doi: 10.1161/01.RES.0000177888.79361.a7
© 2005 American Heart Association, Inc.
Letter to the Editor
Obesity and Endothelial Function
Cardiovascular Division, GKT School of Medicine, King’s College, London
To the Editor:
We read with interest the article by Molnar and colleagues1 exploring the effect of dietary-induced obesity on endothelial function in mice. Molnar et al fed male C57BL/6 mice 1 of 2 high-fat diets from 9 weeks of age for 9 weeks. The investigators then studied endothelial function in femoral arteries using wire myography. Mice became obese, hyperglycemic, and hyperinsulinemic. They report that the mice fed the high-fat diet had lower plasma levels of triglycerides and free fatty acids than control animals.
These data differ from previous studies by Uysal et al2 and by our own group.3 In our study, where mice were fed a high-fat diet from 4 weeks of age, free fatty acids measured at 8 weeks were 1.41±0.1 mmol/L in obese mice compared with 0.42±0.1 mmol/L in lean mice (P<0.01). A similar pattern was seen with triglycerides which were 5.4±0.1 in obese mice compared with 2.2±0.1 mmol/L in lean mice (P<0.01).
Molnar et al also reported that vasodilator responses to both acetylcholine and sodium nitroprusside (SNP) were blunted in obese mice although the constrictor response to phenylephrine was augmented.1 Using a very similar feeding model (although we used only 1 diet; 5286 kcal/kg, Bioserve), we found that the vasodilator response to acetylcholine assessed in aortic rings ex vivo was preserved after both 4 and 8 weeks of high-fat feeding.3 (However, this was at least in part attributable to production of the reactive oxygen species hydrogen peroxide, which acted as a vasodilator in this setting.) Furthermore, we did not find differences in the response to SNP. Of particular interest, at both 4 and 8 weeks feeding we found that the vasoconstrictor response to phenylephrine was blunted in obese mice (opposite to Molnar et al1). We also showed that this was likely to be attributable to increased inducible NO synthase (iNOS)-derived NO, based on both pharmacological and biochemical experiments and the study of iNOS knockout mice.
Molnar et al also explored the effect of insulin on phosphorylation of eNOS and Akt after systemic injection. They found that insulin administration did not lead to eNOS phosphorylation in aortae.1 Again in contrast to their study, we have previously reported that systemic insulin administration leads to aortic eNOS phosphorylation, an effect that is blunted in heterozygous insulin receptor knockout mice.4 We also showed that insulin induces aortic vasorelaxation (reduces vasoconstrictor response to phenylephrine) in an endothelial NO–dependent fashion.4 The latter effect is blunted in high-fat fed mice, an abnormality that occurs after the onset of whole-body insulin resistance and obesity.3
The significant differences between the results of Molnar et al1 and our own previous work3,4 warrant some discussion. It is conceivable that the differences observed were a result of the study of different vessels (aorta versus femoral artery) or possible differences in the diet or time of onset of the diet (4 weeks of age versus 9 weeks of age). However, the reasons for these differences warrants clarification in future studies as it may affect the potential clinical relevance of these data.
Acknowledgments
The authors work was supported by The British Heart Foundation.
References
1. Molnar J, Yu S, Mzhavia N, Pau C, Chereshnev I, Dansky HM. Diabetes induces endothelial dysfunction but does not increase neointimal formation in high-fat diet fed C57BL/6J mice. Circ Res. 2005; 96: 1178–1184.
2. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997; 389: 610–614.[CrossRef][Medline] [Order article via Infotrieve]
3. Noronha BT, Li JM, Wheatcroft SB, Shah AM, Kearney MT. Inducible nitric oxide synthase has divergent effects on vascular and metabolic function in obesity. Diabetes. 2005; 54: 1082–1089.
4. Wheatcroft SB, Shah AM, Li JM, Duncan E, Noronha BT, Crossey PA, Kearney MT. Preserved glucoregulation but attenuation of the vascular actions of insulin in mice heterozygous for knockout of the insulin receptor. Diabetes. 2004; 53: 2645–2652.
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