Psoriasis is an immune-mediated, genetic disease manifesting in the skin or joints or both. A diverse team of clinicians with a range of expertise is often needed to treat the disease. Psoriasis provides many challenges including high prevalence, chronicity, disfiguration, disability, and associated comorbidity. Understanding the role of immune function in psoriasis and the interplay between the innate and adaptive immune system has helped to manage this complex disease, which affects patients far beyond the skin. In this Seminar, we highlight the clinical diversity of psoriasis and associated comorbid diseases. We describe recent developments in psoriasis epidemiology, pathogenesis, and genetics to better understand present trends in psoriasis management. Our key objective is to raise awareness of the complexity of this multifaceted disease, the potential of state-of-the-art therapeutic approaches, and the need for early diagnosis and comprehensive management of patients with psoriasis.

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The association between obesity and impaired insulin sensitivity has long been recognized, although a subgroup of obese individuals seems to be protected from insulin resistance. In this study, we systematically studied differences in adipose tissue biology between insulin-sensitive (IS) and insulinresistant (IR) individuals with morbid obesity. On the basis of glucose infusion rate during euglycemic hyperinsulinemic clamps, 60 individuals with a BMI of 45 Ϯ 1.3 kg/m 2 were divided into an IS and IR group matched for age, sex, and body fat prior to elective surgery. We measured fat distribution, circulating adipokines, and parameters of inflammation, glucose, and lipid metabolism and characterized adipose tissue morphology, function, and mRNA expression in abdominal subcutaneous (sc) and omental fat. IS compared with IR obese individuals have significantly lower visceral fat area (138 Ϯ 27 vs. 316 Ϯ 91 cm 2 ), number of macrophages in omental adipose tissue (4.9 Ϯ 0.8 vs. 13.2 Ϯ 1.4%), mean omental adipocyte size (528 Ϯ 76 vs. 715 Ϯ 81 pl), circulating C-reactive protein, progranulin, chemerin, and retinol-binding protein-4 (all P values Ͻ0.05), and higher serum adiponectin (6.9 Ϯ 3.4 vs. 3.4 Ϯ 1.7 ng/ml) and omental adipocyte insulin sensitivity (all P values Ͻ0.01). The strongest predictors of insulin sensitivity by far were macrophage infiltration together with circulating adiponectin (r 2 ϭ 0.98, P Ͻ 0.0001). In conclusion, independently of total body fat mass, increased visceral fat accumulation and adipose tissue dysfunction are associated with IR obesity. This suggests that mechanisms beyond a positive caloric balance such as inflammation and adipokine release determine the pathological metabolic consequences in patients with obesity.visceral adipose tissue; insulin resistance; inflammation; adipokines; macrophages OBESITY IS ASSOCIATED WITH AN INCREASED RISK of premature death (2) and represents a fast-growing health problem that is reaching epidemic proportions worldwide (21). Obesity significantly increases the risk of developing type 2 diabetes mellitus, hypertension, coronary heart disease, stroke, and several types of cancer (42). For instance, the risk to develop type 2 diabetes is ninefold higher for obese than for lean men (45). Although there is a strong relationship between obesity and insulin resistance (1, 10, 42), and obese individuals become more insulin sensitive with weight loss (32), not all obese patients are insulin resistant (6,14).Data from the European Group for the Study of Insulin Resistance suggest that ϳ25% of obese individuals [body mass index (BMI) Ͼ35 kg/m 2 ] are insulin sensitive (14).It is clinically important to identify insulin-resistant obese persons with an increased risk for developing obesity-associated metabolic and cardiovascular diseases who, therefore, may benefit the most from losing weight (32). Insulin-resistant (IR) and insulin-sensitive (IS) obesity are not clearly defined subgroups but represent the extremes of a continuum, the characterization of which may...

SummaryThe prevalence of obesity and type 2-diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the Glut4-glucose transporter and alterations in adipose-Glut4 expression or function regulate systemic insulin sensitivity. Downregulation of adipose tissue-Glut4 occurs early in diabetes development. Here we report that adipose tissue-Glut4 regulates the expression of carbohydrate responsive-element binding protein (ChREBP), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose-ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We discovered a new mechanism for glucose-regulation of ChREBP: Glucose-mediated activation of the canonical ChREBP isoform (ChREBPα) induces expression of a novel, potent isoform (ChREBPβ) that is transcribed from an alternative promoter. ChREBPβ expression in human adipose tissue predicts insulin sensitivity indicating that it may be an effective target for treating diabetes.

Visceral and subcutaneous adipose tissue display important metabolic differences that underlie the association of visceral obesity with obesity-related cardiovascular and metabolic alterations. Recently, visfatin was identified as an adipokine, which is predominantly secreted from visceral adipose tissue both in humans and mice. In this study, we examined whether visfatin plasma concentrations (using enzyme immunosorbent assay) and mRNA expression (using RT-PCR) in visceral and subcutaneous fat correlates with anthropometric and metabolic parameters in 189 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance. Visfatin plasma concentration correlates positively with the visceral visfatin mRNA expression (r 2 ‫؍‬ 0.17, P < 0.0001), BMI (r 2 ‫؍‬ 0.062, P ‫؍‬ 0.004), percent body fat (r 2 ‫؍‬ 0.048, P ‫؍‬ 0.01), and negatively with subcutaneous visfatin mRNA expression (r 2 ‫؍‬ 0.18, P < 0.0001). However, in a subgroup of 73 individuals, in which visceral fat mass was calculated from computed tomography scans, there was no correlation between plasma visfatin concentrations and visceral fat mass. We found no significant correlation between visfatin plasma concentrations and parameters of insulin sensitivity, including fasting insulin, fasting plasma glucose concentrations, and the glucose infusion rate during the steady state of an euglycemic-hyperinsulinemic clamp independent of percent body fat. Visfatin gene expression was not different between visceral and subcutaneous adipose tissue in the entire study group nor in selected subgroups. We found a significant correlation between visceral visfatin gene expression and BMI (r 2 ‫؍‬ 0.06, P ‫؍‬ 0.001) and percent body fat (measured using dual-energy X-ray absorptiometry) (r 2 ‫؍‬ 0.044, P ‫؍‬ 0.004), whereas no significant association between BMI or percent body fat and subcutaneous visfatin mRNA expression existed (both P >0.5). In conclusion, visfatin plasma concentrations and visceral visfatin mRNA expression correlated with measures of obesity but not with visceral fat mass or waist-tohip ratio. In addition, we did not find differences in visfatin mRNA expression between visceral and subcutaneous adipose tissue in humans. Diabetes 54:2911-2916, 2005 E pidemiological and animal studies reported an association between increased visceral obesity and the prevalence of insulin resistance, type 2 diabetes, and the risk of cardiovascular disease (rev. in 1-3). Moreover, differences in gene expression of adipocyte-secreted molecules suggest that there are intrinsic fat depot-specific differences in the endocrine function of adipose tissue. These differentially expressed adipokines include leptin (4,5), plasminogen activator inhibitor-1 (6), and interleukin-6 (7).Recently, visfatin was identified as a peptide predominantly expressed in and secreted from visceral adipose tissue in both humans and mice (8). This peptide was previously described as a growth factor for early B-cells called pre-B-cell colony-enhancing factor (...