Leptin is essential in maintaining normal vascular compliance independent of body weight

Sikka, Gautam; Yang, Ronghua; Reid, Shaina N.; Benjo, Alexandre; Koitabashi, Norimichi; Camara, Andre; Baraban, Ezra; O’Donnell, Christopher P.; Berkowitz, Dan E.; Barouch, Lili A.

doi:10.1038/ijo.2009.208

Cited by 25 publications

(16 citation statements)

References 12 publications

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“…For example, older (7-9 months old) and younger (2.5-3 months old) ob/ob mice, as well as db/db mice, exhibited higher aortic PWVs and lower aortic compliance. [23][24][25] In addition, mechanical testing of the aortas from obese Zucker (fa/fa) rats showed greater stiffness in the circumferential and longitudinal directions. 26 However, the mechanistic insight into the link between obesity and aortic stiffening has been lacking.…”

Section: Discussionmentioning

confidence: 99%

Increased Aortic Stiffness and Attenuated Lysyl Oxidase Activity in Obesity

Chen¹,

Tsai²,

Tai

et al. 2013

ATVB

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Objective-One potential mechanism through which obesity exerts adverse effects on the vascular system is by increasing aortic stiffness, a change known to be predictive of increased cardiovascular mortality. The aim of this study was to investigate the pathophysiology that links obesity to aortic stiffening. Approach and Results-Obese (ob/ob) mice were used to examine physical, morphological, and molecular changes in the aorta in response to obesity. ob/ob mice had increased aortic pulse wave velocity and tissue rigidity. ob/ob aorta exhibited decreases of lysyl oxidase (LOX) activity and cross-linked elastin, and increases of elastin fragmentation and elastolytic activity. The aortas of ob/ob mice were surrounded by a significant amount of proinflammatory and pro-oxidative perivascular adipose tissue. In vitro studies revealed that the conditioned medium from differentiated adipocytes or the perivascular adipose tissue of ob/ob mice attenuated LOX activity. Furthermore, inhibition of LOX in wild-type lean mice caused elastin fragmentation and induced a significant increase in pulse wave velocity. Finally, we found that obese humans had stiffer arteries and lower serum LOX levels than do normal-weight humans. Conclusion-Our results demonstrated that obesity resulted in aortic stiffening in both humans and mice, and established a causal relationship between LOX downregulation and aortic stiffening in obesity.

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Section: Discussionmentioning

confidence: 99%

Increased Aortic Stiffness and Attenuated Lysyl Oxidase Activity in Obesity

Chen¹,

Tsai²,

Tai

et al. 2013

ATVB

View full text Add to dashboard Cite

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“…However, data are not available in nondiabetic humans, in part because long-term caloric restriction is difficult to achieve in humans. Short-term low-calorie diet caused weight reduction and successfully reduced arterial stiffness and increase vascular compliance in ob / ob mice [40] and obese men [41] when given for 4 and 12 weeks, respectively. Because of the short duration of this intervention, it is likely that the reduced arterial stiffness is primarily due to the lowering of vascular resistance in the smaller vessels rather than slowing down the stiffness of the larger ones.…”

Section: Caloric Restrictionmentioning

confidence: 96%

Molecular Basis of Arterial Stiffening: Role of Glycation – A Mini-Review

Sell

Monnier²

2012

Gerontology

260

183

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Arterial stiffening is a progressive, ubiquitous and irreversible aging process that is interwoven with and accelerated by various diseases such as diabetes, atherosclerosis and hypertension. In large arteries, aging is characterized by decreased turnover of collagen and elastin and increased advanced glycation end-products (AGEs) and cross-links. Elastic fibers undergo lysis and disorganization subsequent to their replacement by collagen and other matrix components. These events cause the loss of elasticity and induce stiffening. Conceptual approaches to minimize AGE accumulation in arteries include caloric restriction, exercise, low dietary intake of AGEs, deglycation enzymes, increased clearance of AGEs, antagonists of AGE receptors and pharmaceutical interventions. Much optimism exists in the ability of ‘AGE breakers’ such as alagebrium (ALT-711) to cleave AGE cross-links and reverse the age-related stiffening of arteries. However, there is little evidence that these agents actually break pre-existing AGE cross-links in vivo. In contrast, many of these anti-AGE agents share in common the ability to chelate metals, thus acting as inhibitors of metal-catalyzed AGE and protein carbonyl formation. Future work on interventions into the causes of arterial stiffness in aging needs to address more rigorously the relationship between stochastic forms of damage, such a glycation and oxidation, and the changes in elastic fiber structure thought to contribute to loss of arterial elasticity.

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“…Whether hyperleptinemia in obesity and OSA serves a protective role or causes detrimental effects in the cardiovascular system is still under debate. While some suggest that elevated leptin induces oxidative stress and sympathetic overactivation (20, 42), others have found the insulin-sensitizing and lipid lowering actions of leptin to be cardioprotective (31, 46).We have previously shown that vascular and myocardial abnormalities in leptin-deficient ob/ob animals are attributable to the disruption of intact leptin signaling independent of body weight (4,28,43). Because IH exposure leads to exacerbation of well-established cardiovascular risk factors of hyperlipidemia and insulin resistance (17,26), and ob/ob animals lack leptin-mediated protection against these developments, we hypothesized that IH may disrupt normal leptin signaling in WT and result in worsening of lipid-induced injury in ob/ob, leading to further exacerbation of cardiovascular function.…”

mentioning

confidence: 99%

Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia

Yang¹,

Sikka

Larson³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl-Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH.

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Leptin is essential in maintaining normal vascular compliance independent of body weight

Cited by 25 publications

References 12 publications

Increased Aortic Stiffness and Attenuated Lysyl Oxidase Activity in Obesity

Increased Aortic Stiffness and Attenuated Lysyl Oxidase Activity in Obesity

Molecular Basis of Arterial Stiffening: Role of Glycation – A Mini-Review

Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia

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