In humans, a hyperactivity of glucocorticoid metabolism was postulated to be involved in the intrauterine programming of the metabolic syndrome in adulthood. We studied in rats the effects of overfeeding, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for neuroendocrine maturation such as late gestation in humans. Overfeeding induced early-onset obesity and accelerated the maturation of the hypothalamo-pituitary-adrenal (HPA) axis together with an upregulation of adipose tissue glucocorticoid receptor (GR) mRNA. In adulthood, neonatally overfed rats presented with moderate increases in basal and stress-induced corticosterone secretion and striking changes in visceral adipose tissue glucocorticoid signaling, that is, enhanced GR and 11␤-hydroxysteroid dehydrogenase type 1 mRNA levels. The above-mentioned alterations in the endocrine status of overfed rats were accompanied by a moderate overweight status and significant metabolic disturbances comparable to those described in the metabolic syndrome. Our data demonstrate for the first time that postnatal overfeeding accelerates the maturation of the HPA axis and leads to permanent upregulation of the HPA axis and increased adipose tissue glucocorticoid sensitivity. Thus, the experimental paradigm of postnatal overfeeding is a powerful tool to understand the pathophysiology of glucocorticoid-induced programming of metabolic axes. Diabetes 54: [197][198][199][200][201][202][203] 2005 N umerous clinical and biological findings indicate that glucocorticoids are involved in the pathophysiology of abdominal obesity and its accompanying complications. Indeed, an excess of glucocorticoids, when associated with hyperinsulinism, favors an increase of lipogenesis and a decrease of lipolysis, together with a stimulation of hepatic neoglucogenesis and an inhibition of peripheral glucose utilization (1). Alterations in the hypothalamo-pituitary-adrenal (HPA) axis have been described in human obesity and in rodent models of obesity. They could involve a hyperactivity of the central command of ACTH secretion, secondary to an increased exposure or sensitization to stress (2) or decreased negative glucocorticoid feedback (3). In addition, changes in peripheral glucocorticoid signaling with increased visceral adipose tissue glucocorticoid receptor (GR) concentrations and local reactivation of circulating inert cortisone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone) driven by 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1) could play a pivotal role (4). However, the origins of the abovementioned dysregulations have not been established.Clinical and experimental evidence shows that the environment during the perinatal period plays an important role in the regulation of both metabolic and hormonal axes in adulthood. In humans, hyperglycemia and hyperinsulinemia in macrosomic fetuses of diabetic mothers were shown to favor later development of overweight (5). Conversely, it has been demonstrated that intrauterine g...

DESBRIERE, RAOUL, VINCENT VUAROQUEAUX, VINCENT ACHARD, SANDRINE BOULLU-CIOCCA, MARTIN LABUHN, ANNE DUTOUR, AND MICHEL GRINO. Increased expression of 11␤-hydroxysteroid dehydrogenase type 1 mRNA in both visceral and subcutaneous adipose tissue of obese patients. Obesity. 2006;14:794 -798. Objective: Data from rodents provide evidence for a causal role of 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1) in the development of obesity and its complications. In humans, 11␤-HSD-1 is increased in subcutaneous adipose tissue (SAT) of obese patients, and higher adipose 11␤-HSD-1 was associated with features of the metabolic syndrome. To date, there is no evidence for an increased expression of 11␤-HSD-1 in human visceral adipose tissue (VAT), although VAT is the major predictor for insulin resistance and the metabolic syndrome. Research Methods and Procedures: 11␤-HSD-1 and hexose-6-phosphate dehydrogenase (the enzyme responsible for the synthesis of nicotinamide adenine dinucleotide phosphate, the cofactor required for 11␤-HSD-1 oxoreductase activity) mRNA levels were measured using real-time quantitative reverse transcriptase-polymerase chain reaction in abdominal SAT and VAT biopsies obtained from 10 normal-weight and 12 obese women. Adiponectin mRNA was used as an internal control.Results: 11␤-HSD-1 mRNA concentrations were significantly increased in both SAT and VAT of obese patients (720% and 450% of controls, respectively; p Ͻ 0.05) and correlated with hexose-6-phosphate dehydrogenase mRNA levels. The level of VAT 11␤-HSD-1 mRNA correlated with anthropometric parameters: BMI (r ϭ 0.41, p ϭ 0.05), waist circumference (r ϭ 0.44, p ϭ 0.04), abdominal sagittal diameter (r ϭ 0.51, p ϭ 0.02), and percentage fat (r ϭ 0.51, p ϭ 0.02). Discussion: Our results demonstrate for the first time that 11␤-HSD-1 mRNA expression is increased in VAT from obese patients. They strengthen the importance of 11␤-HSD-1 in human obesity and its associated complications and suggest the need of clinical studies with specific 11␤-HSD-1 inhibitors.

