Fatty acid oxidation and triacylglycerol hydrolysis are enhanced after chronic leptin treatment in rats.

Leptin acutely increases fatty acid (FA) oxidation and triacylglycerol (TG) hydrolysis and decreases TG esterification in oxidative rodent muscle. However, the effects of chronic leptin administration on FA metabolism in skeletal muscle have not been examined. We hypothesized that chronic leptin treatment would enhance TG hydrolysis as well as the capacity to oxidize FA in soleus (SOL) muscle. Female Sprague-Dawley rats were infused for 2 wk with leptin (LEPT; 0.5 mg x kg(-1) x day(-1)) by use of subcutaneously implanted miniosmotic pumps. Control (AD-S) and pair-fed (PF-S) animals received saline-filled implants. Subsequently, FA metabolism was monitored for 45 min in isolated, resting, and contracting (20 tetani/min) SOL muscles by means of pulse-chase procedures. Food intake (-33 +/- 2%, P < 0.01) and body mass (-12.5 +/- 4%, P = 0.01) were reduced in both LEPT and PF-S animals. Leptin levels were elevated (+418 +/- 7%, P < 0.001) in treated animals but reduced in PF-S animals (-73 +/- 8%, P < 0.05) relative to controls. At rest, TG hydrolysis was increased in leptin-treated rats (1.8 +/- 2.2, AD-S vs. 23.5 +/- 8.1 nmol/g wet wt, LEPT; P < 0.001). In contracting SOL muscles, TG hydrolysis (1.5 +/- 0.6, AD-S vs. 3.6 +/- 1.0 micromol/g wet wt, LEPT; P = 0.02) and palmitate oxidation (18.3 +/- 6.7, AD-S vs. 45.7 +/- 9.9 nmol/g wet wt, LEPT; P < 0.05) were both significantly increased by leptin treatment. Chronic leptin treatment had no effect on TG esterification either at rest or during contraction. Markers of overall (citrate synthase) and FA (hydroxyacyl-CoA dehydrogenase) oxidative capacity were unchanged with leptin treatment. Protein expression of hormone-sensitive lipase (HSL) was also unaltered following leptin treatment. Thus leptin-induced increases in lipolysis are likely due to HSL activation (i.e., phosphorylation). Increased FA oxidation secondary to chronic leptin treatment is not due to an enhanced oxidative capacity and may be a result of enhanced flux into the mitochondrion (i.e., carnitine palmitoyltransferase I regulation) or electron transport uncoupling (i.e., uncoupling protein-3 expression).