**3. Obesity and psoriasis**

Among different MetS components, the association between obesity and psoriasis is the best documented.

Several studies have shown that the severity of PsO may be linked to obesity and a population-based study of mild or severe PsO has demonstrated that the risk of obesity was significantly increased in PsO patients compared with healthy controls. Unlike in other inflammatory diseases, such as rheumatoid arthritis, the risk of obesity is strongly associated with disease severity (Sterry W et al, 2004).

Although it is controversial if psoriasis is the result or the cause of obesity itself , recent data support the obesity is a consequence of psoriasis (Henseler T et al, 1995; Neimann AL et al, 2006; Herron MD et al. 2005).

Obesity is considered the main pathogenic factor in the metabolic syndrome and it is characterized by a low and persistent sistemic inflammatory status, whose mainstay is the adipose tissue (Greenberg et al., 2006).

Adipose tissue is principally divided into two compartments, subcutaneously and centrally: the central one is characterized by omental adipose tissue and other intra-abdominal fat sources such as mesenteric fat. Central adipose tissue, also called visceral fat, is considered more metabolically active than peripheral subcutaneous fat (Kershaw EE et al, 2004; Galic S et al, 2010).

Metabolic Features in Psoriasis 111

exert its angiogenic activity and production of reactive oxigen species, which affect vessel

Resistin is a dimeric protein. In murine models, obesity is associated with rises in circulating resistin concentrations. Resistin increases blood glucose and insulin concentrations and impairs hypoglycaemic response to insulin infusion. In obese mice, antiresistin antibodies decrease blood glucose and improve insulin sensitivity: these data support the hypothesis that in obese rodents, resistin induces insulin resistance and contributes to impaired insulin sensitivity. In humans, the physiological role of resistin must be elucidated and its role in obesity and insulin resistance and/or diabetes is controversial. In humans, as resistin is primarily produced in peripheral blood monocytes and its levels correlate with IL-6 concentrations. the question of its inflammatory role has

Four genes encode for resistin in the mouse and two in humans. Some genetic case control studies demonstrated genetic variations in the resistin gene are associated with insulin resistance and obesity in humans. Others show that the very low resistin mRNA expression in isolated human adipocytes does not correlate consistently with insulin resistance or obesity, making the role of human resistin in insulin resistance unclear. No differences have been observed in resistin expression in adipocytes from normal, insulinresistant, and type 2 diabetic individuals. Mc Ternan et al. reported greater resistin mRNA expression in fat depots in the abdomen than in the thigh, suggesting human resistin could play a role in obesity-related insulin resistance (McTernan et al, 2002; Ronti

Adiponectin is almost exclusively expressed in white adipose tissue, whose expression is inhibited by IL- 6 and TNF-α. Unlike most adipokines, adiponectin expression and serum concentrations are reduced in obese and insulin-resistant states and, in vivo, high plasma adiponectin levels are associated with reduced risk of myocardial infarction. Although further studies are needed to clarify whether adiponectin independently predicts coronary heart disease events, in men with type 2 diabetes, increased adiponectin levels are associated with a moderately decreased risk of coronary heart disease. The association seems to be mediated in part by the effects of adiponectin on high-density lipoprotein cholesterol (HDL), through parallel increases in both. Moreover, it has been demonstrated that weight loss, caloric restriction and thiazoladinedione treatment increase adiponectin plasma levels and gene expression in white adipose tissue (Ronti et

Recent studies have evidenced a high leptin levels and decreased serum levels of adiponectin in obesity, insulin-resistent PsO patients and they emphasized an inverse

The precise physiological events leading to the initiation of the inflammatory response in obesity remain incompletely understood. One theory underlined that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia with a consequent local oxygen supply, cell hypoxia and the activation of cellular stress pathways releasing proinflammatory cytokines and signals. These proinflammatory chemokines attract pro-

correlation between serum levels of adiponectin and IL-6 (Satapathy SK et al, 2004).

walls (Ronti T et al, 2006).

been raised (Ronti et al, 2006).

et al, 2006).

al, 2006).

The importance of adipose tissue location in terms of dysmetabolism risk is evident: patients with excess visceral fat (central obesity) show an higher risk of developing insulin resistance and the features of the metabolic syndrome than patients with excess subcutaneous fat (Kissebach AH et al, 1982).

One of the most commonly used antropometric indexes is BMI (Body mass index), which measures adiposity and body composition as weight in kilograms divided by the square ofthe height measurement in metres (kg/m2). BMI have high specificity, but low sensitivity to identify adiposity and excess body fat (Okorodudu DO et al, 2010).

