Leptin Induces Mitochondrial Superoxide Production and Monocyte Chemoattractant Protein-1 Expression in Aortic Endothelial Cells by Increasing Fatty Acid Oxidation via Protein Kinase A*

By Sho-ichi Yamagishi, D. Edelstein, Xue-liang Du, Y. Kaneda, M. Guzmán, M. Brownlee. Journal of Biological Chemistry, 2001

657 citations recorded by the source corpus.

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTFA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid oxidation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS. These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.

Subfields: Endocrine and Autonomic Systems, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/4b9d61dc118d301bc82e3dee2855e2271ba1a4e3

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In Endocrine and Autonomic Systems

1. Barry M. Popkin

In Epidemiology

1. J. Bastard
2. M. Yorek
3. B. Fève
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5. W. Sivitz
6. M. Qatanani
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In Physiology

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Citations in the corpus

• Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. (2018, background): “bovine aortic endothelial cells by increasing fatty acid oxidation via PKA activation, and that its effects are additive with those of glucose [176].”
• Adipokines: the missing link between insulin resistance and obesity. (2008, background): “[14] Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzman M, Brownlee M.”
• Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010, positive): “This follows from evidence that elevated glucose or free fatty acids or both drive the formation of ROS (87, 237, 335), impairing both b-cell insulin release and insulin sensitivity and contributing to the complications of diabetes (31, 87, 117).”
• Mechanisms of obesity-associated insulin resistance: many choices on the menu. (2007, background): “The increase in ROS in the prediabetic stage is more likely due to obesity-related elevations of FAs that cause oxidative stress due to increased mitochondrial uncoupling and oxidation, leading to the increased production of ROS (Wojtczak and Schonfeld 1993; Carlsson et al. 1999; Rao and Reddy 2001;”
• Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. (2004, background): “Similarly, the adipokine leptin (which is involved in the regulation of body adiposity and weight) induces mitochondrial O2 production in cultured bovine aortic endothelial cells by increasing fatty acid oxidation via protein kinase A (171).”
• Cardiovascular actions of insulin. (2007, neutral): “ROS production (306), up-regulates expression of angio-”
• Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. (2002, background): “Elevated FFA can cause oxidative stress due to increased mitochondrial uncoupling (19, 20) and -oxidation (21, 22), leading to the increased production of ROS.”