Leptin and the regulation of endothelial function in physiological and pathological conditions

Abstract

Obesity and the accompanying metabolic syndrome are among the most important causes of cardiovascular pathologies associated with endothelial dysfunction, such as arterial hypertension and atherosclerosis. This detrimental effect of obesity is mediated, in part, by excessive production of the adipose tissue hormone leptin. Under physiological conditions leptin induces endothelium-dependent vasorelaxation by stimulating nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Leptin activates endothelial NO synthase (eNOS) through a mechanism involving AMP-activated protein kinase (AMPK) and protein kinase B/Akt, which phosphorylates eNOS at Ser(1177) , increasing its activity. Under pathological conditions, such as obesity and metabolic syndrome, the NO-mediated vasodilatory effect of leptin is impaired. Resistance to the acute NO-mimetic effect of leptin is accounted for by chronic hyperleptinaemia and may result from different mechanisms, such as downregulation of leptin receptors, increased levels of circulating C-reactive protein, oxidative stress and overexpression of suppressor of cytokine signalling-3. In short-lasting obesity, impaired leptin-induced NO production is compensated by EDHF; however, in advanced metabolic syndrome, the contribution of EDHF to the haemodynamic effect of leptin becomes inefficient. Resistance to the vasodilatory effects of leptin may contribute to the development of arterial hypertension owing to unopposed stimulation of the sympathetic nervous system by this hormone.

Obesity, bariatric surgery and oxidative stress

“…It may lead to membrane permeability, fluidity and integrity changes, which may eventually result in severe cytotoxicity. 10,25 The obese patients in our study showed high TBARS levels before bariatric surgery compared to the control group. This suggests that the patients were predisposed to develop many diseases, as well as to face accelerated aging, because the cytotoxicity caused by lipid oxidation favors uncontrolled cell growth and/or cell death.…”

“…24 Furthermore, excess of body fat also affects the mitochondrial metabolism and promotes hyperleptinemia, thus favoring the occurrence of oxidative stress. [8][9][10] The formation of lipid peroxidation (LPO) products is one of the consequences from oxidative stress. It may lead to membrane permeability, fluidity and integrity changes, which may eventually result in severe cytotoxicity.…”

“…This process stimulates the proliferation and activation of monocytes and macrophages, as well as the production of IL-6 and TNF-α. 9,10 Thus, since obesity may pose other health risks, the efficient identification of high body mass index (BMI) is essential to promote health and reduce morbidity and mortality. 11 In addition to BMI, it is important to quantify cellular, molecular or biochemical markers that indicate tissue or cell changes.…”

Role of lipocytocins in the pathogenesis of metabolic syndrome

“…Êð³ì òîãî, íà ñó÷àñíîìó åòàï³ âèâ÷àºòüñÿ ïîøêîäaeóþ÷èé âïëèâ ëåïòèíó íà åíäîòåë³é ñó-äèí, ùî ïîëÿãຠó çíèaeåíí³ ðåëàêñàö³¿ àðòåð³é, ïîñèëåíí³ êàëüöèô³êàö³¿ ñóäèí ³ ó ïîòåíö³þâàíí³ ïðîòðîìáîòè÷íî¿ àãðåãàö³¿ òðîìáîöèò³â øëÿõîì âçàºìî䳿 ì³ae ëåïòèíîì ³ éîãî ðåöåïòîðàìè íà òðîìáîöèòàõ [37,38]. Âñå öå äîçâîëÿº ââàaeàòè ã³ïåðëåïòèíåì³þ îäíèì ³ç ÷èííèê³â, ùî ñïðèÿ-þòü ðîçâèòêó àòåðîñêëåðîòè÷íèõ ïîøêîäaeåíü ñóäèí é àñîö³éîâàíèõ ³ç íèìè çàõâîðþâàíü ñåð-öåâî-ñóäèííî¿ ñèñòåìè.…”

Time dependent effect of obesity on leptin induced hydrogen sulfide mediated relaxation of peripheral resistance arteries

“…Leptin, produced by white adipose tissue in amounts proportional to energy stores, not only inhibits food intake and increases energy expenditure, but also has many e ects on peripheral tissues including the cardiovascular system (3,4). In physiological conditions leptin has no e ect on blood pressure because induces balanced stimulation of sympathetic nervous system (SNS) and endothelium-dependent vasorelaxation (5). Conditions of chronic hyperleptinemia such as obesity, metabolic syndrome or type 2 diabetes are associated with selective leptin resistance; that is pressor SNS-dependent e ect of leptin is preserved whereas its vasodilating e ect is impaired (6)(7)(8).…”