Waist circumference (WC), alone or in combination with BMI, has been shown to be an accurate predictor of visceral fat directly reflecting total abdominal fat mass but failing to quantify the visceral and subcutaneous fat compartments individually (Kashihara H et al, 2009).

The visceral adipose tissue is not only an energy storage organ, but also an important component of the immune system through the adipocytes' expression of toll receptors and a real active endocrine organ producing proinflammatory cytokines (TNF-alpha, IL-6), free fatty acids, procoagulant molecules and bioactive products called adipokines (Ronti et al, 2006).

Many adipokines have been identified, such as leptin, visfatin, resistin and adiponectin; they act in a communications network with other tissues and organs such as the skeletal muscle, adrenal cortex, brain and sympathetic nervous system and participate in appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis (Ronti T et al, 2006).

In particular, leptin and resistin appear to be two proinflammatory cytokines, while adiponectin has anti-inflammatory properties (Ronti T et al, 2006).

Leptin, a 16-kD adipocyte-derived cytokine, is synthesized and released from fat cells in response to changes in body fat. Leptin circulates partially bound to plasma proteins and enters the CNS by diffusion through capillary junctures in the median eminence and by saturable receptor transport in the choroid plexus. In the hypothalamus, leptin binds to receptors that stimulate anorexigenic peptides such as proopiomelanocortin and cocaineand amphetamine-regulated transcript and inhibit orexigenic peptides, such as neuropeptide Y. Leptin reduces intracellular lipid levels in skeletal muscle, liver and pancreatic beta cells, thereby improving insulin sensitivity. There is strong evidence showing that the dominant action of leptin is to act as a 'starvation signal': leptin declines rapidly during fasting.Therefore, leptin deficiency was perceived as a state of unmitigated starvation, leading to compensatory responses, such as hyperphagia, decreased metabolic rate and changes in hormone levels, designed to restore energy balance. The concept of 'leptin resistance' was introduced when increased adipose leptin production was observed in obese individuals, who were not leptin-deficient. Moreovere, some studies suggest leptin may affect vascular structure with an angiogenic activity and contributes to arterial thrombosis through the platelet leptin receptor. Leptin also stimulates production of reactive oxygen species as a result of monocyte activation. Therefore, in an obese subject leptin may no longer be able to regulate caloric intake and energy balance, but may still

The importance of adipose tissue location in terms of dysmetabolism risk is evident: patients with excess visceral fat (central obesity) show an higher risk of developing insulin resistance and the features of the metabolic syndrome than patients with excess

One of the most commonly used antropometric indexes is BMI (Body mass index), which measures adiposity and body composition as weight in kilograms divided by the square ofthe height measurement in metres (kg/m2). BMI have high specificity, but low sensitivity

Waist circumference (WC), alone or in combination with BMI, has been shown to be an accurate predictor of visceral fat directly reflecting total abdominal fat mass but failing to quantify the visceral and subcutaneous fat compartments individually (Kashihara H et al,

The visceral adipose tissue is not only an energy storage organ, but also an important component of the immune system through the adipocytes' expression of toll receptors and a real active endocrine organ producing proinflammatory cytokines (TNF-alpha, IL-6), free fatty acids, procoagulant molecules and bioactive products called adipokines (Ronti et al,

Many adipokines have been identified, such as leptin, visfatin, resistin and adiponectin; they act in a communications network with other tissues and organs such as the skeletal muscle, adrenal cortex, brain and sympathetic nervous system and participate in appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid

In particular, leptin and resistin appear to be two proinflammatory cytokines, while

Leptin, a 16-kD adipocyte-derived cytokine, is synthesized and released from fat cells in response to changes in body fat. Leptin circulates partially bound to plasma proteins and enters the CNS by diffusion through capillary junctures in the median eminence and by saturable receptor transport in the choroid plexus. In the hypothalamus, leptin binds to receptors that stimulate anorexigenic peptides such as proopiomelanocortin and cocaineand amphetamine-regulated transcript and inhibit orexigenic peptides, such as neuropeptide Y. Leptin reduces intracellular lipid levels in skeletal muscle, liver and pancreatic beta cells, thereby improving insulin sensitivity. There is strong evidence showing that the dominant action of leptin is to act as a 'starvation signal': leptin declines rapidly during fasting.Therefore, leptin deficiency was perceived as a state of unmitigated starvation, leading to compensatory responses, such as hyperphagia, decreased metabolic rate and changes in hormone levels, designed to restore energy balance. The concept of 'leptin resistance' was introduced when increased adipose leptin production was observed in obese individuals, who were not leptin-deficient. Moreovere, some studies suggest leptin may affect vascular structure with an angiogenic activity and contributes to arterial thrombosis through the platelet leptin receptor. Leptin also stimulates production of reactive oxygen species as a result of monocyte activation. Therefore, in an obese subject leptin may no longer be able to regulate caloric intake and energy balance, but may still

to identify adiposity and excess body fat (Okorodudu DO et al, 2010).

subcutaneous fat (Kissebach AH et al, 1982).

metabolism and haemostasis (Ronti T et al, 2006).

adiponectin has anti-inflammatory properties (Ronti T et al, 2006).

