4 The general low-grade chronic inﬂammatory state, closely related to obesity, may aﬀect insulin action by suppressing insulin receptor signalling via serine phos- phorylation of insulin receptor substrates at metabolically relevant sites [104]. Because favourable metabolic and hemodynamic actions of insulin share common intracellular transduction pathways [105], inﬂammation may simultane- ously contribute to both IR and vascular dysfunction, two cardinal and interrelated features of the Mets. Moreover, macrophages become activated and secrete inﬂammatory cytokines such as TNF-alpha and IL.6 which in turn decrease insulin action on adipocytes, determine hypoadiponectin, and increase leptin production [98, 106]. TNF-α indeed plays a central role in the pathophysiology of IR and vascular damage in patients with obesity; the deletion of the TNF-α gene or the TNF receptors has proven eﬀective to improve insulin action in both genetic and dietary models of rodent obesity. Overexpression of TNF-α has previously been reported in obese adipose tissue [62, 107], as well as in the skeletal muscle of insulin-resistant animals and humans and exposure to TNF-α acutely inhibits insulin-stimulated glucose uptake. Additionally, TNF-α-induced vasculopa- thy is characterized by increased vascular reactive oxygen species. We have previously demonstrated that TNF-α neutraliza- tion with the monoclonal antibody inﬂiximab ameliorates insulin-stimulated vascular reactivity in Mets [108]. Our ﬁndings suggest that increased oxidative stress is involved in mediating the eﬀects of TNF-α on insulin-stimulated vasodilator capacity. The beneﬁcial action on vascular reactivity demonstrated in our study proposes a novel mechanism by which TNF-α activation might be involved, viaincreased oxidative stress, in the pathophysiology of vascular dysfunction in patients with obesity-related MetS. The degree to which any particular adipose-derived inﬂammatory mediator enters the blood stream and plays a role in metabolic and cardiovascular disorders has not yet been established [109]. An emerging area of interest is the role of perivascular adipose tissue (PVAT) in regulating local vascular tone [110]. The presence of adipose tissue around the heart and the great vessels has been recently recognized as an independent cardiovascular risk factor. The perivascular adipose tissue (PVAT) is the potential source of the mediators leading to obesity-related vascular damage. Because of the absence of the fascial boundaries, epicar- dial adipose tissue may locally interact and aﬀect the coro- nary arteries and myocardium through paracrine actions of pro- and anti-inﬂammatory adipokines and other bioactive molecules [111]. Thus, the epicardial and perivascular adipose tissue could mechanically and functionally modulate the function of the myocardium and vasculature thereby possibly playing a role in obesity-related atherosclerosis [112]. Several studies demonstrated that epicardial fat pro- duces a number of bioactive molecules as well as TNF- alpha, IL-6, IL-1, resistin, free fatty acid, and adiponectin that could aﬀect cardiovascular morphology and function [113–117]. Cardiology Research and Practice Moreover, recent studies have shown that perivascular adipocytes physiologically exert anticontractile eﬀects which are both NO dependent and independent. In particular, adipokines released from fat depots have local rather than systemic vasoregulatory eﬀects, a mech- anism deﬁned as vasocrine signaling. In healthy subjects, PVAT seems to mediate an anticontractile eﬀect in medium- and small-sized arteries [118, 119]. Adiponectin is the main candidate for this role based on the ﬁnding that the anticontractile properties of the fat are abolished entirely with an adiponectin type 1 receptor blocking fragment [119]. Importantly, this eﬀect of PVAT is lost in patients with obesity-related metabolic syndrome, and conformational changes in perivascular fat have been shown to associate with lots of its anticontractile properties likely due to inﬂam- matory, vasoconstrictor, and oxidative mechanisms. Recent studies has demonstrated a positive correlation between epi- cardial adipose tissues volume and coronary atherosclerosis using multislice computed tomography [120]. Moreover, Hosogai and colleagues demonstrated that PVAT of obese mice is hypoxic and that hypoxia stimulated an inﬂammatory phenotype and a loss of the anticontractile properties. This eﬀect is mediated by endoplasmic reticulum stress and posttranscriptional regulation. Because hypoxia is a prominent feature of adipose tissue in obese individ- uals and is thought to cause adipocyte dysfunction and tissue inﬂammation [121], these ﬁndings further support a prominent role for PVAT-derived inﬂammatory cytokines in adversely modulating vascular function. Of note, the obese phenotype could be reproduced by adding the inﬂammatory cytokines IL-6 or TNF-α to the PVAT around healthy vessels, which in turn could be blocked by cytokine antagonists. In conclusion, these studies suggest that PVAT in obese individuals predominately exerts inﬂuence that contributes to vascular disease and may act both locally (paracrine) and downstream (vasocrine), through outside-to-inside signal- ing. 6. Renal Effects of Obesity The most common types of morphological renal lesions observed in renal biopsies of obese patients are mainly focal and segmental glomerulosclerosis and glomerulomegaly [122]. The podocyte foot process eﬀacement described in the ADP knockoutmice probably represents an earlier stage of kidney involvement. Early changes occurring in the presence of only mild metabolic abnormalities and mild hyperten- sion in the absence of diabetes mellitus include increased glomerular cell proliferation, increased mesangial matrix, thicker basement membrane, and increased expression of glomerular transforming growth factor-beta [50]. In a recent study, Lamacchia and colleagues demon- strated that para- and perirenal fat thickness is an indepen- dent predictor of kidney dysfunction and increased renal resistance in patients with type 2 diabetes [123]. The mechanisms of obesity-induced renal injury are not fully understood and are likely to involve a combination of