of LA. Nine-week old male ZDF (fa/fa) rats were fed a chow diet supplemented with 3 g LA per kg diet or pair fed for two weeks (8 rats per treatment). We determined changes in blood triacylglycerol, insulin, non-esterified fatty acids, and ketone bodies concentrations. We analyzed the expression of genes and proteins involved in fatty acid and triacylglycerol metabolism in liver, epididymal fat, and skeletal muscle. Feeding LA to ZDF rats (a) corrected severe hypertriglyceridemia, (b) lowered abdominal fat mass, (c) raised circulating fibroblast growth factor-21 and Fgf21 liver gene expression, (d) repressed lipogenic gene expression of ATP-citrate synthase (Acly), acetyl-coA carboxylase 1 (Acaca), fatty acid synthase (Fasn), sn-glycerol-3-phosphate acyltransferase 1 (Gpam), adiponutrin (Pnpla3) in the liver and adipose tissue, (e) decreased hepatic protein levels of ACC1/2, FASN and 5'-AMP-activated protein kinase catalytic subunit alpha (AMPK alpha), (f) did not change phospho-AMPK alpha/AMPK alpha and phospho-ACC/ACC ratios, (g) stimulated liver gene expression of PPAR alpha target genes camitine O-palmitoyltransferase 1 beta (Cpt1b) and acyl-CoA thioesterase 1 (Acot1) but not carnitine O-palmitoyltransferase 1 beta (Cpt1a). This is evidence that short-term LA feeding to obese rats reverses severe hypertriglyceridemia. FGF21 may mediate the beneficial metabolic effects of LA. (C) 2013 Elsevier Inc. All rights reserved.