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Figure 25.2 Potential mechanisms leading to the increased formation of small dense LDL and decreased levels of HDL. TG, triglyceride metabolic abnormality results in increased FFA levels in both peripheral and portal circulation which leads to higher esterification of these substrates, to reduced degradation of apolipoprotein B, and to an increased synthesis and secretion of VLDL particles (15).

The association between abdominal obesity, hy-pertriglyceridaemia and small dense LDLs, which are more susceptible to oxidation, appears to be the most robust cluster in term of cardiovascular risk. However, this aggregation is liable to correction since it was shown that weight loss normalizes the physico-chemical properties of LDL. A hypocaloric diet and modest weight reduction induce a significant reduction of triglyceride concentrations within a few weeks (30). However, a longer period is necessary to bring about a reduction in total cholesterol and LDL cholesterol, and an increase in HDL cholesterol. When weight loss is achieved by a combination of diet and physical exercise, the improvement in lipid profile appears to be more consistent and stable (31).

Hypertension

The association between obesity and hypertension has been extensively documented by several studies and specifically from the Framingham Study and the National Health and Nutrition Examination

Figure 25.3 Relationship between obesity, diet, hypertension and endothelial dysfunction. SNS, sympathetic nervous system

Survey (32-35). In general, obesity and hypertension both are predictors of ACVD, obese people are more prone to hypertension, and most hypertensive patients are obese. Obesity and weight gain are predictors of hypertension independently from the age of onset of obesity; moreover, weight loss is associated with a reduction of blood pressure (36). Yet the pathophysiology of the relationship between obesity and hypertension has not been thoroughly clarified.

Obesity is characterized by an increased intravascular volume which appears to be a key factor in determining hypertension in these subjects. From a haemodynamic standpoint there is a resetting of pressor natriuresis in obesity, i.e. the maintenance of an expanded extracellular volume despite elevated blood pressure. This means that there must be an enhancement in tubular renal reabsorption (37). Some studies have claimed an important role for hyperinsulinaemia (Figure 25.3). Excessively elevated insulin would induce medullary vasoconstriction which plays an important part in forcing renal tubular reabsorption (38). Hyperinsulinaemia also stimulates the sympathetic nervous system (SNS), which in turn favours vasoconstriction of the deep medullary blood vessels which further increases sodium reabsorption (39,40). Insulin determines a dose-dependent increase of plasma noradrenaline (norepinephrine) concentration and of noradrena-line spillover from muscle. In obese patients there is also an exaggerated pressor response to noradrenaline, a reduced threshold to its pressor effect, and a reduced clearance of noradrenaline (41). In insulin-

resistant states the vasodilatory effect of insulin wanes and this phenomenon is closely related to the degree of insulin resistance. Hyperinsulinaemia stimulates the sodium/hydrogen countertransport. This leads to an intracellular accumulation of sodium and calcium which, in turn, increases the susceptibility of vascular smooth muscle cells to the hypertensive effect of noradrenaline and angioten-sin (42).

In obese patients chronic hyperinsulinaemia may also lead to an inappropriate activation of the re-nin-angiotensin-aldosterone system and to an altered function of atrial natriuretic peptide (43).

Insulin also has the ability to increase intracellu-lar calcium. Regulation of intracellular Ca2+ plays a key role in obesity, insulin resistance and hypertension, and disorder of [Ca2+]i may represent a factor linking these three conditions (44). In the insulin-resistant state, such as obesity, there is a lack of the insulin-mediated decrease in [Ca2 + ]i; this leads to increased vascular resistance.

As well as the prominent effect of insulin on the aetiology of hypertension, other factors could mediate the increase in blood pressure observed in obese patients. Steroids could also play a role in the relationship between obesity and hypertension since these hormones may determine fat distribution and the type of obesity (45,46). Recently it has been hypothesized that central obesity may reflect a 'Cushing's disesase of the omentum'. Glucocorticoids not only regulate the differentiation of adipose stromal cells but they also affect the function of adipocytes. In fact adipose stromal cells from omentum can generate active cortisol through the expression of the 11^-hydroxysteroid dehydrogenase (47). In vivo such a mechanism would ensure a constant exposure of blood vessels to glucorticoid, thus aggravating the obesity-related hypertension. Furthermore, the excess of androgens observed in women with abdominal fat deposition and the increased response of cortisol to stress in men with reduced testosterone may contribute to the development of hypertension (48).