Epicardial fat is a relatively neglected component of the heart and could be an important risk factor of cardiac disease. The objective of our study was to assess the relationship between epicardial adipose tissue (EAT) extent, fat distribution, and coronaropathy in a group of adult victims of accidental or suspicious sudden death. In 56 cadavers, we performed 34 measurements of EAT from five computerized photographs of the heart (anterior and posterior faces, and three ventricle transversal slices) and analyzed their relationship with anthropometric markers of adiposity (BMI, waist and leg circumference, thickness of abdominal and thigh subcutaneous adipose tissue (SAT)), with the presence and staging of coronary artery disease (CAD), and with markers of myocardial hypertrophy. Simple linear regressions showed that EAT measurements are highly intercorrelated (r from 0.4 to 0.6, P < 0.001), and correlate with age, waist circumference, and heart weight, and to a lesser extent, with BMI, abdominal SAT thickness, and leg SAT thickness. Multiple regression showed that age, waist circumference, and heart weight significantly and independently correlate with EAT (P < 0.0001). No other anthropometric measurement was found independently correlated with EAT. The EAT/myocardium ratios correlated positively with age and waist circumference. Anterior and posterior areas of EAT were found significantly increased in patients with CAD and correlated positively with CAD staging (P = 0.0034, r = 0.38). Anterior EAT surface was found positively associated with CAD (P = 0.01), independently of age and other adiposity measurements. Prospective studies are needed to assess the risk of occurrence/progression of CAD that relate to EAT excess.

Aims/hypothesis Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation. Methods CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture. Results CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal-vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell-cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes. Conclusions/interpretation Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.

Objective-Because obesity and insulin resistance (IR) are strongly associated with liver steatosis (LS), we investigated the relation between the degree of LS and plasminogen activator inhibitor-1 (PAI-1) in ob/ob mice, in C57/BL6 mice with alcoholic LS, and in severely obese humans. Methods and Results-In both mouse models, plasma PAI-1 levels were associated with PAI-1 expression in the liver and with the degree of LS. Liver PAI-1 antigen was associated with the tumor necrosis factor receptor-II (TNFRII) antigen, whereas association with TNF antigen content was found in ob/ob mice only. No significant correlation between plasma PAI-1 and PAI-1 expression in adipose tissue of ob/ob mice was observed. Furthermore, the relation between plasma PAI-1 levels and body weight was positive in ob/ob mice but negative in C57/BL6 mice (both PϽ0.001). In humans, PAI-1 levels were correlated with the degree of LS, and 26% of plasma PAI-1 activity was independently explained by LS and serum insulin levels. Conclusions-Plasma PAI-1 levels are more closely related to fat accumulation and PAI-1 expression in the liver than in adipose tissue. In steatotic liver, PAI-1 antigen content is associated with those of TNF and TNFRII. Therefore, we suggest that TNF pathway dysregulation in LS could be involved in increased plasma PAI-1 in obesity with IR. Key Words: liver steatosis Ⅲ PAI-1 Ⅲ adipose tissue Ⅲ insulin resistance P lasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of fibrinolysis. PAI-1 modulates the development of atherosclerosis in mice, 1,2 and an elevated plasma PAI-1 concentration is predictive for myocardial infarction in humans. 3,4 Interestingly, the predictive value of circulating PAI-1 levels is highly dependent on the insulin resistance syndrome. 4,5 Despite several efforts in the last few years, the mechanism of increased plasma PAI-1 concentration in insulin resistance associated with android obesity is not completely understood. PAI-1 is expressed in murine as well as in human adipose tissue, 6 -9 and its expression in adipose tissue is correlated positively with body mass index (BMI). 9 -11 Human visceral adipose tissue expresses more PAI-1 than does subcutaneous abdominal adipose tissue. 7,12 Furthermore, PAI-1 expression in only abdominal, but not in femoral subcutaneous adipose tissue, is associated with the features of insulin resistance. 11 Therefore, it has been postulated that in the insulin resistance syndrome with central obesity, abdominal adipose tissue is an important source of plasma PAI-1. Of note, an increase in plasma PAI-1 is also observed in lipodystrophy associated with antiretroviral treatment in HIV patients. These patients typically have prominent, peripheral fat wasting and maintained or decreased visceral fat depots and are insulin resistant. Interestingly, the difference in plasma PAI-1 levels between HIV patients and healthy controls was independent of HIV infection status and was not affected after adjustment for visceral fat estimation but was rather explained by...

Abstract-Elevated plasma plasminogen activator inhibitor (PAI)-1 observed during insulin resistance has been connected with an excessive PAI-1 adipose tissue secretion mainly by visceral fat. Our aim was to compare the localization of PAI-1 in human visceral and subcutaneous fats. PAI-1 secretion was also investigated in vitro during human adipocyte differentiation. PAI-1 antigen and mRNA were localized in the stromal area of the tissue and were also present in a few CD14-positive monocytes, in direct contact with adipocytes. In addition, in subcutaneous tissue, PAI-1 mRNA contents, determined by using real-time polymerase chain reaction, were higher in the stromal fraction than in the adipocyte fraction. PAI-1 mRNA-positive cells were 5-fold more frequent in the visceral area than in the subcutaneous stromal area (Pϭ0.004). Such a difference was also observed for PAI-1 mRNA content between both whole adipose tissues. In contrast to leptin, during adipocyte differentiation, PAI-1 secretion did not follow adipocyte maturation. In situ hybridization in culture did not reveal PAI-1 mRNA in lipid-filled cells. Our results demonstrate that PAI-1 production is mainly due to stromal cells, which were more numerous in the visceral than in the subcutaneous depot. These results could explain the strong relationship observed between circulating PAI-1 levels and the accumulation of visceral fat.

Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.

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