2009).

2006).

exert its angiogenic activity and production of reactive oxigen species, which affect vessel walls (Ronti T et al, 2006).

Resistin is a dimeric protein. In murine models, obesity is associated with rises in circulating resistin concentrations. Resistin increases blood glucose and insulin concentrations and impairs hypoglycaemic response to insulin infusion. In obese mice, antiresistin antibodies decrease blood glucose and improve insulin sensitivity: these data support the hypothesis that in obese rodents, resistin induces insulin resistance and contributes to impaired insulin sensitivity. In humans, the physiological role of resistin must be elucidated and its role in obesity and insulin resistance and/or diabetes is controversial. In humans, as resistin is primarily produced in peripheral blood monocytes and its levels correlate with IL-6 concentrations. the question of its inflammatory role has been raised (Ronti et al, 2006).

Four genes encode for resistin in the mouse and two in humans. Some genetic case control studies demonstrated genetic variations in the resistin gene are associated with insulin resistance and obesity in humans. Others show that the very low resistin mRNA expression in isolated human adipocytes does not correlate consistently with insulin resistance or obesity, making the role of human resistin in insulin resistance unclear. No differences have been observed in resistin expression in adipocytes from normal, insulinresistant, and type 2 diabetic individuals. Mc Ternan et al. reported greater resistin mRNA expression in fat depots in the abdomen than in the thigh, suggesting human resistin could play a role in obesity-related insulin resistance (McTernan et al, 2002; Ronti et al, 2006).

Adiponectin is almost exclusively expressed in white adipose tissue, whose expression is inhibited by IL- 6 and TNF-α. Unlike most adipokines, adiponectin expression and serum concentrations are reduced in obese and insulin-resistant states and, in vivo, high plasma adiponectin levels are associated with reduced risk of myocardial infarction. Although further studies are needed to clarify whether adiponectin independently predicts coronary heart disease events, in men with type 2 diabetes, increased adiponectin levels are associated with a moderately decreased risk of coronary heart disease. The association seems to be mediated in part by the effects of adiponectin on high-density lipoprotein cholesterol (HDL), through parallel increases in both. Moreover, it has been demonstrated that weight loss, caloric restriction and thiazoladinedione treatment increase adiponectin plasma levels and gene expression in white adipose tissue (Ronti et al, 2006).

Recent studies have evidenced a high leptin levels and decreased serum levels of adiponectin in obesity, insulin-resistent PsO patients and they emphasized an inverse correlation between serum levels of adiponectin and IL-6 (Satapathy SK et al, 2004).

The precise physiological events leading to the initiation of the inflammatory response in obesity remain incompletely understood. One theory underlined that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia with a consequent local oxygen supply, cell hypoxia and the activation of cellular stress pathways releasing proinflammatory cytokines and signals. These proinflammatory chemokines attract pro-

Metabolic Features in Psoriasis 113

Moreover, levels of soluble TNF-α receptors are directly proportional to total and LDL cholesterol concentrations and inversely correlated with certain HDL cholesterol subfraction

Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin

Several studies have demonstrated a potential association between PsO and increased serum fasting glucose levels, hyperinsulinemia, insulin-resistance, and type 2 diabetes. However, insulin resistance does not significantly correlate with PsO disease severity and

Insulin resistance is a characteristic feature of most patients with Type 2 diabetes mellitus and is one of the MetS clinical features. Insulin is a pleiotropic hormone stimulating nutrient transport into cells, regulating gene expression, modifying enzymatic activity and

Insulin exerted to these multiple functions through several intracellular signaling cascades, such as the phosphatidylinositol 3-kinase (PI3K)-AKT (also called protein kinase B (PKB)) pathway and the Ras-mitogen activated protein kinase (MAPK) pathway. PI3K-AKT is largely responsible for insulin action on glucose uptake and in the suppression of gluconeogenesis, while MAPK mediates gene expression and controls cell growth and differentiation, interacting with the first pathway. The insulin action is evidenced on target tissue, such as liver, adipose tissue and skeletal muscle (De Luca C et

