HEALTH NEWS

Study Title:

Obesity Causes Heart Disease

Study Abstract

Hyperleptinemia accompanying obesity affects endothelial nitric oxide (NO) and is a serious factor for vascular disorders. NO, superoxide (O2–), and peroxynitrite (ONOO–) nanosensors were placed near the surface (5 ± 2 µm) of a single human umbilical vein endothelial cell (HUVEC) exposed to leptin or aortic endothelium of obese C57BL/6J mice, and concentrations of calcium ionophore (CaI)-stimulated NO, O2–, ONOO– were recorded. Endothelial NO synthase (eNOS) expression and L-arginine concentrations in HUVEC and aortic endothelium were measured. Leptin did not directly stimulate NO, O2–, or ONOO– release from HUVEC. However, a 12-h exposure of HUVEC to leptin increased eNOS expression and CaI-stimulated NO (625 ± 30 vs. 500 ± 24 nmol/l control) and dramatically increased cytotoxic O2– and ONOO– levels. The [NO]-to-[ONOO–] ratio ([NO]/[ONOO–]) decreased from 2.0 ± 0.1 in normal to 1.30 ± 0.1 in leptin-induced dysfunctional endothelium. In obese mice, a 2.5-fold increase in leptin concentration coincided with 100% increase in eNOS and about 30% decrease in intracellular L-arginine. The increased eNOS expression and a reduced L-arginine content led to eNOS uncoupling, a reduction in bioavailable NO (250 ± 10 vs. 420 ± 12 nmol/l control), and an elevated concentration of O2– (240%) and ONOO– (70%). L-Arginine and sepiapterin supplementation reversed eNOS uncoupling and partially restored [NO]/[ONOO–] balance in obese mice. In obesity, leptin increases eNOS expression and decreases intracellular L-arginine, resulting in eNOS an uncoupling and depletion of endothelial NO and an increase of cytotoxic ONOO–. Hyperleptinemia triggers an endothelial NO/ONOO– imbalance characteristic of dysfunctional endothelium observed in other vascular disorders, i.e., atherosclerosis and diabetes.



From press release:

Obese people who don’t have high cholesterol or diabetes might think they’re healthy – despite the extra pounds. But new Ohio University research suggests that obesity raises levels of the hormone leptin, which can be as big a threat to the cardiovascular system as cholesterol.

Tadeusz Malinski and colleagues have published the first study to directly observe how high levels of leptin can create a cascade of harmful biochemical changes in the body. Leptin, a peptide hormone produced by fat cells, helps regulate body weight by acting on the hypothalamus to suppress appetite and burn stored fat.

But an excess of fat in the body can produce too much of the hormone, which, in turn, can lower levels of bioavailable nitric oxide. Nitric oxide, produced by the endothelial cells, supports healthy cardiovascular function by relaxing blood vessels and maintaining good blood flow, explained Malinski, who has developed special nanosensors that can detect levels of the substance.

In addition, Malinski found that the high levels of leptin stimulate greater production of superoxide. It reacts with nitric oxide to create peroxynitrite, a very toxic molecule that can impact DNA replication and damage endothelial cells in the vascular system.

“The nanosensors provide a more direct method of determining what processes are occurring in the body. Previously, researchers didn’t have a clear idea of how this works,” said Malinski, the Marvin and Ann Dilley White Distinguished Professor of Biomedical Sciences at Ohio University.

The study, which examined the process in single human cells and also obese mice models, was published in a recent issue of the American Journal of Physiology – Heart and Circulatory Physiology.

Though obesity is closely associated with heart failure, scientists haven’t fully understood the relationship, Malinski noted. The new study suggests that increased levels of leptin alone can cause long-term cardiovascular damage similar to hypertension, arthrosclerosis, diabetes and other disorders.

“Now that we know the exact molecules responsible for the damage, we can design a method to mollify the effect of obesity on the cardiovascular system,” Malinski said.

The study was funded by the National Heart, Lung and Blood Institute, the Marvin White Endowment and the Biomimetic Nanoscience and Nanotechnology Program at Ohio University.

Co-authors on the study were Mykhaylo Korda and Ruslan Kubant, both research associates in the Malinski lab at Ohio University.

Study Information

Mykhaylo Korda, Ruslan Kubant, Stephen Patton, and Tadeusz Malinski
Leptin-induced endothelial dysfunction in obesity.
American Journal of Physiology – Heart and Circulatory Physiology
2008 August
Ohio University.