Thus in obese subjects both blood volume and cardiac output are increased but the peripheral vascular resistance is normal rather than decreased; this unexpectedly normal peripheral resistance is possibly determined by enhanced adrenergic tone; altered endothelial function, activation of renin-an-giotensin systems, and possibly increased levels of neuropeptide Y (NPY), which has been shown to be a potent vasoconstrictor (49).

All these neurohumoral and haemodynamic alterations, as well as blood pressure levels, significantly improved after weight loss. This finding provides additional proof that they all play an important role in the development and progression of hypertension in obesity (50-52).

Haemosticand Endothelial Factors

Obesity predisposes to thrombosis by altering both the concentration and the activity of several factors involved in the coagulative and fibrinolytic processes. A closed and independent correlation between body mass index and fibrinogen levels has been observed (53,54). Fibrinogen was shown to correlate also with WHR and with the other components of the metabolic syndrome. Elevated fibrinogen levels are an independent risk factor for ACVD and it may partly explain the increased prevalence of cardiovascular mortality in the obese patients. A positive correlation was also shown between factor VII, von Willebrand and BMI (55). At variance, no change in the activity of antithrombin III was observed while protein C levels were increased.

A defect in fibrinolysis, usually observed in states of insulin resistance and in overweight patients, has been claimed as a key step in the development and progression of atherosclerotic lesions. This hypothesis has been supported by the finding of increased levels of plasminogen activator inhibitor (PAI)-1 antigen and decreased levels of tissue plasminogen activator (tPA) (56,57). A direct correlation between BMI and PAI-1 activity has been shown; furthermore, a correlation has been also observed between PAI-1, the degree of insulin resistance, and the degree of abdominal fat deposition. A defect in the fibrinolytic process is now considered as one of the most prominent in the metabolic syndrome. It has been recently shown that the adipose tissue is a site of active PAI-1 production which is a function of cell size and of their lipid content (58). Overproduction of PAI-1 is determined by an increased PAI-1 gene expression. Visceral rather than subcutaneous adipose tissue is a site of inappropriate PAI-1 production. This excessive PAI-1 production by visceral fat may partly explain its more pronounced atherogenic potential (59). It has been shown that insulin stimulates PAI-1 production, which may therefore be increased in state of insulin resistance. PAI-1 gene expression is stimulated by insulin both hepatocytes and endothelial cells (60). Recently, the potential role of VLDL and of its receptor in mediating VLDL-induced PAI-1 expression has also been demonstrated in in vitro studies (61,62). Therefore, in obesity several mechanisms such as elevated insulin levels, excessive visceral fat deposition, and increased VLDL contribute to the impaired fib-rinolytic apparatus.

Platelet function was also shown to be impaired in the presence of insulin resistance (63). In this metabolic setting the altered insulin action on cyclic nucleotides is diminished; this leads to an increased inward calcium flux, enhanced platelet aggregation and hence to an increase thrombotic risk (64).

It has been recently hypothesized that the metabolic syndrome may represent an altered immu-nological response. In patients with visceral obesity an increase in acute phase proteins such as sialic acid, C-reactive protein, and the interleukin-6 (65). It has also been shown that tumour necrosis factor (TNFa) (also known as 'cachectin'), a pleiotropic cytokine involved in many metabolic responses in both normal and pathophysiological states, may also have a central role in obesity, modulating energy expenditure, fat deposition and insulin resistance (66). How TNFa-related insulin resistance is mediated is not fully clear, although phosphoryla-tion of serine residues on insulin receptor substrate (IRS) 1 has previously been shown to be important

(67). An approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNFa knockout mice was found, suggesting that insulin receptor signalling is an important target for TNFa

The increase in inflammatory cytokines may contribute to impairment of the early steps in intracel-lular insulin signalling not only through a direct effect but also indirectly by altering endothelial function. Yudkin and colleagues have found a close relationship between cytokine levels and the amount of visceral fat deposition which is a site of active TNFa production (69). Yudkin's group also reported an increased secretion of interleukin-6 by subcutaneous adipose tissue (70). TNFa has been implicated as an inducer of the synthesis of PAI-1. Recent findings suggest that TNFa stimulation of PAI-1 is potentiated by insulin, and that adipocyte generation of reactive oxygen centred radicals mediates the induction of PAI-1 production by TNFa

As a whole these data support the hypothesis that total fat mass determines a low chronic inflammatory state which may not only induce an insulin resistance state but could also favour the development and progression of atherosclerotic damage in the blood vessels.