In the liver, insulin regulates glucose metabolism depending on the meal or starvation, while in adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid efflux out of adipocytes (De Luca

Increased levels of TNF-alpha, IL-6 and FFAs produced by excess visceral adipose tissue can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction and they can determine the production of other inflammatory-related

TNF-alpha causes a decrease in the autophosphorylation of tyrosine residues of insulin receptor (IR) and phosphorylation of insulin receptor substrate 1 (IRS-1) (Hotamisligil GS,

Thus, in psoriasis obesity and insulin resistance have a proinflammatory effect perpetuated

The liver plays a central role in lipid metabolism, importing serum free fatty acids and

manufacturing, storing and exporting lipids and lipoproteins (Adams LA et al, 2005).

levels (Gottlieb A et al, 2008).

resistance ( Fig.2).

al, 2008).

C et al, 2008).

2003).

**5. NAFLD** 

**4. Insulin-resistance** 

duration (Gottlieb A et al, 2008).

regulating energy homeostasis (De Luca C et al, 2008).

factors, such as CRP (Gottlieb A et al, 2008).

through a positive feedback loop in PsO patients.

inflammatory macrophages into the adipose tissue with the creation of crown-like structures around hypertrophic dead or dying adipocytes. Furthermore, these macrophages release cytokines that stimulate an inflammation in neighboring adipocytes developing a vicious circle (Esposito K et al, 2004; Das UN, 2001).

Thus, excess adipose tissue results in elevated levels of pro-inflammatory adipokines, resulting in an imbalance between increased inflammatory stimuli and decreased antiinflammatory mechanism leading to persistent low-grade inflammation (Wajchenberg BL et al, 2000; Esposito K et al, 2004; Das UN, 2001).

Among proinflammatory cytokines, TNF-a and IL-6 represent two driving cytokines, which link psoriasis with many MetS components, such as obesity-related insulin-resistance (Ronti T et al, 2006).

In humans TNF-α is synthesized and secreted by adipocytes and stromovascular cells: adipose tissue TNF-α is not secreted in systemic circulation and acts in an autocrine and paracrine pathways. Adipose tissue TNF-α mRNA correlates with body mass index, percentage of body fat and hyperinsulinaemia; weight loss decreases TNF-α levels (Ronti T et al, 2006).

TNF-α modifies the gene expression profile of adipocytes and liver with an increased release and production of FFAs, cholesterol and VLDL; elevated IL-6 levels appears to be associated with decreased levels of HDL cholesterol, which may contribute to a state of chronic inflammation (Gottlieb A et al, 2008).

Fig. 2. The vicious circle linking obesity and hyperinsulinemia

inflammatory macrophages into the adipose tissue with the creation of crown-like structures around hypertrophic dead or dying adipocytes. Furthermore, these macrophages release cytokines that stimulate an inflammation in neighboring adipocytes developing a vicious

Thus, excess adipose tissue results in elevated levels of pro-inflammatory adipokines, resulting in an imbalance between increased inflammatory stimuli and decreased antiinflammatory mechanism leading to persistent low-grade inflammation (Wajchenberg BL et

Among proinflammatory cytokines, TNF-a and IL-6 represent two driving cytokines, which link psoriasis with many MetS components, such as obesity-related insulin-resistance

In humans TNF-α is synthesized and secreted by adipocytes and stromovascular cells: adipose tissue TNF-α is not secreted in systemic circulation and acts in an autocrine and paracrine pathways. Adipose tissue TNF-α mRNA correlates with body mass index, percentage of body fat and hyperinsulinaemia; weight loss decreases TNF-α levels (Ronti T

TNF-α modifies the gene expression profile of adipocytes and liver with an increased release and production of FFAs, cholesterol and VLDL; elevated IL-6 levels appears to be associated with decreased levels of HDL cholesterol, which may contribute to a state of

circle (Esposito K et al, 2004; Das UN, 2001).

al, 2000; Esposito K et al, 2004; Das UN, 2001).

chronic inflammation (Gottlieb A et al, 2008).

Fig. 2. The vicious circle linking obesity and hyperinsulinemia

(Ronti T et al, 2006).

et al, 2006).

Moreover, levels of soluble TNF-α receptors are directly proportional to total and LDL cholesterol concentrations and inversely correlated with certain HDL cholesterol subfraction levels (Gottlieb A et al, 2008).

Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance ( Fig.2).
