Leptin Activates Cardiac Fatty Acid Oxidation Independent of Changes in the AMP-activated Protein Kinase-Acetyl-CoA Carboxylase-Malonyl-CoA Axis

Abstract

Leptin regulates fatty acid metabolism in liver, skeletal muscle, and pancreas by partitioning fatty acids into oxidation rather than triacylglycerol (TG) storage. Although leptin receptors are present in the heart, it is not known whether leptin also regulates cardiac fatty acid metabolism. To determine whether leptin directly regulates cardiac fatty acid metabolism, isolated working rat hearts were perfused with 0.8 mM [9,10-3 H]palmitate and 5 mM [1-14 C]glucose to measure palmitate and glucose oxidation rates. Leptin (60 ng/ml) significantly increased palmitate oxidation rates 60% above control hearts (p < 0.05) and decreased TG content by 33% (p < 0.05) over the 60-min perfusion period. In contrast, there was no difference in glucose oxidation rates between leptin-treated and control hearts. Although leptin did not affect cardiac work, oxygen consumption increased by 30% (p < 0.05) and cardiac efficiency was decreased by 42% (p < 0.05). AMP-activated protein kinase (AMPK) plays a major role in the regulation of cardiac fatty acid oxidation by inhibiting acetyl-CoA carboxylase (ACC) and reducing malonyl-CoA levels. Leptin has also been shown to increase fatty acid oxidation in skeletal muscle through the activation of AMPK. However, we demonstrate that leptin had no significant effect on AMPK activity, AMPK phosphorylation state, ACC activity, or malonyl-CoA levels. AMPK activity and its phosphorylation state were also unaffected after 5 and 10 min of perfusion in the presence of leptin. The addition of insulin (100 microunits/ml) to the perfusate reduced the ability of leptin to increase fatty acid oxidation and decrease cardiac TG content. These data demonstrate for the first time that leptin activates fatty acid oxidation and decreases TG content in the heart. We also show that the effects of leptin in the heart are independent of changes in the AMPK-ACC-malonyl-CoA axis.Leptin is a peptide hormone synthesized by adipocytes (1) that plays a key role in the regulation of appetite and energy expenditure through its actions in the hypothalamus (reviewed in Ref. 2). Accumulating evidence now suggests that leptin can also regulate energy homeostasis through direct actions on peripheral lipid and glucose metabolism (reviewed in Ref. 3). In liver, skeletal muscle, and pancreas, leptin partitions fatty acids toward fatty acid oxidation rather than TG 1 storage. For instance, in vivo elevation of leptin levels in normal rats leads to a depletion of TG content in liver, skeletal muscle, and pancreas without an increase in plasma fatty acids or ketones, suggesting intracellular oxidation (4). Furthermore, leptin treatment of isolated muscle results in increased fatty acid oxidation and decreased incorporation of fatty acids into TG (5-7). The mechanism by which leptin increases fatty acid oxidation and decreases TG content in peripheral tissues is not completely understood. Recently, leptin was suggested to acutely increase fatty acid oxidation in skeletal muscle through the activation of AMP-activated protein kinas...

Effect of Obesity and Insulin Resistance on Myocardial Substrate Metabolism and Efficiency in Young Women

“…These previous studies demonstrated that increased MV O 2 , MFAUp, and MFAO were associated with decreased efficiency. [27][28][29] The results of the present study show that obese humans, who have alterations in MV O 2 and myocardial fatty acid metabolism, also have changes in the translation of energy to contractile function.…”

“…The young, obese women in the present study displayed evidence of insulin resistance, on the basis of plasma glucose AUC during an oral glucose tolerance test, that was presumably responsible for increased MFAUp, MFAU, and MFAO, although increased levels of adipokines, such as leptin, may also be partly responsible for the increased myocardial fatty acid metabolism in obesity. 29,30 In addition, hyperinsulinemia, which stimulates insulin-like growth factor-1 (IGF-1) receptors, is also likely involved in the pathogenesis of myocardial hypertrophy observed in obese women in the present study. 31 However, obese subjects in the present study did not yet manifest clinical or echocardiographic evidence of contractile dysfunction, which suggests that more prolonged alterations in substrate metabolism and increased myocardial mitochondrial oxidative stress are needed to decrease LV contractility.…”

“…This pattern of substrate metabolism parallels that seen in obese animals that are studied early in the course of their progression from insulin resistance to type II diabetes and in isolated working rat heart models that are infused with leptin. 5,29 The increases in MFAUp and MFAO in these models were not accompanied by a concomitant decrease in glucose oxidation.…”

Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver

“…Leptin may also have effects on the AMPK system. It has been shown that leptin directly and indirectly activates AMPK in skeletal muscle (7) and white adipocytes (44), although not in heart (45). The effects of leptin on AMPK in liver are not fully known.…”

Activation of leptin expression by an inhibitor of carnitine palmitoyltransferase-1

“…6 One recent report indicates that leptin can also stimulate fatty acid oxidation independent of changes in AMPK activity. 7 In addition to these direct effects on fatty acid metabolism, leptin also activates sympathetic nervous system activity 2 leading to adipocyte lipolysis and increased systemic fatty acid oxidation. 2 Thus, serum leptin can activate systemic fatty acid oxidation both directly at the level of intermediary metabolism and indirectly via modulation of sympathetic tone.…”