Steinberg and colleagues have shown that in obese patients there is altered endothelial-mediated vasodilation and a reduced insulin haemodynamic response which is closely related to the degree of insulin resistance (72). A common link between the decreased insulin vascular and metabolic effects may be provided by altered intracellular phos-phatidylinositol-3-kinase activity (73). On the other hand, obesity is characterized by increased levels of hypertension, increased oxidized LDL, increased FFA levels which all combine to alter endothelial function.

Recently it has been shown that in obese subjects acetylcholine-stimulated vasodilation is blunted and that the increase in forearm blood flow is inversely related to BMI, WHR, and insulin action (74).

Diabetes Mellitus

Impaired glucose tolerance and non-insulin-dependent diabetes mellitus represents the almost inevitable outcome in the natural history of obese subjects, in particular of those with abdominal fat accumulation (75). The evolution of obesity toward overt diabetes is characterized by the onset of peripheral insulin resistance, hyperglycaemia, and finally by reduced ^-cell secretory capacity. Several mechanisms are involved in insulin resistance in subjects at risk for type 2 diabetes. Transport of insulin across the capillary endothelium is altered due to a reduced capillary permeability to insulin. The transport of insulin across the endothelial barrier not only limits the rate at which insulin stimulates glucose uptake by skeletal muscle, but appears also to determine the rate at which insulin suppresses liver glucose output. In addition, a strong correlation has been demonstrated between FFA and liver glucose output under a variety of experimental conditions (76). Moreover if FFAs are main tained at basal concentrations during insulin administration, glucose output fails to decline. Finally, if FFAs are reduced independent of insulin administration, glucose output is reduced. These points support the concept that insulin, by regulating adipocyte lipolysis, controls liver glucose production. Thus, the adipocyte appears to be a critical mediator between insulin and liver glucose output. Evidence that FFAs also suppress skeletal muscle glucose uptake and insulin secretion from the ^-cell supports the overall central role of the adipocyte in the regulation of glycaemia. Insulin resistance at the fat cell may be an important component of the overall regulation of glycaemia because of the relationships between FFA and glucose production, glucose uptake and insulin release. It is possible that insulin resistance at the adipocyte itself can be a major cause of the dysregulation of carbohydrate metabolism in the prediabetic state (77).

Several prospective studies have conclusively shown that obesity is an important risk factor for the development of diabetes (78). The Framingham Study has shown that there is an increased incidence of impaired glucose tolerance in obese subjects (32). Once hyperglycaemia is established, this represents an independent risk factor for ACVD. Hyperglycaemia causes a direct negative effect on the vessel wall through an array of mechanisms, the most important being: (1) protein glycation, in particular the glycation of LDL: these modified lipoproteins have a prolonged half-life; (2) the accumulation of modified lipoproteins which can induce excessive cross-linking of collagen and other matrix proteins; (3) increased oxidative stress; (4) increased polyol pathway and the consequent increase of the NADH/NAD ratio; (5) activation of protein kinase C (PKC). This latter effect brings about the induction of cellular matrix and cytokines which eventually leads to vascular cell proliferation (79). Several studies have shown that hyperglycaemia is a risk factor for ACVD (80): a 1% increase in HbA1c results in a 10% increase in coronary events. High fasting plasma glucose predicts not only coronary events but also fatal and non-fatal stroke. The hy-perinsulinaemia associated with insulin resistance, which is a common feature of non-insulin-dependent diabetes mellitus, appears to play a major role in the development and progression of ACVD in obese people with diabetes (81,82). This subject is described in detail in Chapter 24.

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